Search tips
Search criteria

Results 1-25 (1320403)

Clipboard (0)

Related Articles

1.  Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial. 
BMJ : British Medical Journal  1991;303(6803):622-626.
OBJECTIVE--To investigate the apparent increased risk of severe hypoglycaemia associated with use of human insulin by comparing the pattern of symptoms of hypoglycaemia with human insulin and porcine insulin. DESIGN--Randomised controlled double blind crossover trial of treatment with human insulin and porcine insulin, with two treatment periods of six weeks. SETTING--Diabetes outpatient department of a university teaching hospital in Berne, Switzerland. PATIENTS--44 patients (25 men, 19 women) aged 14 to 60 years, with insulin dependent diabetes mellitus. All patients met the following criteria: receiving treatment with fast acting soluble insulin and long acting protamine insulin; performing multiple daily fingerstick blood glucose self measurements; and had stable glycaemic control with about one mild hypoglycaemic episode a week during the preceding two months. INTERVENTION--Patients were randomised to receive either human or porcine insulin for six weeks and were then changed over to the other type of insulin for a further six weeks. MAIN OUTCOME MEASURE--Questionnaire recording "autonomic" and "neuroglycopenic" symptoms that occurred during hypoglycaemic episodes confirmed by a blood glucose concentration less than or equal to 2.8 mmol/l. RESULTS--Insulin doses and blood glucose, glycated haemoglobin A1c, and fructosamine concentrations were similar during the two treatment periods. 493 questionnaires on hypoglycaemia (234 during treatment with human insulin and 259 during treatment with porcine insulin) were analysed. With human insulin patients were more likely to report lack of concentration (52% v 35%, p = 0.0003) and restlessness (53% v 45%, p = 0.004) and less likely to report hunger (33% v 42%, p = 0.016) than during treatment with porcine insulin. The difference in the pattern of symptoms during the two treatments was similar to that between the 12 patients with a history of recurrent hypoglycaemic coma and the 32 patients without such a history. CONCLUSIONS--The pattern of symptoms associated with human insulin could impair patients' ability to take appropriate steps to avoid severe hypoglycaemia. Caution should be exercised when transferring patients from animal insulin to human insulin, and a large scale randomised trial of the two types of insulin may be justified.
PMCID: PMC1671054  PMID: 1932903
2.  Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin. 
BMJ : British Medical Journal  1993;306(6871):167-171.
OBJECTIVES--To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN--Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING--Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS--17 patients with insulin dependent diabetes mellitus of more than five years' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES--Glycaemic control and frequency of hypoglycaemic episodes during two months' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS--Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS--These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.
PMCID: PMC1676615  PMID: 8443479
3.  Elderly Patients with Diabetes Experience a Lower Rate of Nocturnal Hypoglycaemia with Insulin Degludec than with Insulin Glargine: A Meta-Analysis of Phase IIIa Trials 
Drugs & Aging  2013;30(12):1009-1018.
Background and Objective
Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients.
Hypoglycaemia data from patients ≥65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to-target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned meta-analysis. Overall, 917/4345 (21 %) randomised patients in the seven trials were elderly (634 IDeg, 283 IGlar). Overall confirmed hypoglycaemia was defined as <3.1 mmol/L or severe hypoglycaemia (symptoms requiring external assistance). Nocturnal hypoglycaemia included confirmed episodes from 0001 to 0559 hours (inclusive). Treatment comparisons of hypoglycaemia in T1DM patients were not performed due to low numbers of elderly patients with T1DM randomised (43 IDeg, 18 IGlar); statistical comparisons were also not made for severe hypoglycaemia due to the low number of events.
In elderly patients with T2DM, the rate of overall confirmed hypoglycaemia was significantly lower with IDeg than IGlar [estimated rate ratio (ERR) 0.76 (0.61; 0.95)95 % CI]; nocturnal confirmed hypoglycaemia was also significantly lower with IDeg [ERR 0.64 (0.43; 0.95)95 % CI]. Confirmed hypoglycaemia occurred in the majority of T1DM patients, whereas severe episodes occurred infrequently and at similar rates in both treatment groups in T1DM and T2DM.
Results of this pre-planned meta-analysis in elderly patients with diabetes demonstrate a significant reduction in hypoglycaemic events with IDeg relative to IGlar.
PMCID: PMC3832772  PMID: 24170235
4.  Diabetes: glycaemic control in type 2 (drug treatments) 
BMJ Clinical Evidence  2012;2012:0609.
Diabetes mellitus is a progressive disorder of glucose metabolism. It is estimated that about 285 million people between the ages of 20 and 79 years had diabetes worldwide in 2010, or 5% of the adult population. Type 2 diabetes may occur with obesity, hypertension, and dyslipidaemia (the metabolic syndrome), which are powerful predictors of cardiovascular disease. Without adequate blood-glucose-lowering treatment, blood glucose levels may rise progressively over time in people with type 2 diabetes. Microvascular and macrovascular complications may develop.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of blood-glucose-lowering medications in adults with type 2 diabetes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2010 (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 194 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: alpha-glucosidase inhibitors (AGIs), combination treatment (single, double, and triple), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins (including conventional [human] and analogue, different regimens, different length of action), meglitinides, metformin, sulphonylureas, and thiazolidinediones.
Key Points
Diabetes mellitus affects about 6.5% of people aged 20 to 79 years worldwide. In 2010, an estimated 285 million people have diabetes, over 85% of whom have type 2 diabetes.
