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1.  Physician Reasons for Nonpharmacologic Treatment of Hyperglycemia in Older Patients Newly Diagnosed with Type 2 Diabetes Mellitus 
Diabetes Therapy  2012;3(1):5.
Introduction
To identify reasons why primary care physicians (PCPs) do not treat older patients newly diagnosed with type 2 diabetes mellitus (T2DM) with antihyperglycemic agents following diagnosis.
Methods
US PCPs were surveyed via the internet regarding their reasons for not treating patients aged >65 years diagnosed with T2DM and had not yet initiated antihyperglycemic therapy for ≥6 months after diagnosis. PCPs were requested to provide relevant clinical information for untreated older patients and select applicable reasons for not initiating treatment from a list of 35 possibilities, grouped into five categories.
Results
A total of 508 PCPs completed the online survey and provided complete clinical data for 770 patients. The reasons provided by the first-ranked physician for not initiating antihyperglycemic therapy were related to diet and exercise (57.5%); mild hyperglycemia (23.8%); patient’s concerns (13.4%); concerns about antihyperglycemic agents (3.0%); and comorbidities and polypharmacy (2.3%). The “diet and exercise” category was the most common first-ranked non-treatment reason, regardless of recent hemoglobin A1c (HbA1c) stratum. Reasons within the “patient’s concerns,” “concerns related to antihyperglycemic agents,” and “comorbidities and polypharmacy” categories tended to be selected more often as first-ranked reasons by physicians for patients with higher HbA1c values. Of the 158 patients whose physicians planned to initiate antihyperglycemic therapy within the next month, 54.4% already had a most recent HbA1c value above their physician-stated threshold for treatment initiation.
Conclusion
In the PCPs studied, there was a tendency to select appropriate reasons for non-treatment with antihyperglycemic agents given their patients’ glycemic status. However, there was inertia related to the initiation of pharmacological therapy in some older patients with newly diagnosed T2DM. Important factors included physicians’ perceptions of “mild” hyperglycemia and the HbA1c threshold for using antihyperglycemic agents.
doi:10.1007/s13300-012-0005-8
PMCID: PMC3508110  PMID: 22700283
Antihyperglycemic agents; Clinical inertia; Elderly; Non-treatment; Type 2 diabetes mellitus
2.  Factors associated with initiation of antihyperglycaemic medication in UK patients with newly diagnosed type 2 diabetes 
Aim
To assess the factors associated with antihyperglycaemic medication initiation in UK patients with newly diagnosed type 2 diabetes.
Methods
In a retrospective cohort study, patients with newly diagnosed type 2 diabetes were identified during the index period of 2003-2005. Eligible patients were ≥ 30 years old at the date of the first observed diabetes diagnosis (referred to as index date) and had at least 2 years of follow-up medical history (N = 9,158). Initiation of antihyperglycaemic medication (i.e., treatment) was assessed in the 2-year period following the index date. Adjusted Cox regression models were used to examine the association between time to medication initiation and patient age and other factors.
Results
Mean (SD) HbA1c at diagnosis was 8.1% (2.3). Overall, 51% of patients initiated antihyperglycaemic medication within 2 years (65%, 55%, 46% and 40% for patients in the 30- < 45, 45- < 65, 65- < 75, 75+ age groups, respectively). Among the treated patients, median (25th, 75th percentile) time to treatment initiation was 63 (8, 257) days. Of the patients with HbA1c ≥ 7.5% at diagnosis, 87% initiated treatment within 2 years. These patients with a higher HbA1c also had shorter time to treatment initiation (adjusted hazard ratio (HR) = 2.44 [95% confidence interval (CI): 1.61, 3.70]; p < 0.0001). Increasing age (in years) was negatively associated with time to treatment initiation (HR = 0.98 [95% CI: 0.97, 0.99]; p < 0.001). Factors significantly associated with shorter time to treatment initiation included female gender and use of cardiovascular medications at baseline or initiated during follow up.
Conclusions
In this UK cohort of patients with newly diagnosed type 2 diabetes, only 51% had antihyperglycaemic medication initiated over a 2-year period following diagnosis. Older patients were significantly less likely to have been prescribed antihyperglycaemic medications. Elevated HbA1c was the strongest factor associated with initiating antihyperglycaemic medication in these patients.
doi:10.1186/1472-6823-12-1
PMCID: PMC3353844  PMID: 22397700
Clinical inertia; Age; Type 2 diabetes mellitus; Antihyperglycaemic medication
3.  Open randomised prospective comparative multi-centre intervention study of patients with cystic fibrosis and early diagnosed diabetes mellitus 
BMC Pediatrics  2014;14:70.
Background
Diabetes mellitus may be present in patients with cystic fibrosis starting in the second decade of life. The prevalence increases rapidly with increasing age. As life-expectancy increases in cystic fibrosis, cystic fibrosis related diabetes will be diagnosed more frequently in the future.
Up to date, no data are available to answer the question if cystic fibrosis related diabetes should always initially be treated by insulin therapy. Missing data regarding oral antidiabetic treatment of newly diagnosed cystic fibrosis related diabetes are an important reason to recommend insulin treatment. Several centres report the successful management of cystic fibrosis related diabetes using oral anti-diabetic drugs at least for some years. Oral therapies would be less invasive for a patient group which is highly traumatized by a very demanding therapy. Based on an initiative of the German Mukoviszidosis-Foundation, the present study tries to answer the question, whether oral therapy with repaglinide is as effective as insulin therapy in cystic fibrosis patients with early diagnosed diabetes mellitus.
Methods/Design
In all cystic fibrosis patients with an age of 10 years or older, an oral glucose tolerance test is recommended. The result of this test is classified according to the WHO cut off values. It is required to have two diabetes positive oral glucose tolerance tests for the diagnosis of diabetes mellitus.
This study is a multi-national, multicentre, open labelled, randomized and prospective controlled parallel group’s trial, with 24 months treatment.
The primary objective of this trial is to compare the glycaemic control of oral therapy with Repaglinide with insulin injections in patients with cystic fibrosis related diabetes after 2 years of treatment.
The trial should include 74 subjects showing cystic fibrosis related diabetes newly diagnosed by oral glucose tolerance test during annual screening for cystic fibrosis related diabetes.
Patients are randomised by central fax randomisation.
Primary endpoint is mean HbA1c after 24 months of treatment. Secondary endpoints are change in FEV1% predicted and change in BMI-Z-score.
Discussion
There is only one prospective study comparing oral antidiabetic drugs to insulin in the treatment of CFRD without fasting hyperglycaemia. The results regarding BMI after 6 months and 12 months showed an improvement for the insulin treated patients and were inconsistent for those treated with repaglinide. HbA1c and lung function (FEV1%pred) were unchanged for either group. The authors compared the changes -12 months to baseline and baseline to +12 months separately for each group. Therefore a direct comparison of the effect of repaglinide versus insulin on BMI, HbA1c and FEV1%pred was not presented. According to our protocol, we will directly compare treatment effects (HbA1c, BMI, FEV1%pred) in between both groups. The actual Cochrane report regarding “Insulin and oral agents for managing CFRD” stated that further studies are needed to establish whether there is clear benefit for hypoglycemic agents. We expect that the results of our study will help to address this clinical need.
Trial registration
ClinicalTrials.gov Identifier: NCT00662714
doi:10.1186/1471-2431-14-70
PMCID: PMC3975280  PMID: 24620855
Cystic fibrosis; Diabetes mellitus; Lung diseases; Genetic diseases; Inborn; Repaglinide; Insulin; HbA1c; Clinical trial
4.  Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus 
Abstract
Concept of Diabetes Mellitus:
Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long‐term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.
Classification (Tables 1 and 2, and Figure 1):
 Etiological classification of diabetes mellitus and glucose metabolism disorders
Note: Those that cannot at present be classified as any of the above are called unclassifiable.
The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions.
 Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseases
The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions.
 A scheme of the relationship between etiology (mechanism) and patho‐physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as ‘diabetes mellitus’. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare.
The classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β‐cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non‐insulin‐ requiring, insulin‐requiring for glycemic control, and insulin‐dependent for survival. The two former conditions are called non‐insulin‐dependent diabetes and the latter is known as insulin‐dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment.
Diagnosis (Tables 3–7 and Figure 2):
 Criteria of fasting plasma glucose levels and 75 g oral glucose tolerance test 2‐h value
*Casual plasma glucose ≥200 mg/dL (≥11.1 mmol/L) and HbA1c≥6.5% are also regarded as to indicate diabetic type.
Even for normal type, if 1‐h value is 180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for <180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow‐up observation, etc.). Fasting plasma glucose level of 100–109 mg/dL (5.5–6.0 mmol/L) is called ‘high‐normal’: within the range of normal fasting plasma glucose.
Plasma glucose level after glucose load in oral glucose tolerance test (OGTT) is not included in casual plasma glucose levels. The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).
 Procedures for diagnosing diabetes mellitus
*The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). **Hyperglycemia must be confirmed in a non‐stressful condition. OGTT, oral glucose tolerance test.
 Disorders and conditions associated with low HbA1c values
 Situations where a 75‐g oral glucose tolerance test is recommended
*The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).
 Definition and diagnostic criteria of gestational diabetes mellitus
(IADPSG Consensus Panel, Reference 42, partly modified with permission of Diabetes Care).
 Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).
Categories of the State of Glycemia:  Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2‐h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2‐h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS).
Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0–6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6–5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently.
Clinical Diagnosis:  1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be ‘diabetic type’. Re‐examination is conducted on another day, and if ‘diabetic type’ is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re‐examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose.2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination.• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results.4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re‐examined after an appropriate interval.5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions.
Epidemiological Study:  For the purpose of estimating the frequency of diabetes mellitus, ‘diabetes mellitus’ can be substituted for the determination of ‘diabetic type’ from a single examination. In this case, HbA1c≥6.5% alone can be defined as ‘diabetes mellitus’.
Health Screening:  It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level.
Gestational Diabetes Mellitus:  There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy:
1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L)2 1‐h value of ≥180 mg/dL (10.0 mmol/L)3 2‐h value of ≥153 mg/dL (8.5 mmol/L)
However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00074.x, 2010)
doi:10.1111/j.2040-1124.2010.00074.x
PMCID: PMC4020724  PMID: 24843435
Diabetes mellitus; Clinical diagnosis; HbA1c
5.  Mortality in Pharmacologically Treated Older Adults with Diabetes: The Cardiovascular Health Study, 1989–2001 
PLoS Medicine  2006;3(10):e400.
Background
Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age.
Methods and Findings
From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989–2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65–74 y versus ≥75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin.
Conclusions
DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
The negative impact on mortality of diabetes persists into old age. Elderly people with diabetes might be twice as likely to die from CVD as people without diabetes. More aggressive treatment of CVD risk factors in older patients should be considered.
Editors' Summary
Background.
Diabetes is a growing global health problem. By 2030, 300 million people worldwide may have this chronic, incurable disorder, double the current number. People with diabetes have dangerously high amounts of sugar in their blood. Blood-sugar levels are normally controlled by insulin, a hormone made by the pancreas that tells cells to absorb sugar from the blood. This control fails in people with diabetes, either because they make no insulin (type 1 diabetes) or because their cells are insensitive to insulin (type 2 diabetes). Type 1 diabetes is controlled with insulin injections; type 2 diabetes is controlled with diet, exercise, and pills that reduce blood-sugar levels. Long-term complications of diabetes include kidney failure, blindness, and nerve damage. Individuals with diabetes also have an increased risk of developing cardiovascular disease (CVD)—heart problems, strokes, and poor circulation—because of damage to their blood vessels.
Why Was This Study Done?
Epidemiological studies (investigations of disease patterns, causes, and control in populations) have indicated that diabetes increases the risk of death (mortality) from CVD in young and middle-aged people, but it is not known whether this is also true for old people. It is also not known what effect long-term treatment for diabetes has on mortality or whether the risk of death from CVD is decreasing in diabetic people as it is in the general US population. This information would help physicians provide health care and lifestyle advice to people with diabetes. In this study, the researchers have investigated mortality patterns in elderly diabetic people by looking at data collected between 1989 and 2001 by the US Cardiovascular Health Study, an observational study of nearly 6,000 people aged over 65 years (in this type of study participants are observed without imposing any specific changes to their lifestyle, behavior, medical care, or treatments).
What Did the Researchers Do and Find?
Participants were screened at the start of the Cardiovascular Health Study for CVD and diabetes (defined as drug-treated disease), for established CVD risk factors such as high blood pressure and smoking, for recently recognized CVD risk factors (for example, subclinical CVD), and for psychosocial factors associated with diabetes that might influence mortality, such as frailty and depression. At this time, about 5% of the participants were taking oral hypoglycemic agents for diabetes and about 3% were taking insulin. During the 11-year study, 40% of the participants died. After adjusting for CVD risk factors and psychosocial factors, the researchers calculated that people treated with oral hypoglycemic agents were 1.3 times as likely to die from all causes and people treated with insulin were twice as likely to die as people without diabetes. The risk of death from CVD was about twice as high in both groups of diabetic participants as in non-diabetic participants; the risk of death from coronary heart disease was increased about 2.5-fold. These adjusted relative risks are very similar to those found in previous studies. The researchers also report that participants treated with insulin were six times more likely to die from infectious diseases or renal failure than nondiabetic participants, and women treated with insulin had a particularly high mortality risk.
What Do These Findings Mean?
These findings indicate that the negative impact on mortality of diabetes persists into old age and that death from CVD is currently declining in both older diabetic people and nondiabetic people. In addition, they show that diabetic people treated with insulin are at a greater risk of dying relative to people without diabetes and those taking oral hypoglycemic agents. This might reflect the type of diabetes that these people had, but this was not investigated. How long participants had had diabetes was also not considered, nor how many people developed diabetes during the study. These and other limitations might mean that the reported excess mortality due to diabetes is an underestimate. Nevertheless, the estimate that elderly people with diabetes are twice as likely to die from CVD as people without diabetes is important. Many elderly people die anyway because of CVD, so this increased risk represents many more deaths than the similar increased risk in younger diabetic populations. Yet, elderly people often receive less-intensive management of CVD risk factors than younger people. The results of this study suggest that rectifying this situation could prolong the lives of many elderly people with diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030400.
MedlinePlus encyclopedia has pages on diabetes, heart disease, stroke and poor circulation
The US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on diabetes
Information for patients on prevention, diagnosis, and management of diabetes is available from the America Diabetes Association
Patient information is available from the American Heart Association on all aspects of heart disease, including its association with diabetes
Wikipedia pages on diabetes and cardiovascular disease (note that Wikipedia is a free online encyclopedia that anyone can edit)
Further information is available about the Cardiovascular Health Study
doi:10.1371/journal.pmed.0030400
PMCID: PMC1609124  PMID: 17048978
6.  Motor Vehicle Crashes in Diabetic Patients with Tight Glycemic Control: A Population-based Case Control Analysis 
PLoS Medicine  2009;6(12):e1000192.
Using a population-based case control analysis, Donald Redelmeier and colleagues found that tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.
Background
Complications from diabetes mellitus can compromise a driver's ability to safely operate a motor vehicle, yet little is known about whether euglycemia predicts normal driving risks among adults with diabetes. We studied the association between glycosylated hemoglobin (HbA1c) and the risk of a motor vehicle crash using a population-based case control analysis.
Methods and Findings
We identified consecutive drivers reported to vehicle licensing authorities between January 1, 2005 to January 1, 2007 who had a diagnosis of diabetes mellitus and a HbA1c documented. The risk of a crash was calculated taking into account potential confounders including blood glucose monitoring, complications, and treatments. A total of 57 patients were involved in a crash and 738 were not involved in a crash. The mean HbA1c was lower for those in a crash than controls (7.4% versus 7.9%, unpaired t-test, p = 0.019), equal to a 26% increase in the relative risk of a crash for each 1% reduction in HbA1c (odds ratio = 1.26, 95% confidence interval 1.03–1.54). The trend was evident across the range of HbA1c values and persisted after adjustment for measured confounders (odds ratio = 1.25, 95% confidence interval 1.02–1.55). The two other significant risk factors for a crash were a history of severe hypoglycemia requiring outside assistance (odds ratio = 4.07, 95% confidence interval 2.35–7.04) and later age at diabetes diagnosis (odds ratio per decade = 1.29, 95% confidence interval 1.07–1.57).
