Long-acting Insulin Analogues Glargine Research Articles

ATOS study: effectiveness and safety of insulin glargine 300 U/mL in the real world clinical practice in insulin-naïve type 2 diabetic patients in the Russian Federation

Rationale: Basal insulin glargine 300 U/mL (Gla-300) is a second-generation basal insulin analogue that has comparable efficacy and lower variability compared to the first generation long-acting insulin analogue glargine 100 U/mL.
 Aim: To assess the effectiveness and safety of Gla-300 in insulin-nave type 2 diabetic patients in the real world practice in Russia.
 Materials and methods: ATOS (NCT03703869) was a 12-month, prospective observational international multicenter study. The study included 4422 adults ( 18 years) with uncontrolled type 2 diabetes (HbA1c 7 and 11%) with 1 oral anti-hyperglycemic drug and for whom the treating physician had decided to add Gla-300. We performed a post-hoc sub-analysis of the study participants recruited in Russia.
 Results: The Russian study group included 1493 patients receiving Gla-300. At 6 months, 25.9% of the patients achieved their predefined individualized HbA1c target and 53.3% achieved their HbA1c target at month 12. Their mean ( SD) HbA1c level decreased from 9.3 0.9% at baseline to 7.6 0.7% and 7.2 0.7 at months 6 and 12. The incidence of hypoglycemia was generally low; overall, severe hypoglycemia was reported only in 0.07% and 0.13% of the patients at 6 and 12 months. The baseline average daily dose of Gla-300 was 13.2 4.9 Units; it to 23.6 9.1 and 26.0 9.8 Units at months 6 and 12.
 Conclusion: In the real world setting, initiation of insulin Gla-300 in type 2 diabetic patients who had been out of their target glucose range with oral hypoglycemic agents is associated with improved glycemic control and low risk of hypoglycemia.

Long-term exposure to insulin and volumetric mammographic density: observational and genetic associations in the Karma study

BackgroundLong-term insulin exposure has been implicated in breast cancer etiology, but epidemiological evidence remains inconclusive. The aims of this study were to investigate the association of insulin therapy with mammographic density (MD) as an intermediate phenotype for breast cancer and to assess associations with long-term elevated circulating insulin levels using a genetic score comprising 18 insulin-associated variants.MethodsWe used data from the KARolinska MAmmography (Karma) project, a Swedish mammography screening cohort. Insulin-treated patients with type 1 (T1D, n = 122) and type 2 (T2D, n = 237) diabetes were identified through linkage with the Prescribed Drug Register and age-matched to 1771 women without diabetes. We assessed associations with treatment duration and insulin glargine use, and we further examined MD differences using non-insulin-treated T2D patients as an active comparator. MD was measured using a fully automated volumetric method, and analyses were adjusted for multiple potential confounders. Associations with the insulin genetic score were assessed in 9437 study participants without diabetes.ResultsCompared with age-matched women without diabetes, insulin-treated T1D patients had greater percent dense (8.7% vs. 11.4%) and absolute dense volumes (59.7 vs. 64.7 cm3), and a smaller absolute nondense volume (615 vs. 491 cm3). Similar associations were observed for insulin-treated T2D, and estimates were not materially different in analyses comparing insulin-treated T2D patients with T2D patients receiving noninsulin glucose-lowering medication. In both T1D and T2D, the magnitude of the association with the absolute dense volume was highest for long-term insulin therapy (≥ 5 years) and the long-acting insulin analog glargine. No consistent evidence of differential associations by insulin treatment duration or type was found for percent dense and absolute nondense volumes. Genetically predicted insulin levels were positively associated with percent dense and absolute dense volumes, but not with the absolute nondense volume (percentage difference [95% CI] per 1-SD increase in insulin genetic score = 0.8 [0.0; 1.6], 0.9 [0.1; 1.8], and 0.1 [− 0.8; 0.9], respectively).ConclusionsThe consistency in direction of association for insulin treatment and the insulin genetic score with the absolute dense volume suggest a causal influence of long-term increased insulin exposure on mammographic dense breast tissue.

