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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.
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.
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.
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.
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.
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 
To assess the factors associated with antihyperglycaemic medication initiation in UK patients with newly diagnosed type 2 diabetes.
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.
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.
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.
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.
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.
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.
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 Identifier: NCT00662714
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 
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)
PMCID: PMC4020724  PMID: 24843435
Diabetes mellitus; Clinical diagnosis; HbA1c
5.  The impact of new insights and revised practice guidelines on prescribing drugs in the treatment of Type 2 diabetes mellitus 
The aim of this study was to investigate the impact of new insights and revised guidelines on initial and follow-up treatment with antihyperglycaemic drugs over the period 1998–2003.
The InterAction Database (IADB), which contains pharmacy dispensing data from 53 community pharmacies in the Northern and Eastern part of the Netherlands, was used in this study. Prevalence and incidence rates of oral antihyperglycaemic drug use were calculated for each year. Follow-up treatment was compared for two cohorts of initial users of oral antihyperglycaemic drugs, starting treatment either 1 year before or 1 year after guideline revision.
The prevalence and incidence rate of oral antihyperglycaemic drug use increased over the study period from 1.8% to 2.4% (P < 0.001) and 0.3% to 0.4% (P= 0.04). The proportion of metformin as initial treatment increased rapidly in the observation period from 14% to 50% (P < 0.001). Initial users of metformin in 2000 received additional treatment with a sulphonylurea in the follow-up period less often compared with those who started metformin in 1998 (46%vs. 60%, P < 0.004). In contrast, initial users of sulphonylurea in 2000 received additional treatment with metformin more often compared with those who started a sulphonylurea in 1998 (42%vs. 36%, P < 0.008). The new drugs, thiazolidinediones and meglitinides, were seldom used as initial treatment
New insights and the revision of the practice guideline were followed by a significant increase in both initial and follow-up treatment with metformin among patients with Type 2 diabetes mellitus.
PMCID: PMC1885194  PMID: 16796700
diabetes; guidelines; metformin
6.  Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus 
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of antihyperglycaemic agents with an insulin-independent mode of action. Dapagliflozin is a member of the SGLT2 inhibitors class that has received marketing authorization in Europe and the US for use in patients with type 2 diabetes. This review summarizes current evidence from clinical trials assessing the clinical efficacy and safety of dapagliflozin, and presents data regarding its cost-effectiveness. Treatment with dapagliflozin results in similar reduction in haemoglobin A1c with other oral antihyperglycaemic drugs, which is preserved over 4 years of treatment. However, compared with most antidiabetic agents, dapagliflozin provides additional clinical benefits including body weight loss and blood pressure reduction. Moreover, treatment with dapagliflozin does not increase risk for hypoglycaemia, but is associated with increased incidence of mild to moderate urinary and genital tract infections. A pivotal outcomes trial of dapagliflozin is expected to clarify its effect on cardiovascular endpoints, whilst a causative relationship between dapagliflozin and select malignancies is unlikely. Finally, based on recent economic evaluations dapagliflozin seems to be a cost-effective option for type 2 diabetes in some settings.
PMCID: PMC4406879  PMID: 25941564
BMS512148; cost-effectiveness; dapagliflozin; Farxiga®; Forxiga®; sodium–glucose cotransporter 2 (SGLT2); type 2 diabetes mellitus; Xigduo®
7.  Mortality in Pharmacologically Treated Older Adults with Diabetes: The Cardiovascular Health Study, 1989–2001 
PLoS Medicine  2006;3(10):e400.
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.
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
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
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
PMCID: PMC1609124  PMID: 17048978
8.  Antihyperglycaemic treatment patterns, observed glycaemic control and determinants of treatment change among patients with type 2 diabetes in the United Kingdom primary care: a retrospective cohort study 
The initial treatment strategy for patients with type 2 diabetes includes lifestyle change recommendations. When patients are not successful in controlling their blood glucose levels through healthier lifestyle pharmaceutical agents are recommended. The objective of this study is to identify determinants of initial treatment change following initiation of non-insulin antihyperglycaemic treatment (OAD) for UK patients with type 2 diabetes.
A retrospective cohort study using primary care data from the Clinical Practice Research Datalink between January 2006 and February 2011. Each patient had an OAD prescription. The main treatment pattern outcomes were discontinuation, switching, augmentation and initiation of insulin. Glycaemic control was assessed using HbA1c.