Conclusions
In this selected population, tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Around 8% of the US population has diabetes, a group of diseases in which the body cannot control levels of glucose (sugar) in the blood. It can lead to serious complications and premature death, but suitable treatment can control the disease and lower the risk of complications.
Type 1 diabetes occurs when the body's immune system prevents the production of insulin, the hormone that controls blood glucose. It accounts for 5%–10% of diabetes cases in adults and the vast majority of cases in childhood. Patients with type 1 diabetes need to inject insulin to survive. Type 2 diabetes is associated with older age, obesity, family history of diabetes, lack of physical activity, and race/ethnicity. As obesity rates rise worldwide, it is expected that the prevalence of type 2 diabetes will increase.
Why Was This Study Done?
Some complications of diabetes affect the ability to drive safely. Prolonged periods of high blood sugar levels can damage eyesight and nerves throughout the body, resulting in pain, tingling, and reduction of feeling or muscle control. Over time, some diabetics may become unaware of the early symptoms of an abnormally low blood sugar level (hypoglycemia) that can cause confusion, clumsiness, or fainting. Severe hypoglycemia can result in seizures or a coma.
It is common for driver licensing authorities to require evidence that a diabetic person's condition is well controlled before they issue a driving license. One measure of this is the percentage of hemoglobin in their blood that has joined up with glucose, known as HbA1c. This provides a measure of average blood glucose levels over the previous 8–12 weeks. A lower reading is considered an indicator of good diabetic control, but conversely, a blood glucose level that is too low can cause hypoglycemia. Normal nondiabetic HbA1c is between 3.5% and 5.5%, but 6.5% is considered good for people with diabetes.
In this study the researchers tested whether blood glucose levels, as measured by levels of HbA1c, were statistically associated with the risk of a motor vehicle crash.
What Did the Researchers Do and Find?
The authors studied 795 diabetic adults who had been in contact with the driver licensing authority in Ontario, Canada between January 1, 2005 and January 1, 2007 and for whom HbA1c levels were recorded. HbA1c levels varied between 4.4% and 14.7%.
Of the drivers considered, 57 were involved in a car crash and 738 were not. The authors found that lower HbA1c levels were associated with an increased risk of a motor vehicle crash, even when they took into account other factors such as time since diagnosis, treatment, age, age when diagnosed, and, if taking insulin, age insulin started.
The authors also found that the risk of a crash quadrupled when a driver had a history of severe hypoglycemia that required outside help and that there was an increase in risk when diabetes had first been diagnosed at an older age.
What Do These Findings Mean?
The authors conclude by emphasizing the difficulty in knowing whether someone with diabetes is fit to drive. They suggest that a patient's HbA1c level is neither necessary nor sufficient to determine whether a diabetic person is fit to drive and these results, which agree with some other studies, call into question the current legal framework of the US, UK, Canada, Germany, Holland, and Australia, which single out diabetic drivers for medical review.
The finding that lower HbA1c levels are associated with an increased risk of a crash is surprising, as it suggests that a driver is less safe if they control their diabetes well. However, a statistical link does not prove that one event causes another. Unknown social or medical factors might explain the results. In this case, the authors point out that a major drawback of their study is that it is not randomized and drivers have free will in choosing how tightly to control their diabetes and also how carefully they drive. The authors considered whether time spent driving might explain the results, but discounted this for several reasons. One more plausible explanation is that intensive treatment to attain a lower HbA1c level for better general health raises the risk of hypoglycemic episodes.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000192.
Wikipedia includes an article on diabetes (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The American Diabetes Association publishes information on diabetes in English and Spanish
The American Diabetes Association also publishes information on US states regulation of drivers with diabetes
The World Health Organization of the United Nations Diabetes Programme works to prevent diabetes, minimize complications, and maximize quality of life
doi:10.1371/journal.pmed.1000192
PMCID: PMC2780354  PMID: 19997624
7.  New treatments for patients with type 2 diabetes mellitus. 
Postgraduate Medical Journal  1996;72(853):657-662.
In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes.
PMCID: PMC2398637  PMID: 8944206
8.  Achievement of cardiovascular risk factor targets in young adults with diabetes mellitus 
Background
Many patients with diabetes mellitus fail to achieve treatment targets recommended in recognized guidelines. Little data is available in this area relating to young adults.
Objective
To assess whether treatment goals for glycosylated hemoglobin (HbA1c), blood pressure, lipid-lowering, and process outcomes for microvascular screening are being achieved in young adults with diabetes mellitus.
Methods
A retrospective clinical record audit of 202 consecutive patients with type 1 and type 2 diabetes, aged predominantly 18–45 years, attending a specialist diabetes center in Brisbane, Australia, was conducted. Assessment was made as to whether goals for HbA1c, blood pressure, lipid lowering, and microvascular screening were being achieved. Descriptive statistics and comparison of continuous variables were produced.
Results
Mean (SD) HbA1c was 8.30% (±1.5) with no statistical difference between patients with type 1 and type 2 diabetes (P = 0.44). Sixteen percent of patients (12% type 1, 31% type 2) had an HbA1c of < 7%. Eighty-three percent of patients had blood pressure ≤130/80 mmHg. Sixteen percent of patients with type 1 and 37% with type 2 diabetes were achieving combined lipid targets. Only 34% and 9% of patients who had an indication (and no documented contraindication) for lipid-lowering and antiplatelet therapy, respectively, were prescribed such agents. There was a significant difference in achievement of macrovascular treatment targets in patients with type 1 and type 2 diabetes, but no difference in screening or treatment outcomes in microvascular disease. Patients below the age of 25 years were less likely to achieve macrovascular treatment targets.
Conclusion
A large number of young adult patients with diabetes mellitus do not achieve recognized treatment targets. There appears to be less emphasis placed on macrovascular risk factor targets compared with previous audits in older patients, in patients with type 1 diabetes compared with type 2 diabetes and in patients younger than 25 years.
doi:10.2147/DMSOTT.S13791
PMCID: PMC3047960  PMID: 21437108
diabetes mellitus; complications; vascular risk; hypertension; cholesterol; glycated hemoglobin
9.  Hypoglycaemic events in patients with type 2 diabetes in the United Kingdom: associations with patient-reported outcomes and self-reported HbA1c 
Background
One possible barrier to effective diabetes self-management is hypoglycaemia associated with diabetes medication. The current study was conducted to characterize hypoglycaemic events among UK patients with type 2 diabetes (T2D) treated with antihyperglycaemic medications, and assess the relationship between experience of hypoglycaemic events and health outcomes, including glycaemic control, health-related quality of life, impairment to work and non-work activities, treatment satisfaction, adherence to treatment, fear of hypoglycaemia, and healthcare resource use.
Methods
An online survey of 1,329 T2D patients in UK drawn from an opt-in survey panel was conducted in February of 2012 with monthly follow-up questionnaires for five months. Measures included self-reported HbA1c, EQ-5D, Work Productivity and Activity Impairment questionnaire, Diabetes Medication Satisfaction Tool, Morisky medication adherence scale, the Hypoglycaemia Fear Survey (revised), and self-reported healthcare resource use. Comparisons were conducted using t-tests and chi-square tests for continuous and categorical variables, respectively.
Results
Baseline comparisons showed that worse HbA1c, greater diabetes-related healthcare resource use, greater fear of hypoglycaemia, and impaired health outcomes were associated with experience of hypoglycaemia in the four weeks prior to baseline. Longitudinal results were similar in direction but differences on few measures were significant.