Pharmacological Management of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes in the setting of poor glycemic control. The initial management for GDM includes intensive lifestyle modification, which often requires behavioral and nutritional changes to optimize glycemic control. Pharmacotherapy for GDM is initiated when glycemic targets are not met. The rapid-acting bolus analogues aspart and lispro achieve postprandial targets with less hypoglycemia compared to regular insulin, with similar fetal outcomes. The long-acting insulin analogues glargine and detemir appear safe with similar maternal/fetal outcomes compared to NPH. While insulin has been the mainstay therapy for women with GDM to improve glycemic control when lifestyle modifications are insufficient, certain oral antihyperglycemic drugs (OADs) can be considered as alternative treatment options for GDM but continue to be controversial for use as first-line treatment options compared to insulin by many professional bodies. Metformin has good efficacy and short-term safety data but it freely crosses the placenta and long-term safety data are lacking. Glyburide has good efficacy and short-term data but it also crosses the placenta and may be associated with increased rates of large-for-gestational-age (LGA) infants and neonatal hypoglycaemia when compared with insulin. This review aims to give an overview of the pharmacological treatment for women with GDM including some of the known safety profiles of current therapeutic options.

THE USE OF ULTRA-LONG-ACTING INSULIN ANALOGUE DEGLUDEC IN TYPE 1 DIABETES MELLITUS IN CLINICAL PRACTICE: THE INFLUENCE ON QUALITY OF LIFE AND SATISFACTION WITH TREATMENT

Background: Maintenance of stable glycemic control is an important prerequisite of effective treatment of patients with type 1 diabetes mellitus (DM). The ultra-long-acting basal insulin degludec allows for reduction of glycemic variability and for a substantial reduction in the rates of hypoglycemia with equivalent glycemic control. Evaluation of the impact of this novel insulin on diabetes-dependent quality of life and patient satisfactions with the treatment is necessary for comprehensive assessment of treatment efficacy.Aim: To study changes of glycated hemoglobin (HbA1c), rates of hypoglycemia, diabetes-dependent quality of life and treatment satisfaction in patients with type 1 DM, who have been switched to insulin degludec.Materials and methods: This open 12-week observational comparative study included 25 patients with type 1 DM (median age, 36 [20; 63] years), who were switched to insulin degludec in combination with a ultra-short insulin analogue. The control group included 21 patients with type 1 DM (median age, 40 [23; 63] years), who continued their treatment with a long-acting insulin analogue glargine. At baseline and at week 12 after switching to insulin degludec, we assessed HbA1c level, mean insulin dose, depression score, diabetes-dependent quality of life and patient satisfaction with the treatment with the use of the Russian versions of the diabetes-specific questionnaires “Audit of Diabetes-Dependent Quality of life” (RuADDQoL), and “Diabetes Treatment Satisfaction Questionnaire” (DTSQ), respectively.Results: At 3 months, there was a significant reduction of the HbA1c levels in the main and the control groups to 7.57% (Ме 7.5 [7.1; 8.4]; р=0.03) and 8.18% (Ме 7.8% [7.4; 8.7]; р=0.04), respectively. The mean reduction of this parameter under treatment with degludec was slightly higher than under treatment with glargine (0.73 vs 0.57%, respectively), at 3 months the difference being statistically significant (p=0.034). To achieve an equivalent glycemic control, the mean daily dose of insulin degludec was reduced by 26%. Switching to insulin degludec was associated with a significant reduction in non-severe hypoglycemia rates by 45% (р<0.001). In the main group, there was an improvement of the mean total weighted score of Ru-ADDQoL from -2.2 (Ме -1.28 [-2; -0.86]) at baseline to -1.5 (Ме -1.28 [-2; -0.86]) at 12 week, with positive changes in the most domains, demonstrating the improvement of quality of life In the reference group, the mean total weighted Ru-ADDQoL score at 3 months increased 0.4 (Me 0.1 [-0.56; -1] to -1.51 (Me -1.23 [-2; -1]). In the glargine group there were no significant changes on any of the Ru-ADDQoL domains. There was a significant improvement in the patients satisfaction with treatment in the degludec group, with an increase of the average DTSQ score by 5 in 3 months of therapy.Conclusion: Based on the results of this short-term observational study, the following conclusion can be drawn: treatment with insulin degludec in type 1 DM is as effective as treatment with insulin glargine; however, it allows for reduction of the mild hypoglycemia rates by 45%. Therefore, this insulin can be recommended, first of all, to those type 1 DM patients who demonstrate substantial glycemic fluctuations, frequent hypoglycemia, hypoglycemic unawareness or who do not achieve the glycemic goals of treatment. Finally, this would lead to better health-related quality of life and more treatment satisfaction.