63,060 patients initiated OAD therapy 2006–2010 and 3.4% were prescribed insulin during follow-up. 26% with at least four years of follow-up remained on the initial treatment. Metformin dominated (90%) in UK primary care. Around 75% had a record of HbA1c testing prior to initiating therapy. On initiating OAD, half the patients had HbA1c values >65 mmol/mol and one quarter >80 mmol/mol. The initial values of HbA1c were reduced after 12 months and remained stable. There were 15%-18% of patients whose values increased since initiating OAD. Increased baseline HbA1c is associated with increased chance of augmentation and decreased chance of discontinuation. HbA1c values at 1 year were associated with a three-fold increase in the chance of augmentation, 130% increase in the chance of switching and 14% increase in the chance of discontinuation with each 10 mmol/mol increase. Following initiation of OAD, HbA1c was reduced by an average of 16 mmol/mol during the first year.
There are patients for whom glycaemic control worsens and a majority remained above the recommended level, suggesting an unmet need despite the availability of many OAD.
PMCID: PMC4161267  PMID: 25163796
Type 2 diabetes mellitus; Oral antidiabetics; Non-insulin antihyperglycaemic therapy; Treatment patterns; Population based; Cohort
9.  Hematologic Complications, Healthcare Utilization, and Costs in Commercially Insured Patients with Myelodysplastic Syndrome Receiving Supportive Care 
American Health & Drug Benefits  2012;5(7):455-465.
Myelodysplastic syndrome (MDS) is rare in people aged <50 years. Most patients with this disorder experience progressive worsening of blood cytopenias, with an increasing need for transfusion. The more advanced and severe the disorder, the greater the risk that it will progress to acute myeloid leukemia. Therapy is typically based on the patient's risk category, age, and performance status. Supportive care alone is a major option for lower-risk, older patients with MDS or those with comorbidities. The only potentially curative treatment option is hematopoietic stem-cell transplantation, which is typically used to treat high-risk, younger patients.
To describe and compare the hematologic complications, healthcare utilization, and costs of supportive care in patients with MDS aged <50 years and in older patients aged ≥50 years.
Using the i3/Ingenix LabRx claims database, this retrospective study included patients who were continuously enrolled (ie, 6 months preindex through 1 year postindex) in the study and who had an initial claim of MDS (index date) between February 1, 2007, and July 31, 2008. Patients treated with hypomethylating agents or thalidomide analogues were excluded. Claims included information on office visits, medical procedures, hospitalizations, drug use, and tests performed. The hematologic complications, costs, and utilization analyses were stratified by age into 2 age-groups—patients aged <50 years and those aged ≥50 years. The MDS-related diagnoses, utilization, and costs were analyzed postindex. The data used in this study spanned the period from August 1, 2006, to July 31, 2009.
We identified 1133 newly diagnosed patients with MDS who received supportive care only during the study period; of these, 19.5% were younger than age 50 years. These younger patients included more females (62.0% vs 52.5%; P = .011) and had fewer comorbidities (mean Charlson comorbidy index, 1.2 vs 2.4; P <.001) and physician office visits than those aged ≥50 years. Postindex, compared with the older patients, the younger patients had less use of erythropoietin therapy and fewer transfusions, anemia diagnoses, and potential complications of neutropenia and pneumonia diagnoses; however, more diagnoses of neutropenia and of decreased white blood cell counts were seen in the younger patients than in the older patients (P ≤.034 for all comparisons). Furthermore, younger patients had fewer mean office visits in the postindex period than older patients (17.5 vs 24.2, respectively; P <.001) and fewer hospitalizations (32.1% vs 44.6%, respectively; P = .004), but they had a longer (although not statistically significant) mean length of hospital stay (21 vs 14 days, respectively; P = .131). Mean total healthcare charges were $96,277 (median, $21,287) in younger patients compared with $84,102 (median, $39,402) in older patients, although this difference, too, was not significant.
MDS is associated with frequent and prolonged hospitalizations, frequent outpatient visits, and high costs in younger and in older patients who are receiving supportive care. Although this study shows that younger patients aged <50 years do not have significantly higher costs overall, a small proportion may have a higher healthcare utilization and cost-related burden of MDS than patients aged ≥50 years.
PMCID: PMC4031699  PMID: 24991341
10.  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.
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).
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
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
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
PMCID: PMC2780354  PMID: 19997624
11.  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
12.  Achievement of cardiovascular risk factor targets in young adults with diabetes mellitus 
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.
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.
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.
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.
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.