Conclusions
In real-world UK T2D patients, hypoglycaemia is associated with worse self-reported glycaemic control, behaviours that contribute to worse glycaemic control, and impairment in patient-reported outcomes.
doi:10.1186/1472-6823-13-59
PMCID: PMC3878264  PMID: 24351086
Hypoglycaemia; Hypoglycaemic events; Health related quality of life; Hypoglycaemia fear; Treatment satisfaction
10.  Behavioural Interventions for Type 2 Diabetes 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this report is to determine whether behavioural interventions1 are effective in improving glycemic control in adults with type 2 diabetes.
Background
Diabetes is a serious chronic condition affecting millions of people worldwide and is the sixth leading cause of death in Canada. In 2005, an estimated 8.8% of Ontario’s population had diabetes, representing more than 816,000 Ontarians. The direct health care cost of diabetes was $1.76 billion in the year 2000 and is projected to rise to a total cost of $3.14 billion by 2016. Much of this cost arises from the serious long-term complications associated with the disease including: coronary heart disease, stroke, adult blindness, limb amputations and kidney disease.
Type 2 diabetes accounts for 90–95% of diabetes and while type 2 diabetes is more prevalent in people aged 40 years and older, prevalence in younger populations is increasing due to a rise in obesity and physical inactivity in children.
Data from the United Kingdom Prospective Diabetes Study (UKPDS) has shown that tight glycemic control can significantly reduce the risk of developing serious complications in type 2 diabetics. Despite physicians’ and patients’ knowledge of the importance of glycemic control, Canadian data has shown that only 38% of patients with diabetes have HbA1C levels in the optimal range of 7% or less. This statistic highlights the complexities involved in the management of diabetes, which is characterized by extensive patient involvement in addition to the support provided by physicians. An enormous demand is, therefore, placed on patients to self-manage the physical, emotional and psychological aspects of living with a chronic illness.
Despite differences in individual needs to cope with diabetes, there is general agreement for the necessity of supportive programs for patient self-management. While traditional programs were didactic models with the goal of improving patients’ knowledge of their disease, current models focus on behavioural approaches aimed at providing patients with the skills and strategies required to promote and change their behaviour.
Several meta-analyses and systematic reviews have demonstrated improved health outcomes with self-management support programs in type 2 diabetics. They have all, however, either looked at a specific component of self-management support programs (i.e. self-management education) or have been conducted in specific populations. Most reviews are also qualitative and do not clearly define the interventions of interest, making findings difficult to interpret. Moreover, heterogeneity in the interventions has led to conflicting evidence on the components of effective programs. There is thus much uncertainty regarding the optimal design and delivery of these programs by policymakers.
Evidence-Based Analysis of Effectiveness
Research Questions
Are behavioural interventions effective in improving glycemic control in adults with type 2 diabetes?
Is the effectiveness of the intervention impacted by intervention characteristics (e.g. delivery of intervention, length of intervention, mode of instruction, interventionist etc.)?
Inclusion Criteria
English Language
Published between January 1996 to August 2008
Type 2 diabetic adult population (>18 years)
Randomized controlled trials (RCTs)
Systematic reviews, or meta-analyses
Describing a multi-faceted self-management support intervention as defined by the 2007 Self-Management Mapping Guide (1)
Reporting outcomes of glycemic control (HbA1c) with extractable data
Studies with a minimum of 6-month follow up
Exclusion Criteria
Studies with a control group other than usual care
Studies with a sample size <30
Studies without a clearly defined intervention
Outcomes of Interest
Primary outcome: glycemic control (HbA1c)
Secondary outcomes: systolic blood pressure (SBP) control, lipid control, change in smoking status, weight change, quality of life, knowledge, self-efficacy, managing psychosocial aspects of diabetes, assessing dissatisfaction and readiness to change, and setting and achieving diabetes goals.
Search Strategy
A search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1996 and August 2008. Abstracts were reviewed by a single author and studies meeting the inclusion criteria outlined above were obtained. Data on population characteristics, glycemic control outcomes, and study design were extracted. Reference lists were also checked for relevant studies. The quality of the evidence was assessed as being either high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The search identified 638 citations published between 1996 and August 2008, of which 12 met the inclusion criteria and one was a meta-analysis (Gary et al. 2003). The remaining 11 studies were RCTs (9 were used in the meta-analysis) and only one was defined as small (total sample size N=47).
Summary of Participant Demographics across studies
A total of 2,549 participants were included in the 11 identified studies. The mean age of participants reported was approximately 58 years and the mean duration of diabetes was approximately 6 years. Most studies reported gender with a mean percentage of females of approximately 67%. Of the eleven studies, two focused only on women and four included only Hispanic individuals. All studies evaluated type 2 diabetes patients exclusively.
Study Characteristics
The studies were conducted between 2002 and 2008. Approximately six of 11 studies were carried out within the USA, with the remaining studies conducted in the UK, Sweden, and Israel (sample size ranged from 47 to 824 participants). The quality of the studies ranged from moderate to low with four of the studies being of moderate quality and the remaining seven of low quality (based on the Consort Checklist). Differences in quality were mainly due to methodological issues such as inadequate description of randomization, sample size calculation allocation concealment, blinding and uncertainty of the use of intention-to-treat (ITT) analysis. Patients were recruited from several settings: six studies from primary or general medical practices, three studies from the community (e.g. via advertisements), and two from outpatient diabetes clinics. A usual care control group was reported in nine of 11 of the studies and two studies reported some type of minimal diabetes care in addition to usual care for the control group.
Intervention Characteristics
All of the interventions examined in the studies were mapped to the 2007 Self-management Mapping Guide. The interventions most often focused on problem solving, goal setting and encouraging participants to engage in activities that protect and promote health (e.g. modifying behaviour, change in diet, and increase physical activity). All of the studies examined comprehensive interventions targeted at least two self-care topics (e.g. diet, physical activity, blood glucose monitoring, foot care, etc.). Despite the homogeneity in the aims of the interventions, there was substantial clinical heterogeneity in other intervention characteristics such as duration, intensity, setting, mode of delivery (group vs. individual), interventionist, and outcomes of interest (discussed below).
Duration, Intensity and Mode of Delivery
Intervention durations ranged from 2 days to 1 year, with many falling into the range of 6 to 10 weeks. The rest of the interventions fell into categories of ≤ 2 weeks (2 studies), 6 months (2 studies), or 1 year (3 studies). Intensity of the interventions varied widely from 6 hours over 2 days, to 52 hours over 1 year; however, the majority consisted of interventions of 6 to 15 hours. Both individual and group sessions were used to deliver interventions. Group counselling was used in five studies as a mode of instruction, three studies used both individual and group sessions, and one study used individual sessions as its sole mode of instruction. Three studies also incorporated the use of telephone support as part of the intervention.
Interventionists and Setting
The following interventionists were reported (highest to lowest percentage, categories not mutually exclusive): nurse (36%), dietician (18%), physician (9%), pharmacist (9%), peer leader/community worker (18%), and other (36%). The ‘other’ category included interventionists such as consultants and facilitators with unspecified professional backgrounds. The setting of most interventions was community-based (seven studies), followed by primary care practices (three studies). One study described an intervention conducted in a pharmacy setting.
Outcomes
Duration of follow up of the studies ranged from 6 months to 8 years with a median follow-up duration of 12 months. Nine studies followed up patients at a minimum of two time points. Despite clear reporting of outcomes at follow up time points, there was poor reporting on whether the follow up was measured from participant entry into study or from end of intervention. All studies reported measures of glycemic control, specifically HbA1c levels. BMI was measured in five studies, while body weight was reported in two studies. Cholesterol was examined in three studies and blood pressure reduction in two. Smoking status was only examined in one of the studies. Additional outcomes examined in the trials included patient satisfaction, quality of life, diabetes knowledge, diabetes medication reduction, and behaviour modification (i.e. daily consumption of fruits/vegetables, exercise etc). Meta-analysis of the studies identified a moderate but significant reduction in HbA1c levels -0.44% 95%CI: -0.60, -0.29) for behavioural interventions in comparison to usual care for adults with type 2 diabetes. Subgroup analyses suggested the largest effects in interventions which were of at least duration and interventions in diabetics with higher baseline HbA1c (≥9.0). The quality of the evidence according to GRADE for the overall estimate was moderate and the quality of evidence for the subgroup analyses was identified as low.