Type 2 diabetes is often associated with obesity, hypertension, and dyslipidaemia, which are all powerful predictors of cardiovascular disease. For that reason, the treatment of type 2 diabetes requires a multifactorial approach, including lifestyle advice, treatment of hypertension, and lowering of lipid levels.
Without adequate blood-glucose-lowering treatment, blood glucose levels may rise progressively over time in people with type 2 diabetes. Microvascular and macrovascular complications may develop.
Metformin reduces HbA1c effectively compared with placebo. The UK Prospective Diabetes Study (UKPDS) RCT found that metformin may be moderately protective against mortality and cardiovascular morbidity, but further high-quality studies are needed.We found no evidence to suggest that metformin increases the risk of lactic acidosis.
Sulphonylureas reduce HbA1c by 1% compared with placebo, and they may reduce microvascular complications compared with diet alone. They can cause weight gain and hypoglycaemia. One review found that the risk of hypoglycaemia was highest with glibenclamide compared with other second-generation sulphonylureas.
The effectiveness of the combination of metformin and sulphonylurea on mortality and morbidity is unknown.
Meglitinides reduce HbA1c by about 0.4–0.9% compared with placebo, but robust data are sparse.
Alpha-glucosidase inhibitors reduce HbA1c by about 0.8% compared with placebo. We found no reports of dangerous adverse effects.
Thiazolidinediones reduce HbA1c by 1.0% compared with placebo but may increase the risk of congestive heart failure and bone fractures. Rosiglitazone increases the risk of MI. DRUG ALERT: Rosiglitazone has been withdrawn from the market in many countries because the benefits of treatment are no longer thought to outweigh the risks.
Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce HbA1c by about 0.6–0.7% compared with placebo. We found no long-term data on effectiveness and safety.
Glucagon-like peptide-1 (GLP-1) analogues reduce HbA1c compared with placebo and result in weight loss. We found no long-term data on effectiveness and safety.
Combined oral drug treatment may reduce HbA1c levels more than monotherapy, but increases the risk of hypoglycaemia.
Insulin improves glycaemic control in people with inadequate control of HbA1c on oral drug treatment, but is associated with weight gain, and an increased risk of hypoglycaemia.
Adding metformin to insulin may reduce HbA1c levels compared with insulin alone, with less weight gain.
Insulin analogues, short-acting, long-acting, and combined in various regimens, seem no more effective than conventional (human) insulin in reducing HbA1c levels. However, in people presenting with recurrent hypoglycaemic episodes, long-acting insulin analogues may be preferred above human insulin.
Long-acting insulin analogues seem equally effective at reducing HbA1c.
There is lack of evidence about the effectiveness of various insulin analogue regimens after once-daily long-acting insulin has failed.
The effectiveness of insulin basal bolus regimens is not well established.
PMCID: PMC3462437  PMID: 23862772
5.  Research: Complications Self-reported non-severe hypoglycaemic events in Europe 
Diabetic Medicine  2013;31(1):92-101.
Hypoglycaemia presents a barrier to optimum diabetes management but data are limited on the frequency of hypoglycaemia incidents outside of clinical trials. The present study investigated the rates of self-reported non-severe hypoglycaemic events, hypoglycaemia awareness and physician discussion of events in people with Type 1 diabetes mellitus or insulin-treated Type 2 diabetes mellitus.
People in seven European countries aged >15 years with Type 1 diabetes or insulin–treated Type 2 diabetes (basal-only, basal-bolus and other insulin regimens) were recruited via consumer panels, nurses, telephone recruitment and family referrals. Respondents completed four online questionnaires. The first questionnaire collected background information on demographics and hypoglycaemia-related behaviour, whilst all four questionnaires collected data on non-severe hypoglycaemic events in the preceding 7 days.
Analysis was based on 11 440 respondent-weeks from 3827 respondents. All participants completed the first questionnaire and 57% completed all four. The mean number of events/respondent–week was 1.8 (Type 1 diabetes) and 0.4–0.7 (Type 2 diabetes, with different insulin treatments) corresponding to annual event rates of 94 and 21–36, respectively. A total of 63% of respondents with Type 1 diabetes and 49–64% of respondents with Type 2 diabetes, treated with different insulin regimens, who experienced hypoglycaemic events, reported impaired hypoglycaemia awareness or unawareness. A high proportion of respondents rarely or never informed their general practitioner/specialist about hypoglycaemia: 65% (Type 1 diabetes) and 50–59% (Type 2 diabetes). Overall, 16% of respondents with Type 1 diabetes and 26% of respondents with Type 2 diabetes reported not being asked about hypoglycaemia during routine appointments.
Non-severe hypoglycaemic events are common amongst people with Type 1 diabetes and insulin–treated Type 2 diabetes in real-world settings. Many rarely or never inform their general practitioner/specialist about their hypoglycaemia and the real burden of hypoglycaemia may be underestimated.
PMCID: PMC4232857  PMID: 23796113
6.  Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials 
Diabetes, Obesity & Metabolism  2012;15(2):175-184.
Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM).
Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed.
Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98]95%CI, RR:0.64[0.48;0.86]95%CI and RR:0.14[0.03;0.70]95%CI. In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94]95%CI and RR:0.68[0.57;0.82]95%CI). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94]95%CI). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations.
The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.
PMCID: PMC3752969  PMID: 23130654
confirmed hypoglycaemia; insulin degludec; insulin glargine; nocturnal hypoglycaemia; severe hypoglycaemia
7.  Insulin degludec is not associated with a delayed or diminished response to hypoglycaemia compared with insulin glargine in type 1 diabetes: a double-blind randomised crossover study 
Diabetologia  2013;57(1):40-49.