Current trends in the diagnosis and management of gestational diabetes mellitus in the United States*

Objective: To assess current practice patterns among members of the Society for Maternal–Fetal Medicine (SMFM) with respect to the diagnosis and management of gestational diabetes mellitus (GDM).Methods: A 38 question survey on GDM diagnosis and management was distributed to SMFM members.Results: 2330 SMFM members were surveyed with a 40% response rate. Overall, 90.6% of respondents recommend a 2-step (versus a 1-step) diagnostic test. Cutoff values for the 1-h-50 g glucose challenge test vary from 130–140 mg/dL, but the majority (83%) adopts Carpenter Coustan criteria for the 3-h-100 g oral glucose tolerance test. The majority recommend glucose testing four times a day, with 55% preferring post-prandial testing at 2 h. Glyburide is used by 57% as a first-line agent, while 4% use metformin. Long-acting insulin analogs (glargine and/or detemir) are used by 46% and 33.6% of respondents, respectively. Antenatal testing is recommended by 38.7% for diet-controlled GDM compared to 98.7% for pharmacologically controlled GDM, with 56% starting by 34 weeks gestation. Most respondents recommend delivery of diet-controlled GDM at 40 weeks and pharmacologically controlled GDM at 39 weeks. Most (69%) offer elective cesarean section for an estimated fetal weight of >4500 g.Conclusions: There is significant variation in the diagnosis and management of GDM among SMFM members.

Comparative effectiveness and safety of three different basal insulins in patients with type 2 diabetes in a real world setting (ORBIT): a multicentre, prospective, registry study