Summary of Meta-Analysis of Studies Investigating the Effectiveness of Behavioural Interventions on HbA1c in Patients with Type 2 Diabetes.
Based on one study
Conclusions
Based on moderate quality evidence, behavioural interventions as defined by the 2007 Self-management mapping guide (Government of Victoria, Australia) produce a moderate reduction in HbA1c levels in patients with type 2 diabetes compared with usual care.
Based on low quality evidence, the interventions with the largest effects are those:
- in diabetics with higher baseline HbA1c (≥9.0)
- in which the interventions were of at least 1 year in duration
PMCID: PMC3377516  PMID: 23074526
11.  Risk of Cardiovascular Disease and Total Mortality in Adults with Type 1 Diabetes: Scottish Registry Linkage Study 
PLoS Medicine  2012;9(10):e1001321.
Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.
Background
Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.
Methods and Findings
The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.
Conclusions
Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background. People with diabetes are more likely to have cardiovascular disease such as heart attacks and strokes. They also have a higher risk of dying prematurely from any cause. Controlling blood sugar (glucose), blood pressure, and cholesterol can help reduce these risks. Some people with type 1 diabetes can achieve tight blood glucose control through a strict regimen that includes a carefully calculated diet, frequent physical activity, regular blood glucose testing several times a day, and multiple daily doses of insulin. Other drugs can reduce blood pressure and cholesterol levels. Keeping one's weight in the normal range and not smoking are important ways in which all people, including those with type 1 diabetes can reduce their risks of heart disease and premature death.
Why Was This Study Done? Researchers and doctors have known for almost two decades what patients with type 1 diabetes can do to minimize the complications from the disease and thereby reduce their risks for cardiovascular disease and early death. So for some time now, patients should have been treated and counseled accordingly. This study was done to evaluate the current risks for have cardiovascular disease and premature death amongst people living with type 1 diabetes in a high-income country (Scotland).
What Did the Researchers Do and Find? From a national register of all people with type 1 diabetes in Scotland, the researchers selected those who were older than 20 years and alive at any time from January 2005 to May 2008. This included about 19,000 people who had been diagnosed with type 1 diabetes before 2005. Another 2,600 were diagnosed between 2005 and 2008. They also obtained data on heart attacks and strokes in these patients from hospital records and on deaths from the natural death register. To obtain a good picture of the current relative risks, they compared the patients with type 1 diabetes with the non-diabetic general Scottish population with regard to the risk of heart attacks/strokes and death from all causes. They also collected information on how well the people with diabetes controlled their blood glucose, on their weight, and whether they smoked.
They found that the current risks compared with the general Scottish population are quite a bit lower than those of people with type 1 diabetes in earlier decades. However, people with type 1 diabetes in Scotland still have much higher (more than twice) the risk of heart attacks, strokes, or premature death than the general population. Moreover, the researchers found a high number of deaths in younger people with diabetes from coma—caused by either too much blood sugar (hyperglycemia) or too little (hypoglycemia). Severe hyperglycemia and hypoglycemia happen when blood glucose control is poor. When the scientists looked at test results for HbA1c levels (a test that is done once or twice a year to see how well patients controlled their blood sugar over the previous 3 months) for all patients, they found that the majority of them did not come close to controlling their blood glucose within the recommended range.
When the researchers compared body mass index (a measure of weight that takes height into account) and smoking between the people with type 1 diabetes and the general population, they found similar proportions of smokers and overweight or obese people.
What Do these Findings Mean? The results represent a snapshot of the recent situation regarding complications from type 1 diabetes in the Scottish population. The results suggest that within this population, strategies over the past two decades to reduce complications from type 1 diabetes that cause cardiovascular disease and death are working, in principle. However, there is much need for further improvement. This includes the urgent need to understand why so few people with type 1 diabetes achieve good control of their blood sugar, and what can be done to improve this situation. It is also important to put more effort into keeping people with diabetes from taking up smoking or getting them to quit, as well as preventing them from getting overweight or promoting weight reduction, because this could further reduce the risks of cardiovascular disease and premature death.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001321
National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on heart disease and diabetes, on general complications of diabetes, and on the HbA1c test (on this site and some others called A1C test) that measures control of blood sugar over the past 3 months
Diabetes.co.uk provides general information on type 1 diabetes, its complications, and what people with the disease can do to reduce their risks
The Canadian Diabetes Association offers a cardiovascular risk self-assessment tool and other relevant information
The American Diabetes Association has information on the benefits and challenges of tight blood sugar control and how it is tested
The Juvenile Diabetes Research Foundation funds research to prevent, cure, and treat type 1 diabetes
Diabetes UK provides extensive information on diabetes for patients, carers, and clinicians
doi:10.1371/journal.pmed.1001321
PMCID: PMC3462745  PMID: 23055834
12.  Eudragit-Based Nanosuspension of Poorly Water-Soluble Drug: Formulation and In Vitro–In Vivo Evaluation 
AAPS PharmSciTech  2012;13(4):1031-1044.
The present study was performed to investigate potential of Eudragit RLPO-based nanosuspension of glimepiride (Biopharmaceutical Classification System class II drug), for the improvement of its solubility and overall therapeutic efficacy, suitable for peroral administration. Nanoprecipitation method being simple and less sophisticated was optimized for the preparation of nanosuspension. Physicochemical characteristics of nanosuspension in terms of size, zeta potential, polydispersity index, entrapment efficiency (% EE) and in vitro drug release were found within their acceptable ranges. The size of the nanoparticles was most strongly affected by agitation time while % EE was more influenced by the drug/polymer ratio. Differential scanning calorimetry and X-ray diffraction studies provided evidence that enhancement in solubility of drug resulted due to change in crystallinity of drug within the formulation. Stability study revealed that nanosuspension was more stable at refrigerated condition with no significant changes in particle size distribution, % EE, and release characteristics for 3 months. In vivo studies were performed on nicotinamide–streptozotocin-induced diabetic rat models for pharmacokinetic and antihyperglycaemic activity. Nanosuspension increased maximum plasma concentration, area under the curve, and mean residence time values significantly as compared to aqueous suspension. Oral glucose tolerance test and antihyperglycaemic studies demonstrated plasma glucose levels were efficiently controlled in case of nanosuspension than glimepiride suspension. Briefly, sustained and prolonged activity of nanosuspensions could reduce dose frequency, decrease drug side effects, and improve patient compliance. Therefore, glimepiride nanosuspensions can be expected to gain considerable attention in the treatment of type 2 diabetes mellitus due to its improved therapeutic activity.
doi:10.1208/s12249-012-9833-0
PMCID: PMC3513456  PMID: 22893314
diabetes mellitus; glimepiride; nanoprecipitation; poloxamer; sustained release
13.  Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin 
BackgroundIn four 24-week controlled studies, the antihyperglycaemic efficacy of saxagliptin was demonstrated in patients with type 2 diabetes mellitus as add-on therapy to glyburide, a thiazolidinedione, or metformin, and when used in initial combination with metformin vs. metformin monotherapy in drug-naive patients.
MethodsData from these studies were analysed to compare the proportions of patients who achieved specific reductions from baseline in glycated haemoglobin [HbA1c; reductions of ≥ 0.5% and ≥ 0.7% in all studies (prespecified); reductions ≥ 1.0% in the add-on studies and ≥ 1.0% to ≥ 2.5% in the initial combination study (post hoc)] for saxagliptin vs. comparator at week 24. We report overall rates of glycaemic response defined by these reductions in HbA1c and rates of response without experiencing hypoglycaemia.
ResultsLarge glycaemic response rates were higher with saxagliptin 2.5 and 5 mg/day than with comparator (HbA1c ≥ 1.0%, 31.7–50.3% vs. 10.3–20.0%) as add-on therapy and higher with saxagliptin 5 mg/day as initial combination with metformin than with metformin monotherapy (HbA1c ≥ 2.0%, 68.3% vs. 49.8%) in drug-naive patients. Addition of saxagliptin was associated with a low incidence of hypoglycaemia; overall response rates and response rates excluding patients who experienced hypoglycaemia were similar. Analysis of several demographic and baseline clinical variables revealed no consistent correlations with response to saxagliptin.