Insulin degludec (Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin; IDeg) is a new basal insulin with an ultra-long flat action profile. The acute physiological responses to hypoglycaemia with IDeg and insulin glargine (A21Gly,B31Arg,B32Arg human insulin; IGlar) were compared.
Twenty-eight adult type 1 diabetic patients with normal hypoglycaemia awareness (age = 41 ± 12 years, HbA1c = 7.8 ± 0.6% [62.8 ± 7 mmol/mol]) were randomised to once-daily IDeg or IGlar for 5 days in a two-period crossover design. Participants and research staff were blinded to group assignment. Patients were assigned the lowest available randomisation number from a set of blinded randomisation codes provided by the trial sponsor. Hypoglycaemia was induced by administering three times the usual daily insulin dose at midnight on day 5. Plasma glucose (PG) was stabilised by glucose clamp (5.5 mmol/l) for 7–9 h post dosing. Next morning, PG was allowed to decrease stepwise from 5.5 to 3.5 mmol/l (maintained for 30 min) to 2.5 mmol/l (for 15 min). PG was then increased to 3.9 mmol/l (for 120 min), before being returned to baseline. Hypoglycaemic symptom score (HSS), hypoglycaemic awareness, cognitive function, counter-regulatory hormones and vital signs were assessed during each glucose plateau. The primary analysis was to compare IDeg vs IGlar with respect to HSS at nadir PG concentration (2.5 mmol/l).
The full analysis set for treatment comparisons comprised data from all 28 exposed patients. Rates of PG decline and PG at nadir were similar for IDeg and IGlar. No treatment differences in HSS (estimated difference: 0.17 [95% CI −1.71, 2.05]; p > 0.05), cognitive function or awareness were observed at any time. Growth hormone and cortisol responses during hypoglycaemia were greater with IDeg than IGlar (AUC treatment ratio [IDeg/IGlar]: 2.44 [1.30, 4.60], p < 0.01; and 1.23 [1.01, 1.50]; p < 0.05), and adrenaline (epinephrine) responses trended higher (1.40 [0.96, 2.04], p = 0.07). The rates of recovery from hypoglycaemia were similar.
IDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia. IDeg may elicit a moderately greater endocrine response, but times to PG recovery were similar for the two insulins.
Trial registration NCT01002768.
Novo Nordisk.
PMCID: PMC3855490  PMID: 24057153
Counter-regulation; Degludec; Glargine; Hormones; Hypoglycaemia; Type 1 diabetes
8.  Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study. 
BMJ : British Medical Journal  1991;303(6803):617-621.
OBJECTIVE--To examine whether transfer from animal insulin to human insulin is associated with an increased risk of severe hypoglycaemia. DESIGN--Matched case-control study of insulin treated diabetic patients admitted to hospital because of hypoglycaemia during 1984-7, the period when human insulin was introduced into treatment. SETTING--Case admissions and control admissions were obtained from eight public hospitals within the Swiss canton of Berne and a second control group comprised members of the Bernese section of the Swiss Diabetes Association. SUBJECTS--94 patients with insulin treated diabetes with a total of 112 admissions for hypoglycaemia during 1984-7 (case admissions), 182 patients with insulin treated diabetes seen in the same hospitals for reasons other than hypoglycaemia with a total of 225 admissions (control admissions), and 86 insulin treated diabetic patients who were members of the Bernese section of the Swiss Diabetes Association. MAIN OUTCOME MEASURES--Type of insulin used at time of admission, glycaemic control as measured by amount of glycated haemoglobin or glucose concentration; severity of hypoglycaemia. RESULTS--Treatment with human insulin at admission was more common in cases than controls (52/112 (46%) admissions v 77/225 (34%); p = 0.003). 116 out of 129 (90%) of admissions taking human insulin had been transferred from animal insulin, mainly because of non-availability of porcine insulins. The ratio of rate of hypoglycaemia in those taking human insulin to the rate in those taking animal insulin was 2.4 (95% confidence interval 1.3 to 4.4). Other risk factors for hypoglycaemia were a history of hypoglycaemic coma (rate ratio of history to no history 3.8, 2.3 to 6.4) and good glycaemic control (rate ratio of good to poor control 3.9, 1.4 to 7.5). With multivariate analysis the increase in rate ratio associated with use of human insulin rose to 3.0 (1.4 to 6.4). Comparison with the diabetes association controls also showed an increased risk associated with use of human insulin (2.2; 1.1 to 4.8). CONCLUSIONS--Transfer of treatment from animal insulin to human insulin was associated with an increased risk of severe hypoglycaemia. Caution should be exercised when transferring diabetic patients to human insulin. Further studies are required to elucidate why this effect occurs.
PMCID: PMC1671049  PMID: 1932902
9.  Cost of severe hypoglycaemia in patients with type 1 diabetes in Spain and the cost-effectiveness of insulin lispro compared with regular human insulin in preventing severe hypoglycaemia 
To determine the costs of severe hypoglycaemia (SH) in a population of patients with type 1 diabetes mellitus in the Spanish healthcare system and the cost-effectiveness of insulin lispro over regular insulin in preventing SH episodes.
A retrospective study of 100 patients in three Spanish health centres was performed. Resource utilisation data were collected only for interventions specifically relating to the hypoglycaemic episode. The direct medical costs determined in the analyses were: costs of hospitalisation, diagnostic tests carried out, costs of treatment administered and other associated costs such as visits to the endocrinologist and re-training in glucose control, transportation and assistance of a care-giver. In addition, indirect costs such as days of lost productivity were measured. The incidence rates of SH for insulin lispro and regular insulin were obtained from the literature. The incremental cost-effectiveness of insulin lispro over regular insulin was calculated.