BackgroundThe three most commonly used basal insulins in patients with type 2 diabetes are neutral protamine Hagedorn (NPH) insulin and the long-acting insulin analogues glargine and detemir. Although randomised controlled trials have shown equivalent efficacy of these three insulins, inconsistencies in safety exist. We aimed to assess the safety and efficacy of these three basal insulins in real-world clinical setting in the ORBIT (Observational Registry for Basal Insulin Treatment) study. MethodsIn this multicentre, 6 month, prospective, registry study, patients were recruited between Nov 25, 2011, and Sept 1, 2014, who were aged 18–80 years, with type 2 diabetes that was inadequately controlled (HbA1C ≥7%, 53 mmol/mol) with oral antidiabetic drugs and who were willing to start treatment with basal insulin were enrolled from 209 hospitals in eight regions of China. Patients who were prescribed any type of insulin in the past 2 years, with clinically significant acute major organ or systemic disease or other condition judged by the investigator that would create difficulty for the 6 month follow-up, or current or planned pregnancy or lactating women were excluded. Type and dose of basal insulin were at the physician's discretion and at the patients' willingness. Assessments were done at baseline (0 month—visit 1), mid-term (3 months—visit 2), and at the end of the study (6 months—visit 3) by investigators during routine practice. During analysis, patients were separated into NPH, glargine, and detemir insulin groups according to their initial prescription of basal insulin. Outcomes included the change in concentration of HbA1c, hypoglycaemia rate, and bodyweight change in the three groups from baseline to 6 months. Propensity scores with regression adjustment were used to balance the baseline differences among the three groups. Intention-to-treat analysis was used to assess the outcomes. FindingsOur findings show that treatment with long-acting insulin analogues is associated with better glycaemic control and less hypoglycaemia and weight gain than treatment with NPH insulin in patients with type 2 diabetes. Interpretation16 341 patients were analysed in the intention-to-treat group and 9002 were analysed in the per-protocol group. In the intention-to-treat population, there were 11 290 (69%) patients treated with glargine, 2135 (13%) patients treated with detemir, and 18% (2916) patients treated with NPH insulin. After controlling for the baseline and process variables in the propensity score regression, the intention-to-treat analysis showed that the reductions in HbA1c in the glargine (2%, SD 2·1, p=0·0014) and detemir (2%, 2·1, p=0·0065) groups were higher than that in the NPH group (2%, 2·2). The detemir group had lower weight gain (−0·1 kg, SD 2·9) than the glargine group (0·1 kg, 3·0; p=0·032) and the NPH group (0·3 kg, 3·1; p<0·0001). Patients in the glargine group had the lowest rate and frequency of minor hypoglycaemia when compared with those in the determir group (10% and 27%, respectively, both p<0·0001) and NPH group (13% and 27%, respectively, both p<0·0001). Whereas no difference was noted in severe hypoglycaemia among the three groups. The rates of severe hypoglycaemia were 0·5% in the glargine group, 0·7% in the determir group, and 0·5% in the NPH groupy (p=0·32 in total), and the frequency of severe hypoglycaemia in the three groups were 6·2, 4·9, and 5·5 times per person per year, respectively (p=0·20 in total). FunderSanofi (Shanghai, China).

Effect of the long-acting insulin analogues glargine and degludec on cardiomyocyte cell signalling and function.

BackgroundThe effects of insulin on cardiomyocytes, such as positive inotropic action and glucose uptake are well described. However, in vitro studies comparing long-acting insulin analogues with regard to cardiomyocyte signalling and function have not been systematically conducted.MethodsInsulin receptor (IR) binding was assessed using membrane embedded and solubilised IR preparations. Insulin signalling was analysed in adult rat ventricular myocytes (ARVM) and HL-1 cardiac cells. Inotropic effects were examined in ARVM and the contribution of Akt to this effect was assessed by specific inhibition with triciribine. Furthermore, beating-rate in Cor.4U® human cardiomyocytes, glucose uptake in HL-1 cells, and prevention from H2O2 induced caspase 3/7 activation in cardiac cells overexpressing the human insulin receptor (H9c2-E2) were analysed. One-way ANOVA was performed to determine significance between conditions.ResultsInsulin degludec showed significant lower IR affinity in membrane embedded IR preparations. In HL-1 cardiomyocytes, stimulation with insulin degludec resulted in a lower Akt(Ser473) and Akt(Thr308) phosphorylation compared to insulin, insulin glargine and its active metabolite M1 after 5- and 10-min incubation. After 60-min treatment, phosphorylation of Akt was comparable for all insulin analogues. Stimulation of glucose uptake in HL-1 cells was increased by 40–60 %, with a similar result for all analogues. Incubation of electrically paced ARVM resulted for all insulins in a significantly increased sarcomere shortening, contractility- and relaxation–velocity. This positive inotropic effect of all insulins was Akt dependent. Additionally, in Cor.4U® cardiomyocytes a 10–20 % increased beating-rate was detected for all insulins, with slower onset of action in cells treated with insulin degludec. H9c2-E2 cells challenged with H2O2 showed a fivefold increase in caspase 3/7 activation, which could be abrogated by all insulins used.ConclusionsIn conclusion, we compared for the first time the signalling and functional impact of the long-acting insulin analogues insulin glargine and insulin degludec in cardiomyocyte cell models. We demonstrated similar efficacy under steady-state conditions relative to regular insulin in functional endpoint experiments. However, it remains to be shown how these results translate to the in vivo situation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0410-9) contains supplementary material, which is available to authorized users.

Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations.

The chemical induction of diabetes with STZ has gained popularity because of the relative ease of rendering normal animals diabetic. Insulin substitution is required in STZ-rats in long-term studies to avoid ketoacidosis and consequently loss of animals. Aim of the present studies was to test different insulin preparations and different ways of administration in their ability to reduce blood glucose in STZ-induced diabetic rats. Single dosing of the long-acting insulin analogue glargine was able to dose-dependently reduce blood glucose over 4 h towards normoglycemia in STZ-treated rats. However, this effect was not sustained until 8 h post injection. A more sustained glucose-lowering effect was achieved using insulin-releasing implants. In STZ-rats, 1 insulin implant moderately lowered blood glucose levels 10 days after implantation, while 2 implants induced normoglycemia over the whole day. According to the glucose-lowering effect 1 as well as 2 insulin implants significantly reduced HbA1c measured after 26 days of implantation. In line with the improved glucose homeostasis due to the implants, urinary glucose excretion was also blunted in STZ-treated rats with 2 implants. Since diabetic nephropathy is one of the complications of longterm diabetes, renal function was characterized in the STZ-rat model. Increases in creatinine clearance and urinary albumin excretion resemble early signs of diabetic nephropathy. These functional abnormalities of the kidney could clearly be corrected with insulin-releasing implants 27 days after implantation. The data show that diabetic STZ-rats respond to exogenous insulin with regard to glucose levels as well as kidney parameters and a suitable dose of insulin implants for glucose control was established. This animal model together with the insulin dosing regimen is suitable to address diabetes-induced early diabetic nephropathy and also to study combination therapies with insulin for the treatment of type 1 diabetes.

The beneficial effect of insulin degludec on nocturnal hypoglycaemia and insulin dose in type 1 diabetic patients: a systematic review and meta-analysis of randomised trials.

Insulin degludec is a new-generation ultra-long-acting basal insulin which offers a significantly more predictable glucose-lowering effect than other long-acting insulin analogues. The aim of this study was to compare the effect of treatment with insulin degludec and long-acting insulin analogues glargine and detemir in type 1 diabetic (T1D) patients by means of a systematic review and meta-analysis. The following electronic databases were searched up to January 2014: MEDLINE, EMBASE and The Cochrane Library. Additional references were obtained from the reviewed articles. There were included randomised controlled trials of at least 12-week duration with basal-bolus regimen therapies in T1D patients. Current analysis included four studies involving 1,846 T1D patients. The combined data from all trials showed a statistically significant reduction in the basal insulin dose (MD -0.042, 95 % CI -0.067 to -0.018, p = 0.001) and the total daily insulin dose (MD -0.072, 95 % CI 0.016 to -0.027, p = 0.002) in the degludec group compared to other long-acting analogues. There was also a significant reduction of nocturnal hypoglycaemia in the degludec group compared to the controls (rate ratio 0.697, 95 % CI 0.617-0.786, p = 0.000). There were no differences between the groups in terms of glycated haemoglobin values, fasting plasma glucose (FPG) and adverse events. Basal-bolus treatment with insulin degludec was superior to long-acting insulin analogues detemir and glargine in reducing the rate of nocturnal hypoglycaemia. In comparison with other long-acting analogues, treatment with insulin degludec was safe and patients obtained similar metabolic control expressed by HbA1c and FPG levels with the added benefit of a reduced basal and total insulin dose.