ConclusionsWhether receiving saxagliptin as an add-on therapy to glyburide, a thiazolidinedione, or metformin or in initial combination with metformin, a greater percentage of patients achieve clinically relevant large reductions in HbA1c vs. comparator, with a low incidence of hypoglycaemia.
doi:10.1111/ijcp.12212
PMCID: PMC3842088  PMID: 23795975
14.  Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23) 
BMJ : British Medical Journal  1998;316(7134):823-828.
Objective: To evaluate baseline risk factors for coronary artery disease in patients with type 2 diabetes mellitus.
Design: A stepwise selection procedure, adjusting for age and sex, was used in 2693 subjects with complete data to determine which risk factors for coronary artery disease should be included in a Cox proportional hazards model.
Subjects: 3055 white patients (mean age 52) with recently diagnosed type 2 diabetes mellitus and without evidence of disease related to atheroma. Median duration of follow up was 7.9 years. 335 patients developed coronary artery disease within 10 years.
Outcome measures: Angina with confirmatory abnormal electrocardiogram; non-fatal and fatal myocardial infarction.
Results: Coronary artery disease was significantly associated with increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, and increased triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose concentration, and a history of smoking. The estimated hazard ratios for the upper third relative to the lower third were 2.26 (95% confidence interval 1.70 to 3.00) for low density lipoprotein cholesterol, 0.55 (0.41 to 0.73) for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01) for haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood pressure. The estimated hazard ratio for smokers was 1.41(1.06 to 1.88).
Conclusion: A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, raised blood pressure, hyperglycaemia, and smoking.
Key messages Coronary artery disease is the major cause of mortality in patients with type 2 diabetes mellitus Patients without evidence of disease related to atheroma at diagnosis of type 2 diabetes mellitus had an increased standardised mortality ratio compared with the population of the United Kingdom 11% of patients in this study had a myocardial infarction or developed angina over a median of 8 years’ follow up The potentially modifiable risk factors for coronary artery disease were increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, hypertension, hyperglycaemia, and smoking; these are also risk factors for coronary artery disease in the general population Evidence is needed on whether modifying these risk factors will reduce coronary artery disease in patients with type 2 diabetes mellitus
PMCID: PMC28484  PMID: 9549452
15.  Evaluation of bone mineral density in type 2 diabetes mellitus patients before and after treatment 
Background
The relationship between bone mineral density (BMD) and type 2 diabetes mellitus (T2DM) has been controversial. Recent studies have revealed adverse impact of antidiabetic drugs on BMD in type 2 diabetic patients. However, the influence of various antihyperglycaemic agents on BMD has not been well studied.
Method
A total of 200 patients with T2DM were screened initially for the study. Finally 67 patients (M:34, F:33) who satisfied the requirement of having been on one year of prescribed therapy were included for analysis.
Results
Bone mineral density was lower in diabetic patients as compared to controls (hip 0.962 ± 0.167 g/cm2 vs 1.013 ± 0.184 g/cm2, P = 0.05; spine 0.929 ± 0.214 g/cm2 vs 1.113 ± 0.186 g/cm2, P < 0.00001). In males BMD was significantly lower at spine (P < 0.00001) and in females BMD was significantly lower in both at the spine (P < 0.00001) and hip (P < 0.032). On multivariate analysis significant positive correlation was found between spine BMD and body mass index (BMI) (r = 0.372, P = 0.002), total cholesterol (r = 0.272, P = 0.026), low-density lipoprotein (r = 0.242, P = 0.047), and triglycerides (r = 0.282, P = 0.021). There was no correlation between BMD and glycosylated haemoglobin (r = 0.158, P = 0.265). A significant decrease in BMD at spine and hip was seen with the use of glitazones and metformin while increase was noted with sulphonylurea and its combination.
Conclusion
Men and women with T2DM have lower BMD. Bone mineral density did not have correlation to glycaemic control. Glitazones, metformin, and insulin are associated with decrease in BMD at spine, and hip, while sulphonylureas are associated with increase in BMD.
doi:10.1016/S0377-1237(11)60120-2
PMCID: PMC3862970  PMID: 24623915
antihyperglycaemic drugs; bone mineral density; type 2 diabetes mellitus
16.  Diabetes: glycaemic control in type 2 
Clinical Evidence  2008;2008:0609.
Introduction
Diabetes mellitus is now seen as a progressive disorder of glucose metabolism, affecting about 5% of the population worldwide, over 85% of whom have type 2 diabetes. Type 2 diabetes may occur with obesity, hypertension and dyslipidaemia (the metabolic syndrome), which are powerful predictors of CVD. Blood glucose levels rise progressively over time in people with type 2 diabetes regardless of treatment, causing microvascular and macrovascular complications.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in adults with type 2 diabetes? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: combined oral drug treatment, diet, education, insulin (continuous subcutaneous infusion), insulin, intensive treatment programmes, meglitinides (nateglinide, repaglinide), metformin, monotherapy, blood glucose self-monitoring (different frequencies), and sulphonylureas (newer or older).
Key Points
Diabetes mellitus is now seen as a progressive disorder of glucose metabolism; it affects about 5% of the population worldwide, over 85% of whom have type 2 diabetes. Type 2 diabetes is often associated with obesity, hypertension, and dyslipidaemia (the metabolic syndrome), which are powerful predictors of CVD.Type 2 diabetes is a disease in which glucose levels rise over time, with or without treatment and irrespective of the type of treatment given. This rise may lead to microvascular and macrovascular complications.
Most people with type 2 diabetes will eventually need treatment with oral hypoglycaemic agents. Metformin reduces glycated haemoglobin by 1−2% and reduces mortality compared with diet alone, without increasing weight, but it can cause hypoglycaemia compared with placebo. Sulphonylureas reduce HbA1c by 1−2% compared with diet alone. Older sulphonylureas can cause weight gain and hypoglycaemia, but the risk of these adverse effects may be lower with newer-generation sulphonylureas. Meglitinides (nateglinide, repaglinide) may reduce HbA1c by 0.4-0.9% compared with placebo, but may cause hypoglycaemia. Combined oral drug treatment may reduce HbA1c levels more than monotherapy, but increases the risk of hypoglycaemia. Insulin is no more effective than sulphonylureas in improving glucose control in people with newly diagnosed type 2 diabetes, and is associated with a higher rate of major hypoglycaemic episodes, and with weight gain.
Individual or group intensive educational programmes may reduce HbA1c compared with usual care, although studies have been of poor quality.
Insulin improves glycaemic control in people with inadequate control of HbA1c from oral drug treatment, but is associated with weight gain, and an increased risk of hypoglycaemia. Adding metformin to insulin improves glucose control compared with insulin alone, but increases gastrointestinal adverse effects. However, the combination may cause less weight gain than insulin alone.
Monitoring of blood glucose levels has not been shown to improve glycaemic control in people not being treated with insulin.
Diet may be less effective than metformin or sulphonylureas in improving glucose control, although sulphonylureas were associated with higher rates of hypoglycaemia. However, there is consensus that weight reduction in people with type 2 diabetes can improve glycaemic control, as well as conferring other health benefits.
PMCID: PMC2907982  PMID: 19450326
17.  HbA1c Levels among Primary Healthcare Patients with Type 2 Diabetes Mellitus in Oman 
Oman Medical Journal  2012;27(6):465-470.
Objectives
To investigate whether younger patients with type 2 diabetes mellitus have higher glycated hemoglobin A1c (HbA1c) levels compared to older patients, and to determine the factors associated with higher HbA1c levels.
Methods
Data from 1,266 patients from all over Oman were used to obtain the mean HbA1c level, odds ratios (OR), and 95% confidence intervals (CI) from multiple logistic regression models with age groups, sex, duration of diabetes, diabetes treatment, body mass index, estimated glomerular filtration rate (eGFR), tobacco use, and healthcare index as predictors of good (HbA1c <7%) vs. poor (≥7%) glycemic control.