The overall mean cost per episode of SH was €366, comprised of 65.4% direct costs and 35.6% indirect costs. The largest cost was for hospitalisation at €183 per episode. The SH episodes incidence rates for 100 patients per year were 33 and 73 for insulin lispro and 48 (p < 0.05) and 117 (p < 0.01) for regular insulin, in the two clinical trials found in the literature. The additional cost to prevent one episode of SH with insulin lispro over regular insulin ranged from €277 to insulin lispro dominance.
Severe hypoglycaemia has a significant impact on the total cost of diabetes. The use of insulin lispro is associated with reductions in annual costs because of SH and, possibly, the overall effect may be cost neutral or cost saving when total costs are considered. The cost of SH should be included in the analysis of total socio-economic burden of diabetes.
Disclosures J. Reviriego and J. Sacristan are currently employees of Lilly Spain. Dr Gomis, Dr Marañes and Dr Ricart have served as consultant and speakers in Lilly medical educational and scientific meetings. In addition all authors at some point have been involved as investigators in Lilly registration trials.
What's knownLittle or none data were available with respect to the costs of acute diabetes-related complications associated with insulin treatment as is the case for severe hypoglycaemia.What's newWe provide valuable information on the impact of therapeutic alternatives such as the use of an insulin analogue (insulin lispro) vs. regular human insulin on the total cost of diabetes.
PMCID: PMC2438603  PMID: 18489577
10.  The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study 
Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy.
Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese).
Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.
Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21).
Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk.
Trial registration number NCT00000620.
PMCID: PMC2803743  PMID: 20061360
11.  Levofloxacin-associated hypoglycaemia complicated by pontine myelinolysis and quadriplegia 
Diabetic Medicine  2008;25(7):856-859.
Central pontine myelinolysis (CPM) usually presents in chronic alcoholics and in patients in whom hyponatraemia has been corrected rapidly. However, CPM may occur in other clinical circumstances, including patients with severe hypoglycaemia. We describe the occurrence of CPM and quadriplegia in a patient who experienced fluoroquinolone-associated severe hypoglycaemia.
Case report
A 63-year-old man with Type 2 diabetes mellitus was admitted to hospital for resection of a large liposarcoma. Renal-dose levofloxacin was utilized as part of an antimicrobial regimen to treat post-operative peritonitis. On days 6–8 of levofloxacin therapy, the patient experienced recurrent hypoglycaemia despite total parenteral nutrition, 10% dextrose containing fluids and cessation of insulin therapy 3 days prior to the first hypoglycaemic episode. Hypoglycaemia resolved within 24 h of stopping levofloxacin. After a final and severe hypoglycaemic event, the patient developed quadriplegia and tonic left deviation of gaze. Magnetic resonance imaging revealed a high-intensity lesion in the central pons consistent with CPM.
Fluoroquinolones should be considered as a potential cause of hypoglycaemia. Severe hypoglycaemia has the potential to cause white matter lesions in the pons. Putative mechanisms include failure of membrane ion channels, oligodendrocyte apoptosis and oxidative stress of glucose reperfusion. Fluoroquinolone-associated hypoglycaemia and hypoglycaemia-induced quadriplegia are both rare and we believe this is the first case report linking the two events.
Diabet. Med. 25, 856–859 (2008)
PMCID: PMC2613252  PMID: 18644072
central pontine myelinolysis; fluoroquinolones; hypoglycaemia; quadriplegia; Type 2 diabetes mellitus
12.  A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations 
Diabetes, Obesity & Metabolism  2011;13(8):677-684.
Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients’ physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic-lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long-acting insulin analogues with protaminated human insulin. Enhancing insulin self-association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long-acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.
PMCID: PMC3380549  PMID: 21410860
insulin analogues; insulin therapy; pharmacology; type 2 diabetes
13.  When glycaemic targets can no longer be achieved with basal insulin in type 2 diabetes, can simple intensification with a modern premixed insulin help? Results from a subanalysis of the PRESENT study 
The aim of this analysis was to assess the efficacy and safety of intensifying insulin therapy from a basal-only regimen to biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes previously failing to reach glycaemic targets.
Methods and patients:
The analysis is based on data from a subpopulation of the Physicians’ Routine Evaluation of Safety and Efficacy of NovoMix® 30 Therapy (PRESENT) study, which was a 6-month observational study in 15 countries. This subanalysis included patients previously receiving long-acting analogue insulin (AB; n = 348), or human basal insulin (long and intermediate acting) (HB; n = 3414), who were transferred to BIAsp 30. Efficacy end-points included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), from baseline to the end of the study. Episodes of hypoglycaemia, adverse events, and physician and patient satisfaction were also recorded. End-points were considered separately by previous basal regimen (AB or HB).
After 6 months' treatment with BIAsp 30, HbA1c was significantly lowered in both groups (−1.60% and −1.42% in the AB and HB groups; p < 0.0001 compared with baseline). Reductions in FPG and PPG were also statistically significant in both groups. The rate (events/patient/year) of overall hypoglycaemia remained relatively constant in patients switching from AB, but it was statistically lower in patients switching from HB (change from baseline −3.8; p < 0.001).
In routine clinical practice, patients with type 2 diabetes who are failing to reach glycaemic targets on basal insulin can achieve better glycaemic control without an increase in overall hypoglycaemia by intensifying with BIAsp 30.
