insulin-degludec and Cardiovascular-Diseases

The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older.. A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs).. Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes.. There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.. We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome.. Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups.. Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Kaplan-Meier Estimate; Male; Middle Aged

DEVOTE was designed to evaluate the cardiovascular safety of insulin degludec (IDeg) vs insulin glargine U100 (IGlar) in patients with T2D at high risk of cardiovascular events. DEVOTE is a phase 3b, multicenter, international, randomized, double-blind, active comparator-controlled trial, designed as an event-driven trial that would continue until 633 positively adjudicated primary events were accrued. The primary end point was the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Patients with T2D at high risk of cardiovascular complications were randomized 1:1 to receive either IDeg or IGlar, each added to background therapies. This trial was designed to demonstrate statistical noninferiority of IDeg vs IGlar for the primary end point. DEVOTE enrolled 7,637 patients between October 2013 and November 2014 at 436 sites in 20 countries. Of these, 6,506 patients had prior cardiovascular disease or chronic kidney disease, and the remainder had multiple cardiovascular risk factors. DEVOTE was designed to provide conclusive evidence regarding the cardiovascular safety of IDeg relative to IGlar in a high-risk population of patients with T2D.

Topics: Aged; Angina, Unstable; Cardiovascular Diseases; Comorbidity; Coronary Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Heart Failure; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Stroke

Real-world evidence of the safety of insulin degludec compared with insulin glargine U100 is sparse. This study sought to investigate the risk of major cardiovascular events, severe hypoglycaemia, and all-cause mortality after initiation of degludec or glargine U100 in the population of Denmark.. All Danish people with diabetes initiating treatment on degludec (n=5159) or glargine (n=4041) in 2016 to 2017 were included in the study. The effect of insulin treatment on the endpoints of major cardiovascular events, severe hypoglycaemia, and all-cause mortality was analysed with Cox proportional hazard models. The models were adjusted for age, sex, diabetes duration, diabetes type, highest completed education, and annual income. The model of severe hypoglycaemia was also adjusted for severe hypoglycaemia prior to baseline. The model of mortality was also adjusted for history of alcohol abuse, use of antidepressants, use of opioids, and use of anxiolytics. Lastly, the models of major cardiovascular events and mortality were also adjusted for Charlson comorbidity index.. Use of degludec resulted in an almost twofold decrease in risk of death (hazard rate [HR]: 0.54, 95% CI: 0.44-0.65) compared with use of glargine. No statistically significant risk changes were found for major cardiovascular events (HR: 0.86, 95% CI: 0.62-1.19) and severe hypoglycaemia (HR: 1.13, 95% CI: 0.66-1.93). The proportion of cause of death due to malignant neoplasm of pancreas was almost doubled for glargine compared with degludec.. These results indicate that insulin degludec has a safer profile with respect to all-cause mortality as compared with insulin glargine U100.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Male; Prognosis; Risk Factors; Survival Rate

In this post hoc analysis we investigated the effects of insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus comparators on cardiovascular (CV) risk markers in participants in the DUAL II (vs. insulin degludec), DUAL V (vs. insulin glargine 100 units/mL) and DUAL VII (vs. basal-bolus therapy) trials, grouped by sex, age (<65 years, ≥65 years) and diabetes duration (<10 years, ≥10 years). Treatment contrasts were in favour of IDegLira in many subgroups for changes from baseline in glycated haemoblogin (DUAL II, DUAL V), body weight (all three trials), systolic blood pressure (BP; all three trials), HDL cholesterol (DUAL VII) and LDL cholesterol (DUAL II, DUAL V). Higher heart rates were seen with IDegLira versus comparators (all three trials) plus significantly higher diastolic BP in men (DUAL V). Differences in treatment effect were seen between sexes in waist circumference (DUAL II), systolic BP (DUAL II, DUAL V) and triglycerides (DUAL VII), and between diabetes durations in LDL cholesterol (DUAL V). In conclusion, IDegLira is associated with a general improvement in CV risk markers compared with basal insulin or basal-bolus therapy after 26 weeks of treatment.

Topics: Aged; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Liraglutide; Male; Middle Aged; Risk Factors; Waist Circumference

To evaluate the short-term cost-effectiveness of insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) from a Canadian public healthcare payer perspective in patients with type 2 diabetes (T2D) who are at high risk of cardiovascular events and hypoglycaemia.. A decision analytic model was developed to estimate costs (2017 Canadian dollars [CAD]) and clinical outcomes (quality-adjusted life years [QALYs]) with degludec vs glargine U100 over a 2-year time horizon. The model captured first major adverse cardiovascular event, death, severe hypoglycaemia and insulin dosing. Clinical outcomes were informed by a post hoc subgroup analysis of the DEVOTE trial (NCT01959529), which compared the cardiovascular safety of degludec and glargine U100 in patients with T2D who are at high cardiovascular risk. High hypoglycaemia risk was defined as the top quartile of patients (n = 1887) based on an index of baseline hypoglycaemia risk factors.. In patients at high hypoglycaemia risk, degludec was associated with mean cost savings (CAD 129 per patient) relative to glargine U100, driven by a lower incidence of non-fatal myocardial infarction, non-fatal stroke and severe hypoglycaemia, which offset the slightly higher cost of treatment with degludec. A reduced risk of cardiovascular death and severe hypoglycaemia resulted in improved effectiveness (+0.0132 QALYs) with degludec relative to glargine U100. In sensitivity analyses, changes to the vast majority of model parameters did not materially affect model outcomes.. Over a 2-year period, degludec improved clinical outcomes at a lower cost as compared to glargine U100 in patients with T2D at high risk of cardiovascular events and hypoglycaemia.

Topics: Aged; Canada; Cardiovascular Diseases; Cost Savings; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Treatment Outcome

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Topics: Canagliflozin; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Treatment Outcome

Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms, particularly cancer. Clinical experience with insulin degludec in pregnant women is very limited. It is therefore best to avoid using this analogue during pregnancy. In France, the concentration of all other insulins injected with a syringe or prefilled pen is 100 units per ml. The new concentration of 200 units per ml contained in insulin degludec prefilled pens creates a risk of confusion and overdose. In practice, there is already a relatively wide range of options available for patients with type 1

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Patient Selection; Risk Assessment; Risk Factors; Treatment Outcome

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Approval; Europe; European Union; Female; Government Agencies; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Male; Product Surveillance, Postmarketing; Public Health; United States; United States Food and Drug Administration