Results
Mean HbA1c levels were 8.9, 8.3, and 7.8 in the age groups 20-39, 40-59 and 60+ years, respectively. After controlling for all other covariates, the OR of good glycemic control increased with age, 40-59 years old (OR=1.7; 95% CI 1.1 to 2.6) and 60+ year (OR=2.5; 95% CI 1.6 to 4.0), female gender (OR=1.5; 95% CI 1.2 to 2.0) and in patients with eGFR ≥60 mL/min/1.73 m2 (OR=1.9; 95% CI 1.1 to 3.3). Longer duration of diabetes (≥5 years) and treatment with oral agents or insulin were inversely related to good glycemic control.
Conclusion
Younger Omani adults exhibit worse glycemic levels compared to older adults posing a formidable challenge to diabetes care teams.
doi:10.5001/omj.2012.111
PMCID: PMC3515045  PMID: 23226816
Diabetes; Oman; HbA1c; Epidemiology
18.  Assessment of Diabetic Polyneuropathy in Inpatient Care: Fasting Blood Glucose, HbA1c, Electroneuromyography and Diabetes Risk Factors 
Acta Informatica Medica  2013;21(2):123-126.
CONFLICT OF INTEREST: NONE DECLARED
Goal
The goals of this study are to: a) determine the prevalence of diabetic polyneuropathy (DPNP) in hospitalized patients with diabetes mellitus (DM) type 2; b) determine the frequency of DPNP in hospitalized patients with type 2 DM in relation to gender, duration of diabetes, fasting blood glucose and HbA1c; c) identify the dominant DPNP symptoms and the presence of variable risk factors in hospitalized patients; and d) determine the frequency and motor nerve conduction velocity of n. peroneus (electroneuromyography) in relation to the treatment of type 2 DM in hospitalized patients with DPNP.
Material and methods
The study was conducted on 141 patients diagnosed with type 2 diabetes who were hospitalized at the Neurological clinic of Clinical Center of Sarajevo University in the period from June 1 2009 to June 1 2010. All patients included in the study were older than 18. Values determined for all subjects are: age, sex, dominant symptoms, duration of type 2 DM, fasting blood glucose, HbA1c, motor conduction velocity of n. peroneus, diabetes risk factors (hyperlipidemia, hypertension, smoking, alcoholism, obesity) and DM treatment type.
Results
Of 141 patients with type 2 DM, DPNP was confirmed in 50 patients (35.5%). Men were slightly more represented in the total sample (51.8%). In a sample of patients with DPNP, there were slightly more male patients (n=26; 52%). The average age of patients with DPNP was higher in men (58.3±12.5) (p<0.05). The average age of the patients with DPNP was 55.1± 13.2. Average values of fasting glucose was higher in the group of patients with DPNP (11.032±5.4 mmol/l) compared to patients without DPNP (9.7±2.8 mmol/l) (p<0.05). Mean values of HbA1C were higher in patients with DPNP (8.212±3.3%) compared to patients without DPNP (6.9±2.6%) (p<0.05). Analysis of DM duration between patients with and without DPNP did not show statistically significant difference (chi-square=3.858, p>0.05). In both groups, most of the patients had duration of DM over 10 years, with a minimum duration of DM of 12 months. There are statistically significant differences in applied DM therapy by gender (chi-square=11.939, p<0.05). Hypertension was more frequent in women (79.2%:69.2%), hyperlipidemia was equally presented in both sexes (50%:50%), obesity was more prevalent among women (25%:7.7%), while alcoholism and smoking were more frequent in men (7.7%:0%; 34.6%:8.3%). There are statistically significant differences in the prevalence of risk factors by gender (chi-square=10.013, p<0.05).
Conclusions
The DPNP incidence was higher in patients with longer duration of the disease, but without significant gender differences. Fasting blood glucose and HbA1c were significantly higher in patients with DPNP compared to patients without DPNP (p<0.05). The dominant symptoms of DPNP were paresthesia (44%) and hypoesthesia (28%). Regarding variable risk factors, the most common were hypertension and hyperlipidemia, without statistical significance in gender distribution, while smoking was significantly more common in men than women (34.6%:8.3%). DPNP was present in 43.2% of men who use insulin therapy, while 54.2% of women with DPNP used oral therapy. The lowest frequency of DPNP was found in patients treated with combined therapy. Motor conduction velocity of n. peroneus was significantly lower in men using insulin therapy and/or combined therapy (p<0.05), whereas in patients on oral therapy there was no significant gender difference. Timely DM type 2 diagnosis with proper treatment and electromyoneurographic monitoring (especially in older men) can prevent onset of diabetic polyneuropathy and contribute to its successful treatment.
doi:10.5455/aim.2013.21.123-126
PMCID: PMC3766543  PMID: 24039336
diabetic polyneuropathy; diabetes mellitus; ENMG; electroneuromyography; HbA1c; inpatient; fasting blood glucose; inpatient
19.  Evidence that upregulation of serum IGF-1 concentration can trigger acceleration of diabetic retinopathy 
BACKGROUND—Acute reduction of chronic hyperglycaemia can accelerate early diabetic retinopathy. In adolescent patients with Mauriac's syndrome, this phenomenon is related to an upregulation of subnormal serum IGF-1 levels.
AIM—To obtain longitudinal data on serum IGF-1 and retinopathy status in poorly controlled adult insulin dependent (type 1) diabetic patients without Mauriac's syndrome, in whom hyperglycaemia is reduced by intensive insulin therapy.
METHODS—Four patients with chronic severe insulin deficiency and early microangiopathy were studied prospectively. Changes in plasma glucose, HbA1c, serum IGF-1 levels, proteinuria, retinopathy, and clinical status were followed up closely.
RESULTS—Reducing hyperglycaemia from >16 mmol/l (equivalent to HbA1c >11%) to <10 mmol/l (HbA1c <8%) within 5 months increased serum IGF-1 levels by 70-220%. While proteinuria and symptomatic neuropathy regressed, retinopathy progressed from the mild to the severe non-proliferative stage with maculopathy (n=4), and to the proliferative stage (n=1). Laser coagulation was commenced upon the appearance of sight threatening macular oedema (n=4).
CONCLUSION—Upregulation of serum IGF-1 preceding retinal deterioration in these patients suggests a cause-effect relation, consistent with earlier experimental and clinical data. 

 Keywords: diabetes mellitus; macular oedema; metabolic control; intensive therapy; glycated haemoglobin A1c; growth factors
PMCID: PMC1722687  PMID: 9924360
20.  The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and treatment of hypertension in adults for 2010.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, randomized trials and systematic reviews of trials were preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the general lack of long-term morbidity and mortality data in this field. Progressive renal impairment was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane Collaboration librarian conducted an independent MEDLINE search from 2008 to August 2009 to update the 2009 recommendations. To identify additional studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to 1500 mg (65 mmol) per day in adults 50 years of age or younger, to 1300 mg (57 mmol) per day in adults 51 to 70 years of age, and to 1200 mg (52 mmol) per day in adults older than 70 years of age; perform 30 min to 60 min of moderate aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week for men or nine standard drinks per week for women; follow a diet that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, and that is low in saturated fat and cholesterol; and consider stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, considerations for initial therapy should include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. The combination of ACE inhibitors and ARBs should not be used, unless compelling indications are present to suggest consideration of dual therapy.
Agents appropriate for first-line therapy for isolated systolic hypertension include thiazide diuretics, long-acting dihydropyridine CCBs or ARBs. In patients with coronary artery disease, ACE inhibitors, ARBs or beta-blockers are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. In selected high-risk patients in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide diuretic. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian lipid treatment guidelines. Selected patients with hypertension who do not achieve thresholds for statin therapy, but who are otherwise at high risk for cardiovascular events, should nonetheless receive statin therapy. Once blood pressure is controlled, low-dose acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to the strength of the evidence and voted on by the 63 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 80% consensus. These guidelines will continue to be updated annually.
SPONSORS:
The Canadian Hypertension Education Program process is sponsored by the Canadian Hypertension Society, Blood Pressure Canada, the Public Health Agency of Canada, the College of Family Physicians of Canada, the Canadian Pharmacists Association, the Canadian Council of Cardiovascular Nurses, and the Heart and Stroke Foundation of Canada.