Disclosure Hak Chul Jang, Serdar Guler and Marina Shestakova have no conflicts of interest.
What's knownBasal insulin is a commonly used insulin initiation regimen in patients with type 2 diabetes who fail to achieve optimal glycaemic control on oral anti-diabetic drugs.As type 2 diabetes takes its natural course of progression, treatment regimens need to be monitored and, when necessary, intensified to maintain acceptable glycaemic control.What's newTo date, there are little data that demonstrate how effective modern premixes can be in type 2 patients who are failing to achieve glycaemic targets with basal insulin.The PRESENT study is a 6-month, prospective, uncontrolled, clinical experience evaluation study using biphasic insulin aspart 30 (BIAsp 30) for type 2 diabetes patients in daily clinical practice in several countries.In this subanalysis, we show that patients failing to achieve good control (as defined by HbA1c) on basal insulin were able to significantly improve their glycaemic control by simply intensifying with the modern premix insulin, BIAsp 30.
PMCID: PMC2438599  PMID: 18479365
14.  The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study  
Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
Design Retrospective epidemiological analysis of data from the ACCORD trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A1C) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors.
Intervention Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.
Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.
Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.
Trial registration NCT00000620.
PMCID: PMC2803744  PMID: 20061358
15.  A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes 
Diabetologia  2008;51(3):408-416.
This 52-week multinational, randomised, open-label, parallel-group, non-inferiority trial compared clinical outcomes following supplementation of oral glucose-lowering drugs with basal insulin analogues detemir and glargine in type 2 diabetic patients.
Insulin-naive adults (n = 582, HbA1c 7.5–10.0%, BMI ≤ 40.0 kg/m2) were randomised 1:1 to receive insulin detemir or glargine once daily (evening) actively titrated to target fasting plasma glucose (FPG) ≤ 6.0 mmol/l. An additional morning insulin detemir dose was permitted if pre-dinner plasma glucose (PG) was >7.0 mmol/l after achieving FPG < 7.0 mmol/l. Due to labelling restrictions, no second glargine dose was allowed.
Baseline HbA1c decreased from 8.6 to 7.2 and 7.1% (NS) with detemir and glargine, respectively. FPG improved from 10.8 to 7.1 and 7.0 mmol/l (NS), respectively. With detemir, 45% of participants completed the study on once daily dosing and 55% on twice daily dosing, with no difference in HbA1c. Overall, 52% of participants achieved HbA1c ≤ 7.0%: 33% (detemir) and 35% (glargine) without hypoglycaemia. Within-participant variability for self-monitored FPG and pre-dinner PG did not differ by insulin treatment, nor did the relative risk of overall or nocturnal hypoglycaemia. Modest reductions in weight gain were seen with detemir vs glargine in completers (3.0 vs 3.9 kg, p = 0.01) and in the intention-to-treat population (2.7 vs 3.5 kg, p = 0.03), primarily related to completers on once-daily detemir. Mean daily detemir dose was higher (0.78 U/kg [0.52 with once daily dosing, 1.00 U/kg with twice daily dosing]) than glargine (0.44 IU/kg). Injection site reactions were more frequent with detemir (4.5 vs 1.4%).
Supplementation of oral agents with detemir or glargine achieves clinically important improvements in glycaemic control with low risk of hypoglycaemia. Non-inferiority was demonstrated for detemir using higher insulin doses (mainly patients on twice daily dosing); weight gain was somewhat reduced with once daily insulin detemir. ID no.: NCT00283751.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-007-0911-x) contains supplementary material, which is available to authorised users.
PMCID: PMC2235909  PMID: 18204830
Body weight; Fasting plasma glucose; Glucose variability; Glucose control; Hypoglycaemia; Insulin detemir; Insulin glargine; Insulin supplementation; Oral glucose-lowering agents; Type 2 diabetes
16.  Lower risk of hypoglycaemia and greater odds for weight loss with initiation of insulin detemir compared with insulin glargine in Turkish patients with type 2 diabetes mellitus: local results of a multinational observational study 
The purpose of this analysis is to evaluate the safety and effectiveness of insulin initiation with once-daily insulin detemir (IDet) or insulin glargine (IGlar) in real-life clinical practice in Turkish patients with type 2 diabetes mellitus (T2DM).
This was a 24-week multinational observational study of insulin initiation in patients with T2DM.
The Turkish cohort (n = 2886) included 2395 patients treated with IDet and 491 with IGlar. The change in glycosylated haemoglobin (HbA1c) from the pre-insulin levels was -2.21% [95% confidence interval (CI) -2.32, -2.09] in the IDet group and -1.88% [95% CI -2.17, -1.59] in the IGlar group at the final visit. The incidence rate of minor hypoglycaemia increased in both groups from the pre-insulin to the final visit (+0.66 and +2.23 events per patient year in the IDet and IGlar groups, respectively). Weight change in the IDet group was -0.23 kg [95% CI -0.49, 0.02 kg], and +1.55 kg [95% CI 1.11, 2.00 kg] in the IGlar group. Regression analysis with adjustment for previously identified confounders (age, gender, duration of diabetes, body mass index, previous history of hypoglycaemia, microvascular disease, number and change in oral anti-diabetic drug therapy, HbA1c at baseline and insulin dose) identified an independent effect of insulin type (IDet versus IGlar) with a risk of at least one episode of hypoglycaemia (odds ratio (OR): 0.33 [95% CI 0.21, 0.52], p <0.0001), and weight loss ≥1 kg (OR: 1.75 [95% CI 1.18, 2.59], p = 0.005), but not on HbA1c (+0.05% [95% CI -0.15, 0.25%], p = 0.6).