Pharmacotherapy in Type 1 Diabetes

Pharmacotherapy in Type 1 Diabetes

Risk of diabetic foot ulceration during treatment with insulin glargine and NPH insulin

To evaluate the effect of the long-acting basal insulin analog glargine compared with neutral protamine Hagedorn (NPH) insulin on the incidence of diabetic foot ulceration (DFU) in patients with diabetes in Germany. A retrospective cohort study was performed using a representative German database (IMS Disease Analyzer) of patients with type 2 diabetes, who started a basal insulin therapy with either insulin glargine or NPH insulin, between July 2000 and September 2007, and continued this therapy for at least 24 months, and whose data were continuously documented.The occurrence of DFU was recorded beginning in the third year after therapy initiation and Kaplan-Meier curves were generated and compared using log-rank tests. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for the incidence of DFU. Patients who fulfilled the inclusion criteria (n=23 395) had started either on insulin glargine (n=9638) or on NPH insulin (n= 13 757).After adjustment for demographic and clinical variables, it was demonstrated that the relative risk to diabetes patients of developing DFS is 64% lower with insulin glargine than with NPH insulin therapy (HR=0.6 I; p=0.0405). The results suggest that, compared with NPH insulin, insulin glargine therapy significantly reduces the risk of DFS in patients with diabetes under real life conditions. Prospective long-term trials are needed to confirm these secondary data analysis results. There were no external sources of funding for this study.The authors have no conflicts of interest to declare.

Health economic evaluation of insulin glargine vs NPH insulin in intensified conventional therapy for type 1 diabetes in Germany

Objective:Basal insulin analogs are well established in the treatment of type 1 diabetes in Germany. However, little is known about their economic impact. The aim of this study for an adult population was to compare, from the perspective of the Statutory Health Insurance (SHI), the cost effectiveness of the long-acting insulin analog glargine (GLA) with intermediate-acting neutral protamine Hagedorn (NPH) insulin in basal bolus therapy, considering the interaction between glycemic control and the rate of hypoglycemia.Methods:A validated discrete event simulation model was adapted to the German setting to project clinical and cost outcomes over 40 years. Resources were valued with German official prices in 2009/2010 Euros. Health-related disutilities were taken from UK sources. Patient characteristics and risk factors were partially extracted from German sources in a sensitivity analysis.Results:In the base-case analysis, GLA was dominant as it increased life expectancy by 0.196 years and improved quality-adjusted life-years (QALYs) by 0.396 units while at the same time leading to savings of €5246 each per patient after 40 years compared to NPH. These results were robust in the sensitivity analyses. Monte Carlo simulation confirmed dominance of GLA in 70% (life-years gained) and 80% (QALYs gained) of the iterations. The price of GLA had the highest impact on savings. In extreme scenarios, incremental cost-effectiveness ratios increased up to €9576 per QALY gained. Limitations of the evaluation included no myocardial re-infarction(s) and no recurrent stroke(s), patient characteristics, risk factors, and disutilities from the UK due to scarce data in Germany, and that not all diabetes-related direct costs were included, namely insulin pens and blood glucose meters.Conclusion:GLA appears to be cost effective or even cost saving among type 1 diabetics with basal bolus therapy from the perspective of SHI compared to NPH depending on the scenario chosen.

Comment on: Morden et al. Further Exploration of the Relationship Between Insulin Glargine and Incident Cancer: A Retrospective Cohort Study of Older Medicare Patients. Diabetes Care 2011;34:1965–1971

Readers of this journal will be familiar with the four studies published simultaneously in Diabetologia in June 2009 relating the long-acting insulin analog glargine to an increased risk of cancer incidence, notably breast cancer (1–4). The four studies were justifiably criticized on design, analysis, and interpretation and were, without argument, inconclusive (5). The recent study by Morden et al. (6) exploring associations between insulin, glargine, and incident cancer in the older patient Medicare database has unfortunately perpetuated these study design weaknesses, and contrary to the authors’ conclusions, the results are far from reassuring. There are five issues that seriously limit the interpretation of this study. First, …

Application of an Insulin Analogue in Six Hypoglycemia-Prone Hemodialysis Patients with Type 2 Diabetes