PMCID: PMC3047960  PMID: 21437108
diabetes mellitus; complications; vascular risk; hypertension; cholesterol; glycated hemoglobin
13.  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,,
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
The objective of this report is to determine whether behavioural interventions1 are effective in improving glycemic control in adults with type 2 diabetes.
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.
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
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
14.  Hypoglycaemic events in patients with type 2 diabetes in the United Kingdom: associations with patient-reported outcomes and self-reported HbA1c 
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.
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.
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.
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.
PMCID: PMC3878264  PMID: 24351086
Hypoglycaemia; Hypoglycaemic events; Health related quality of life; Hypoglycaemia fear; Treatment satisfaction
15.  Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open-label trial 
Diabetes, Obesity & Metabolism  2013;16(6):510-518.
To compare efficacy and safety of two, once-daily basal insulin formulations [insulin lispro protamine suspension (ILPS) vs. insulin glargine (glargine)] added to oral antihyperglycaemic medications (OAMs) and exenatide BID in suboptimally controlled type 2 diabetes (T2D) patients.
This 24-week, open-label, multicentre trial randomized patients to bedtime ILPS (n = 171) or glargine (n = 168). Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of 95% confidence intervals (CIs) for change in haemoglobin A1c (HbA1c) from baseline to week 24 (adjusted for baseline HbA1c) with non-inferiority margin 0.4%.
Non-inferiority of ILPS versus glargine was demonstrated: least-squares mean between-treatment difference (ILPS minus glargine) (95% CI) was 0.22% (0.06, 0.38). Mean HbA1c reduction was less for ILPS- versus glargine-treated patients (−1.16 ± 0.84 vs. −1.40 ± 0.97%, p = 0.008). Endpoint HbA1c < 7.0% was achieved by 53.7% (ILPS) and 61.7% (glargine) (p = NS). Overall hypoglycaemia rates (p = NS) and severe hypoglycaemia incidence (p = NS) were similar. Nocturnal hypoglycaemia rate was higher in patients treated with ILPS versus glargine (p = 0.004). Weight gain was similar between groups (ILPS: 0.27 ± 3.38 kg; glargine: 0.66 ± 3.93 kg, p = NS). Endpoint total insulin doses were lower in patients treated with ILPS versus glargine (0.30 ± 0.17 vs. 0.37 ± 0.17 IU/kg/day, p < 0.001).
ILPS was non-inferior to glargine for HbA1c change over 24 weeks, but was associated with less HbA1c reduction and more nocturnal hypoglycaemia. Treat-to-target basal insulin therapy improves glycaemic control and is associated with minimal weight gain when added to OAMs and exenatide BID for suboptimally controlled T2D.
PMCID: PMC4237556  PMID: 24298995
exenatide; glucagon-like peptide-1 receptor agonist therapy; glycaemic control; HbA1c; hypoglycaemia; insulin glargine; insulin lispro protamine suspension; type 2 diabetes
16.  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.
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.
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
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 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
PMCID: PMC3462745  PMID: 23055834
17.  Antihyperglycaemic and Antinociceptive Activity Evaluation of Methanolic Extract of Whole Plant of Amaranthus Tricolour L. (Amaranthaceae) 
Amaranthus tricolor whole plants are used by folk medicinal practitioners of Bangladesh for treatment of pain, anaemia, dysentery, skin diseases, diabetes, and as a blood purifier. Thus far, no scientific studies have evaluated the antihyperglycaemic and antinociceptive effects of the plant. The present study was carried out to evaluate the possible glucose tolerance efficacy of methanolic extracts of A. tricolour whole plants using glucose-induced hyperglycaemic mice, and antinociceptive effects with acetic acid-induced gastric pain models in mice. In antihyperglycaemic activity tests, the extract at different doses was administered one hour prior to glucose administration and blood glucose level was measured after two hours of glucose administration (p.o.) using glucose oxidase method. The statistical data indicated the significant oral hypoglycaemic activity on glucose-loaded mice at all doses of the extracts tested. Maximum antihyperglycaemic activity was shown at 400 mg extract per kg body weight, which was comparable to that of a standard drug, glibenclamide (10 mg/kg body weight). In antinociceptive activity tests, the extract also demonstrated a dose-dependent significant reduction in the number of writhings induced in mice through intraperitoneal administration of acetic acid. Maximum antinociceptive activity was observed at a dose of 400 mg extract per kg body weight, which compared favourably with that of a standard antinociceptive drug, aspirin, when administered at a dose of 200 mg per kg body weight. The results validate the folk medicinal use of the plant for reduction of blood sugar in diabetic patients as well as the folk medicinal use for alleviation of pain. The results suggest that this plant may possess further potential for scientific studies leading to possible discovery of efficacious antihyperglycaemic and antinociceptive components.