Initiation of basal insulin analogues, IDet and IGlar, were associated with clinically significant glycaemic improvements. A lower risk of minor hypoglycaemia and greater odds of weight loss ≥1 kg was observed with IDet compared with IGlar.
Trial registration
NCT00825643 and NCT00740519
PMCID: PMC4223563  PMID: 25048824
Insulin detemir; Insulin glargine; Basal insulin; Type 2 diabetes; Weight loss; Hypoglycaemia
17.  Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study 
Diabetologia  2009;52(9):1778-1788.
This long-term study was designed to further characterise the retinal safety profile of insulin glargine and human neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus.
An open-label, 5 year, randomised (1:1), multicentre, stratified, parallel-group study conducted in the USA and Canada enrolled individuals with type 2 diabetes and either no or non-proliferative retinopathy (less than severe; Early Treatment Diabetic Retinopathy Study [ETDRS] level less than 53 in both eyes) who were treated with oral hypoglycaemic agents (OHAs) alone, insulin alone or OHAs with insulin for ≥3 months prior to study entry and a baseline HbA1c level of 6.0–12.0%. Patients were randomised by the investigator according to the centralised interactive voice response system to receive twice-daily NPH insulin (n = 509) or once-daily basal insulin glargine (n = 515). The investigator was not blinded to the treatment group to which each participant had been assigned. The main objective of this study was to compare the progression of diabetic retinopathy between treatment groups by analysing the percentage of patients with three or more step progression in the ETDRS retinopathy patient-level severity scale after treatment with either basal insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used.
Similarly sustained glycaemic control was observed in both the insulin glargine and NPH insulin treatment groups. Despite a slightly greater severity of diabetic retinopathy for the insulin glargine group at baseline, three or more step progression in ETDRS score from baseline to end-of-study was similar between treatment groups (14.2% [53/374] of insulin glargine-treated patients vs 15.7% [57/363] of NPH-treated patients); the difference in the incidence of progression was −1.98% (95% CI −7.02, 3.06%). Other measures of retinopathy—the development of proliferative diabetic retinopathy and progression to clinically significant macular oedema—occurred to a similar degree in both treatment groups. No other safety issues, such as unexpected adverse events for either insulin emerged during the 5 year study. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine.
This study shows no evidence of a greater risk of the development or progression of diabetic retinopathy with insulin glargine vs NPH insulin treatment in patients with type 2 diabetes mellitus.
Trial registration NCT00174824
This study was sponsored by sanofi-aventis.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-009-1415-7) contains supplementary material, which is available to authorised users.
PMCID: PMC2723680  PMID: 19526210
CSME; ETDRS; Insulin action; Insulin glargine; Insulin therapy; NPH insulin; Retinopathy; Type 2 diabetes
18.  Incidence and predictors of hypoglycaemia in type 2 diabetes – an analysis of the prospective DiaRegis registry 
Hypoglycaemia is a serious adverse effect of antidiabetic drug therapy. We aimed to determine incidence rates of hypoglycaemia in type-2 diabetic patients and identify predictors of hypoglycaemia when treatment is intensified.
DiaRegis is a prospective German registry that follows 3810 patients with type-2 diabetes referred for treatment intensification because of insufficient glycaemic control on one or two oral antidiabetic drugs.
Out of a total of 3347 patients with data available for the present analysis 473 (14.1%) presented any severity hypoglycaemia over a follow-up of 12 months. 0.4% were hospitalized (mean of 1.3±0.6 episodes), 0.1% needed medical assistance (1.0±0.0), 0.8% needed any help (1.1±0.5) and 10.1% no help (3.4±3.7), and 8.0% had no specific symptoms (3.6±3.5). Patients with incident hypoglycaemia had longer diabetes duration, higher HbA1c and a more frequent smoking history; more had co-morbid disease conditions such as coronary artery disease, peripheral arterial disease, amputation, heart failure, peripheral neuropathy, diabetic retinopathy and clinically relevant depression at baseline. Multivariable adjusted positive predictors of incident hypoglycaemia over the follow-up were prior anamnestic hypoglycaemia, retinopathy, depression, insulin use and blood glucose self-measurement, but not sulfonylurea use as previously reported for anamnestic or recalled hypogylcaemia. On the contrary, glitazones, DPP-4 inhibitors and GLP-1 analogues were associated with a reduced risk of hypoglycaemia.
Hypoglycaemia is a frequent adverse effect in ambulatory patients when antidiabetic treatment is intensified. Particular attention is warranted in patients with prior episodes of hypoglycaemia, microvascular disease such as retinopathy and in patients receiving insulin. On the other hand glitazones, DPP-4 inhibitors and GLP-1 analogues are associated with a reduced risk.
PMCID: PMC3515411  PMID: 23075070
19.  Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial 
Diabetic Medicine  2013;30(11):1298-1304.
The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes.
This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9–4.9 mmol/l.
At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI −1 to 3) [0.07% (95% CI −0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects).
In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine.