Day-to-day insulin requirements often change due to subtle variations in insulin metabolism in patients with type 2 diabetes undergoing hemodialysis. In such cases, intra-hemodialysis hypoglycemia frequently occurs and is a main factor interfering with the delivery of dialysis. As a result, it reduces the quality of life in patients undergoing hemodialysis. The long-acting insulin analogue glargine provides peakless, continuous release over 24 h that approximates a normal basal insulin pattern. Because it has no peak, its use in patients with diabetes undergoing hemodialysis would hypothetically be useful. Specifically, patients would be able to avoid intra-hemodialysis hypoglycemia without the necessity of skipping insulin administration on the day of hemodialysis and achieving adequate glucose control on other days. We recently experienced six cases that switched from treatment with intermediate-acting insulin to a long-acting insulin analogue, which provided better glycemic control by reducing hypoglycemia risk. Limited data are available in the literature concerning insulin analogue usage in patients with diabetes undergoing hemodialysis. Our experience suggests a large-scale prospective investigation is required on this issue. (Korean J Med 2012; 83:647-653)

Insulin Analogs and Cancer

Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time-course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart, and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R), prevalent activation of the extracellular-signaling-regulated kinase (ERK) rather than the protein kinase B (PKB/AKT) intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to receptors for insulin but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine) may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin analogs.

Pharmacotherapy of diabetes and cancer risk

Lines of reports published recently analyzing the association between pioglitazone use and bladder cancer and the subsequent actions taken by regional regulatory agencies and international diabetes organizations rekindle a longrunning controversy over diabetes treatment and cancer risk. An interim report of an ongoing cohort study, one of the representative papers published in the April issue of Diabetes Care, examined the association between pioglitazone therapy and the risk of bladder cancer in 193,099 diabetic patients in the Kaiser Permanente Northern California (KPNC) Diabetes Registry between 1997 and 2002. The patients were C40 years of age and the group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among those who did not use pioglitazone. Overall, the short-term use of pioglitazone was not associated with a risk of bladder cancer [HR 1.2 (95% CI 0.9–1.5)], but its use for more than 2 years was weakly associated with an increased risk (OR 1.4, 95% CI 1.03–2.0) [1]. Surprisingly, France suspended the use of pioglitazone at the beginning of June 2011 and Germany has recommended that pioglitazone should not be started in new patients, based on a recently conducted retrospective cohort study by the French National Health Insurance Agency (Caisse National d’Assurance Maladie) which followed diabetic patients taking antidiabetic medicines between 2006 and 2009. The US Food and Drug Administration (FDA) soon issued a Drug Safety Communication on June 15, 2011 (updated on August 5) regarding the ongoing safety review of pioglitazone and the increased risk of bladder cancer [2]. Based on a review of the data from the KPNC epidemiological study, FDA stated that the long-term use of pioglitazone ([1 year) may be associated with an increased risk of bladder cancer. The FDA acknowledged that the finding was still of nominal statistical significance, and is advising health-care professionals not to use it in patients with active bladder cancer and to prescribe the drug with caution for patients with a prior history of bladder cancer, weighing the benefits of blood glucose control against the unknown risks of cancer recurrence. One month after the FDA’s communication, the European Medicines Agency (EMA) issued a recommendation and the EMA’s Committee for Medicinal Products for Human Use concluded that the benefits of pioglitzone outweigh its risks in a limited population of type 2 diabetes patients, despite the small risk of bladder cancer with this drug. The Committee has made recommendations to reduce the risk of bladder cancer in patients taking the medicines [3]. The series of events mentioned above reminded us of a recent outbreak of controversy related to a possible association between the long-acting insulin analog glargine and an increased risk of cancer. On June 2009, the diabetes community was suddenly shaken with a story relevant to patients with diabetes treated with insulin, when four registry studies that analyzed the association of insulin glargine with the risk of cancer were published in Diabetologia. The American Diabetes Association (ADA) immediately released a statement noting that ‘‘findings from these research papers are conflicting and inconclusive, and the ADA cautions against over-reaction and advises patients using insulin not to stop taking it until more information is available.’’ Regulatory agencies such as the EMA and FDA, international organizations such as the International Diabetes Federation (IDF), K. Kaku (&) M. Hashiramoto Division of Diabetes, Metabolism, and Endocrinology, Kawasaki Medical School, Kurashiki, Japan e-mail: kka@med.kawasaki-m.ac.jp