PMCID: PMC2886555  PMID: 20485689
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
21.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
Objective
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Methods
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Prevalence
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
Diffusion
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
22.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
23.  Community-Based Care for the Management of Type 2 Diabetes 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this report is to determine the efficacy of specialized multidisciplinary community care for the management of type 2 diabetes compared to usual care.
Clinical Need: Target Population and Condition
Diabetes (i.e. diabetes mellitus) is a highly prevalent chronic metabolic disorder that interferes with the body’s ability to produce or effectively use insulin. The majority (90%) of diabetes patients have type 2 diabetes. (1) Based on the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose and blood pressure control significantly reduce the risk of microvascular and macrovascular complications in type 2 diabetics. While many studies have documented that patients often do not meet the glycemic control targets specified by national and international guidelines, factors associated with glycemic control are less well studied, one of which is the provider(s) of care.
Multidisciplinary approaches to care may be particularly important for diabetes management. According guidelines from the Canadian Diabetes Association (CDA), the diabetes health care team should be multi-and interdisciplinary. Presently in Ontario, the core diabetes health care team consists of at least a family physician and/or diabetes specialist, and diabetes educators (registered nurse and registered dietician).
Increasing the role played by allied health care professionals in diabetes care and their collaboration with physicians may represent a more cost-effective option for diabetes management. Several systematic reviews and meta-analyses have examined multidisciplinary care programs, but these have either been limited to a specific component of multidisciplinary care (e.g. intensified education programs), or were conducted as part of a broader disease management program, of which not all were multidisciplinary in nature. Most reviews also do not clearly define the intervention(s) of interest, making the evaluation of such multidisciplinary community programs challenging.
Evidence-Based Analysis Methods
Research Questions
What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a registered nurse, registered dietician and physician (primary care and/or specialist) for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 1]
What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a pharmacist and a primary care physician for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 2]
Inclusion Criteria
English language full-reports
Published between January 1, 2000 and September 28, 2008
Randomized controlled trials (RCTs), systematic reviews and meta-analyses
Type 2 diabetic adult population (≥18 years of age)
Total sample size ≥30
Describe specialized multidisciplinary community care defined as ambulatory-based care provided by at least two health care disciplines (of which at least one must be a specialist in diabetes) with integrated communication between the care providers.
Compared to usual care (defined as health care provision by non-specialist(s) in diabetes, such as primary care providers; may include referral to other health care professionals/services as necessary)
≥6 months follow-up
Exclusion Criteria
Studies where discrete results on diabetes cannot be abstracted
Predominantly home-based interventions
Inpatient-based interventions
Outcomes of Interest
The primary outcomes for this review were glycosylated hemoglobin (rHbA1c) levels and systolic blood pressure (SBP).
Search Strategy
A literature search was performed on September 28, 2008 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Given the high clinical heterogeneity of the articles that met the inclusion criteria, specific models of specialized multidisciplinary community care were examined based on models of care that are currently being supported in Ontario, models of care that were commonly reported in the literature, as well as suggestions from an Expert Advisory Panel Meeting held on January 21, 2009.
Summary of Findings
The initial search yielded 2,116 unique citations, from which 22 RCTs trials and nine systematic reviews published were identified as meeting the eligibility criteria. Of these, five studies focused on care provided by at least a nurse, dietician, and physician (primary care and/or specialist) model of care (Model 1; see Table ES 1), while three studies focused on care provided by at least a pharmacist and primary care physician (Model 2; see Table ES 2).
Based on moderate quality evidence, specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in HbA1c of 1.0% compared with usual care. The effects of this model on SBP, however, are uncertain compared with usual care, based on very-low quality evidence. Specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in both HbA1c of 1.05% (based on high quality evidence) and SBP of 7.13 mm Hg (based on moderate quality evidence) compared to usual care. For both models, the evidence does not suggest a preferred setting of care delivery (i.e., primary care vs. hospital outpatient clinic vs. community clinic).
Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 1
Mean change from baseline to follow-up between intervention and control groups
Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 2
Mean change from baseline to follow-up between intervention and control groups
PMCID: PMC3377524  PMID: 23074528
24.  Tolerability and efficacy of glycemic control with saxagliptin in older patients (aged ≥ 65 years) with inadequately controlled type 2 diabetes mellitus 
Purpose
To assess safety and efficacy of saxagliptin in older patients with type 2 diabetes mellitus (T2DM).
Patients and methods
This was a post hoc analysis of pooled data from older patients (≥65 years of age) from five 24-week phase III trials: three studies of saxagliptin versus placebo as an add-on therapy to metformin, glyburide, or a thiazolidinedione; and two studies of saxagliptin versus placebo as monotherapy in drug-naïve patients. Separate analyses were conducted on one study of initial combination therapy with saxagliptin plus metformin versus metformin monotherapy in drug-naïve patients. The safety analysis population for the five-study pool included 428 patients ≥ 65 years of age with baseline glycated hemoglobin (HbA1c) 7.0% to 10.5% who received saxagliptin 2.5 or 5 mg or placebo, and for the study of initial combination therapy included 69 patients ≥ 65 years of age with baseline HbA1c 8.0% to 12.0% who received saxagliptin 5 mg in combination with metformin or metformin monotherapy. The primary efficacy endpoint was change from baseline HbA1c.
Results
In the five-study pool, the differences in the adjusted mean change from baseline HbA1c among older patients receiving saxagliptin versus placebo were −0.60% (95% confidence interval [CI], −0.99% to −0.21%) for saxagliptin 2.5 mg and −0.55% (−0.97% to −0.14%) for saxagliptin 5 mg; in the initial combination study, the difference was −1.22% (−2.27% to −0.17%) among older patients receiving saxagliptin 5 mg plus metformin versus metformin monotherapy. The results were generally similar in older and younger patients. Saxagliptin was well tolerated; the incidence and types of adverse events were similar for saxagliptin and comparators. Hypoglycemia was reported in 3.0% to 9.4% of patients receiving saxagliptin (0%–8.0% for comparators) and was confirmed (finger stick glucose ≤ 50 mg/dL, with associated symptoms) in 0% to 0.7% (0%–0.7% for comparators); hypoglycemic episodes did not vary by age category and did not require medical intervention.
Conclusion
Saxagliptin was effective and well tolerated, with a low risk of hypoglycemia, when used as monotherapy, add-on therapy, or initial combination therapy with metformin in older patients with T2DM.
doi:10.2147/CIA.S41246
PMCID: PMC3632630  PMID: 23626461
clinical trial; dipeptidyl peptidase-4; DPP-4 inhibitor; hypoglycemia; metformin
25.  Optimal therapy of type 2 diabetes: a controversial challenge 
Aging (Albany NY)  2014;6(3):187-206.
Type 2 diabetes mellitus (T2DM) is one of the most common chronic disorders in older adults and the number of elderly diabetic subjects is growing worldwide. Nonetheless, the diagnosis of T2DM in elderly population is often missed or delayed until an acute metabolic emergency occurs. Accumulating evidence suggests that both aging and environmental factors contribute to the high prevalence of diabetes in the elderly. Clinical management of T2DM in elderly subjects presents unique challenges because of the multifaceted geriatric scenario. Diabetes significantly lowers the chances of “successful” aging, notably it increases functional limitations and impairs quality of life. In this regard, older diabetic patients have a high burden of comorbidities, diabetes-related complications, physical disability, cognitive impairment and malnutrition, and they are more susceptible to the complications of dysglycemia and polypharmacy. Several national and international organizations have delivered guidelines to implement optimal therapy in older diabetic patients based on individualized treatment goals. This means appreciation of the heterogeneity of the disease as generated by life expectancy, functional reserve, social support, as well as personal preference. This paper will review current treatments for achieving glycemic targets in elderly diabetic patients, and discuss the potential role of emerging treatments in this patient population.
PMCID: PMC4012936  PMID: 24753144
type 2 diabetes mellitus; elderly; aging; polypharmacy; glycemic control; treatment

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