PMCID: PMC4208679  PMID: 23952326
20.  Comparison of Optimised MDI versus Pumps with or without Sensors in Severe Hypoglycaemia (the Hypo COMPaSS trial) 
Severe hypoglycaemia (SH) is one of the most feared complications of type 1 diabetes (T1DM) with a reported prevalence of nearly 40%. In randomized trials of Multiple Daily Injections (MDI) and Continuous Subcutaneous Insulin Infusion (CSII) therapy there is a possible benefit of CSII in reducing SH. However few trials have used basal insulin analogues as the basal insulin in the MDI group and individuals with established SH have often been excluded from prospective studies. In published studies investigating the effect of Real Time Continuous Glucose Monitoring (RT-CGM) benefit in terms of reduced SH has not yet been demonstrated. The primary objective of this study is to elucidate whether in people with T1DM complicated by impaired awareness of hypoglycaemia (IAH), rigorous prevention of biochemical hypoglycaemia using optimized existing self-management technology and educational support will restore awareness and reduce risk of recurrent SH.
This is a multicentre prospective RCT comparing hypoglycaemia avoidance with optimized MDI and CSII with or without RT-CGM in a 2×2 factorial design in people with type 1 diabetes who have IAH. The primary outcome measure for this study is the difference in IAH (Gold score) at 24 weeks. Secondary outcomes include biomedical measures such as HbA1c, SH incidence, blinded CGM analysis, self monitored blood glucose (SMBG) and response to hypoglycaemia in gold standard clamp studies. Psychosocial measures including well-being and quality of life will also be assessed using several validated and novel measures. Analysis will be on an intention-to-treat basis.
Most existing RCTs using this study’s interventions have been powered for change in HbA1c rather than IAH or SH. This trial will demonstrate whether IAH can be reversed and SH prevented in people with T1DM in even those at highest risk by using optimized conventional management and existing technology.
Trial Registration
ISRCTN52164803 Eudract No: 2009-015396-27
PMCID: PMC3556156  PMID: 23237320
21.  Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a treat-to-target basal–bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial 
Diabetic Medicine   2008;25(4):442-449.
This 24-month, multi-national, open-label, parallel group trial investigated the long-term efficacy and safety of insulin detemir and Neutral Protamine Hagedorn insulin in combination with mealtime insulin aspart in patients with Type 1 diabetes using a treat-to-target concept.
Patients were randomized 2 : 1 to detemir (n = 331) or NPH (n = 166) groups. Basal insulin was initiated once daily (evening) and titrated individually based on self-measured plasma glucose (PG) levels, aiming for pre-breakfast and pre-dinner targets ≤ 6.0 mmol/l. A second basal morning dose could be added according to pre-defined criteria.
After 24 months, superiority of glycated haemoglobin (HbA1c) was achieved with detemir compared to NPH (detemir 7.36%, NPH 7.58%, mean difference −0.22% points) [95% confidence interval (CI) −0.41 to −0.03%], with reductions of 0.94% and 0.72% points, respectively. Fasting PG (FPGlab) was also lower with detemir (detemir 8.35 mmol/l, NPH 9.43 mmol/l; P = 0.019). Twenty-two per cent of patients treated with detemir reached an HbA1c ≤ 7.0% in the absence of confirmed hypoglycaemia during the last month of treatment vs. 13% on NPH (P = 0.019). Risk of major and nocturnal hypoglycaemia was 69% and 46% lower with detemir than with NPH (P < 0.001), respectively; patients treated with detemir gained less weight (detemir 1.7 kg, NPH 2.7 kg; P = 0.024). The overall safety profile was similar in the two groups and treatment with detemir did not result in any unexpected findings.
Long-term treatment with the insulin analogues detemir + aspart was superior to NPH + aspart in reducing HbA1c, with added benefits of less major and nocturnal hypoglycaemia and less weight gain.
Diabet. Med. 25, 442–449 (2008)
PMCID: PMC2327220  PMID: 18387078
insulin analogues; glycaemic control; hypoglycaemia; Type 1 diabetes; HbA1c
22.  Contemporary Rates of Severe Hypoglycaemia in Youth with Type 1 Diabetes: Variability by Insulin Regimen 
To determine incidence rates of severe hypoglycaemia and compare incidence rates by insulin regimen in a diverse sample of youth with type 1 diabetes from two sites.
In this observational study, 255 youth (51% female) aged 9–15 years receiving varied insulin regimens provided data prospectively for a median of 1.2 years. Reported episodes of severe hypoglycaemia, defined as episodes requiring help from another person for oral treatment or episodes resulting in seizure/coma, and current insulin regimens were collected systematically. Incidence rates were calculated and compared according to insulin regimen in bivariate and multivariate analyses.
At first encounter, participants had a median age of 12.2 years (range 9.0–15.0), median diabetes duration of 4.4 years (range 1.0–13.0) and mean A1C of 67±12 mmol/mol (8.3±1.1%). The incidence rate was 37.6/100-patient-years for all severe hypoglycaemia and 9.6/100-patient-years for seizure/coma. The incidence rate for severe hypoglycaemia was 31.8/100-patient-years on continuous subcutaneous insulin infusion (CSII), 34.4/100-patient-years on basal-bolus injections (B-B) and 46.1/100-patient-years on NPH (NPH vs. CSII: p=.04). The incidence rate for seizure/coma was 4.5/100-patient-years on CSII, 11.1/100-patient-years on B-B, and 14.4/100-patient-years on NPH (NPH vs. CSII: p=.004). In the multivariate analysis, the rate of seizure/coma was significantly higher for those on NPH vs. CSII (rate ratio 2.9, p=.03).
Rates of severe hypoglycaemia in youth with type 1 diabetes remain high. CSII was associated with lower rates of all severe hypoglycaemia and seizure/coma in comparison to NPH.