Diabetes and Ramadan: An Update On Use of Glycemic Therapies During Fasting

The fasting of Ramadan is observed by a large proportion of Muslims with diabetes. Recommendations for the management of diabetes during Ramadan were last published in 2005 by the American Diabetes Association. Several studies in this field have since been published, some addressing the use of new pharmacological agents in managing diabetes during Ramadan. The incritin memetics are potentially safe during Ramadan; the DPP4 inhibitors vildagliptin and sitagliptin provide an effective and safe therapeutic option, administered either alone or in combination with metformin or sulfonylureas. There are no published studies on the use of GLP-1 receptor agonists during Ramadan. Among the sulfonylureas, gliclazide MR (modified release) and glimepride can be safely used during Ramadan, but glibenclamide should be avoided due to the associated risk of hypoglycemia. In selected patients with type 1 and type 2 diabetes, the long-acting insulin analogues glargine and detemir, as well as the premixed insulin analogues, can be used with minimal risk of metabolic derangement or hypoglycemia; the risk is higher in type 1 diabetes. Insulin pumps can potentially empower patients with diabetes and enable safe fasting during the month of Ramadan. Further clinical trials are needed to evaluate the safety and efficacy of new antidiabetic agents and new diabetes-related technologies during Ramadan.

Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study

It has been hypothesized that incidence of and mortality from several malignancies are increased among diabetic patients. Whether certain treatment modalities, including use of metformin, sulfonylureas, or insulins, affect cancer incidence or mortality and whether use of long-acting insulin analogues glargine and detemir may increase cancer incidence more than traditional human insulins are debated. The objective was to investigate the association between specific glucose-lowering agents and cancer incidence in diabetic members of an Israeli health maintenance organization. We studied a cohort of 36,342 diabetic patients aged at least 18 years with no history of cancer or treatment with insulin as of January 1, 2003. For the period from January 2003 to December 2007, we searched pharmacy records for purchases of glucose-lowering agents, including metformin, sulfonylureas, human insulin, and analogue insulins. Incident cancer diagnoses were identified from the health maintenance organization cancer registry. We studied the association of cancer incidence with the use of specific glucose-lowering agents, controlling for age, sex, and baseline glycohemoglobin measurement. Cancer was diagnosed in 6% of the study cohort during 164,652 person-years of follow-up time. Cancer incidence increased with age and varied with medication purchasing patterns. On multivariate analysis, age (hazard ratio [HR], 1.049; confidence interval [CI], 1.045-1.052), male sex (HR, 1.16; CI, 1.065-1.264), and number of insulin purchases (HR, 1.007; CI, 1.001-1.012) were significantly associated with increased cancer risk, whereas number of metformin purchases was associated with reduced cancer risk (HR, 0.996; CI, 0.994-0.998). Male sex, age, and human insulin purchases were associated with increased cancer incidence, whereas metformin purchases were associated with decreased cancer risk. There was a trend for increased cancer incidence associated with use of long-acting insulin analogues, but the number of long-acting insulin analogue users was too small for risk estimates to be conclusive.

Therapeutic effects of metformin in breast cancer: involvement of the immune system?

Breast cancer and associated diabetes mellitus have gained raising interest as an elevated risk of breast cancer prognosis resulting in increased mortality in diabetic patients. In this context, the long-acting insulin analog glargine and other antidiabetics have been discussed to promote tumorigenesis. In contrast, the biguanide class oral antidiabetic metformin has been shown capable of enhancing cell cycle arrest and inducing apoptosis as well as reducing growth factor signaling. Consequently, several studies are underway to evaluate a possible role of metformin in breast cancer treatment. Although mechanisms involved are not definitely clear yet, here, we discuss metformin's anticancer effects including the potential impact of the immune system.

How Basal Insulin Analogs Have Changed Diabetes Care

How Basal Insulin Analogs Have Changed Diabetes Care