PMCID: PMC3847438  PMID: 24311858
Amaranthus tricolour; antihyperglycaemic; antinociceptive; Amaranthaceae
18.  Long-term safety and tolerability of saxagliptin add-on therapy in older patients (aged ≥65 years) with type 2 diabetes 
Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥65 years and <65 years.
Pooled adverse event data from three placebo-controlled trials of 76–206 weeks’ duration in older (≥65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test).
A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥65 years) with saxagliptin and six (none aged ≥65 years) with placebo. Older patients rarely experienced symptomatic confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL; saxagliptin, n=1; placebo, n=2).
Saxagliptin add-on therapy was generally well tolerated in older patients aged ≥65 years with type 2 diabetes mellitus, with a long-term safety profile similar to that of placebo.
PMCID: PMC4158996  PMID: 25214775
older patients; glyburide; metformin; saxagliptin; thiazolidinedione
19.  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.
PMCID: PMC3842088  PMID: 23795975
20.  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
21.  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.
PMCID: PMC3513456  PMID: 22893314
diabetes mellitus; glimepiride; nanoprecipitation; poloxamer; sustained release
22.  Q-Score: development of a new metric for continuous glucose monitoring that enables stratification of antihyperglycaemic therapies 
Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enables complete visualisation of the glucose profile, and the uncovering of metabolic ‘weak points’. A standardised procedure to evaluate the complex data acquired by CGM, and to create patient-tailored recommendations has not yet been developed. We aimed to develop a new patient-tailored approach for the routine clinical evaluation of CGM profiles. We developed a metric allowing screening for profiles that require therapeutic action and a method to identify the individual CGM parameters with improvement potential.
Fifteen parameters frequently used to assess CGM profiles were calculated for 1,562 historic CGM profiles from subjects with type 1 or type 2 diabetes. Factor analysis and varimax rotation was performed to identify factors that accounted for the quality of the profiles.
We identified five primary factors that determined CGM profiles (central tendency, hyperglycaemia, hypoglycaemia, intra- and inter-daily variations). One parameter from each factor was selected for constructing the formula for the screening metric, (the ‘Q-Score’). To derive Q-Score classifications, three diabetes specialists independently categorised 766 CGM profiles into groups of ‘very good’, ‘good’, ‘satisfactory’, ‘fair’, and ‘poor’ metabolic control. The Q-Score was then calculated for all profiles, and limits were defined based on the categorised groups (<4.0, very good; 4.0–5.9, good; 6.0–8.4, satisfactory; 8.5–11.9, fair; and ≥12.0, poor). Q-Scores increased significantly (P <0.01) with increasing antihyperglycaemic therapy complexity. Accordingly, the percentage of fair and poor profiles was higher in insulin-treated compared with diet-treated subjects (58.4% vs. 9.3%). In total, 90% of profiles categorised as fair or poor had at least three parameters that could potentially be optimised. The improvement potential of those parameters can be categorised as ‘low’, ‘moderate’ and ‘high’.
The Q-Score is a new metric suitable to screen for CGM profiles that require therapeutic action. Moreover, because single components of the Q-Score formula respond to individual weak points in glycaemic control, parameters with improvement potential can be identified and used as targets for optimising patient-tailored therapies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12902-015-0019-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4447008  PMID: 25929322
Diabetes mellitus; Continuous glucose monitoring; Patient-tailored therapy; Individualised diabetes management; Metric; Glycemic control
23.  Diabetes: glycaemic control in type 2 
BMJ Clinical Evidence  2008;2008:0609.
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).
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.
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
24.  Population PK/PD analysis of metformin using the signal transduction model 
To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes.
Following the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes.
Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h−1 (4.18%), 113 l (56.6%) and 0.41 h−1, respectively. Covariate analyses revealed that creatinine clearance (CLCR) significantly influenced metformin: CL/F= 52.6 × (CLcr/106.5)0.782. The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 µg ml−1 (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values.
The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.
PMCID: PMC3495146  PMID: 22380769
antihyperglycaemic effect; metformin; PK/PD; signal transduction model; simulation
25.  Evaluation of bone mineral density in type 2 diabetes mellitus patients before and after treatment 
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.
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.
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.
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.
PMCID: PMC3862970  PMID: 24623915
antihyperglycaemic drugs; bone mineral density; type 2 diabetes mellitus

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