PMCID: PMC3597100  PMID: 22417321
Hypoglycaemia; type 1 diabetes; paediatrics; insulin therapy
23.  Continuous subcutaneous insulin infusion versus multiple daily injections 
Hippokratia  2009;13(2):93-96.
Background and aim: Continuous Subcutaneous Insulin Infusion (CSII) and Multiple Daily insulin Injections (MDI) are both strategies aiming to achieve a tight glycemic and metabolic control. However, the choice between them remains controversial. The aim of the present study was to compare the efficacy of MDI (three or more injections daily) with CSII on glycemic control in patients with Type 1 Diabetes Mellitus and assess satisfaction from treatment in the CSII group.
Material and Methods: Seventeen patients with Type 1 Diabetes Mellitus on CSII (previously on MDI) and 17 patients on MDI, matched for age, gender, BMI and duration of diabetes, were retrospectively studied. Glucosylated Hemoglobin A1c (HbA1c), frequency of hypoglycaemias (assessed as self reported episodes), BMI and total units of insulin per day were evaluated at baseline and after 6 months in both groups. CSII group completed a questionnaire concerning motive for treatment selection, advantages, deficiencies and inconvenience at the end of the study. Satisfaction from treatment was assessed with a scale from 0 to10.
Results: CSII group had more hypoglycaemic episodes at baseline than MDI group (16.2±2.8 vs 2.8±1.3, p<0,001). HbA1c (8.4±0.5 before vs 7.3±0.4 after, p<0.05) and total hypoglycaemic episodes per month (16.2±2.8 before vs 8.7±2.3 after, p<0.05) significantly decreased in CSII group 6 months after baseline. On the contrary, total hypoglycaemic episodes per month were increased in MDI group (2.8±1.3 before vs 10.8 ±2,6 after, p<0.05) in order to maintain HbA1c levels. No significant differences were observed in BMI in both groups. Total insulin demands were reduced in the CSII group (49.4±3.3 before vs 39.0±4.6 after, p<0.05) and remained unchanged in MDI group. None of the patients discontinued CSII therapy, while overall satisfaction rate in this group was high. The main motive for CSII selection was frequent hypoglycaemic episodes and glucose fluctuations (10/17). The majority of patients expressed their wish for incorporating glucose trend indicator and/or continuous glucose measurement into pump and reducing pump size (15/17). Most commonly stated advantage was improved flexibility, followed by greater freedom and decreased sense of physical restrictions (10/17). Inconvenience mainly derived from alarm malfunction and catheter or needle occlusion and was reported from a minority of patients (4/17).
Conclusion: CSII group reported more hypoglycaemias than MDI group at baseline but 6 months later had significantly less hypoglycaemic events, while on the contrary, MDI group 6 months after baseline had more frequent and more severe hypoglycaemias. Although baseline hypoglycaemias are not equal between the two groups, we can assume that CSII group achieved less hypoglycaemic events along with significant reduction in HbA1c while utilising less insulin units.
PMCID: PMC2683151  PMID: 19561778
continuous insulin infusion; diabetes mellitus; hypoglycaemia; HbA1c; insulin; insulin pump; intensified insulin treatment
24.  Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review 
BMC Pediatrics  2010;10:50.
Many children with type 1 diabetes have poor glycaemic control. Since the Diabetes Control and Complications Trial (DCCT) showed that tighter control reduces complication rates, there has been more emphasis on intensified insulin therapy. We know that patients and families are afraid of hypoglycaemia. We hypothesised that fear of hypoglycaemia might take precedence over concern about long-term complications, and that behaviour to avoid hypoglycaemia might be at the cost of poorer control, and aimed to evaluate the effectiveness of any interventions designed to prevent that. The objective of this review was to systematically review studies concerning the extent and consequences of fear of hypoglycaemia in parents of children under 12 years of age with type 1 diabetes, and interventions to reduce it.
Data Sources: MEDLINE, EMBASE, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of EASD, ADA and Diabetes UK, Current Controlled Trials,, UK CRN, scrutiny of bibliographies of retrieved papers and contact with experts in the field.
Inclusions: Relevant studies of any design of parents of children under 12 years of age with Type 1 diabetes were included. The key outcomes were the extent and impact of fear, hypoglycaemia avoidance behaviour in parents due to parental fear of hypoglycaemia in their children, the effect on diabetes control, and the impact of interventions to reduce this fear and hypoglycaemia avoidance behaviour.
Eight articles from six studies met the inclusion criteria. All were cross sectional studies and most were of good quality. Parental fear of hypoglycaemia, anxiety and depression were reported to be common. There was a paucity of evidence on behaviour to avoid hypoglycaemia, but there were some suggestions that higher than desirable blood glucose levels might be permitted in order to avoid hypoglycaemia. No studies reporting interventions to reduce parental fear of hypoglycaemia were found.
The evidence base was limited. Parents of children with Type 1 diabetes reported considerable parental fear of hypoglycaemia, affecting both parental health and quality of life. There is some suggestion that hypoglycaemia avoidance behaviours by parents might adversely affect glycaemic control. Trials of interventions to reduce parental anxiety and hypoglycaemia avoidance behaviour are needed. We suggest that there should be a trial of structured education for parents of young children with Type 1 diabetes.
PMCID: PMC2912881  PMID: 20633252
25.  Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin Pumps 
Experimental Diabetes Research  2010;2010:178372.
Aim. Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Results. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial “closed-loop” systems mimicking the pancreatic activity have been also developed. Conclusions. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients.
PMCID: PMC2877202  PMID: 20589066

Results 1-25 (1320403)