Relationship of glycaemic control and hypoglycaemic episodes to 4-year cardiovascular outcomes in people with type 2 diabetes starting insulin

AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time-dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p < 0.0001]. CV death [HR 1.31 (95% CI 1.10-1.57); p = 0.0027] and stroke [HR 1.36 (95% CI 1.17-1.59); p < 0.0001] were both strongly associated with HbA1c, while MI was not [HR 1.05 (95% CI 0.83-1.32)]. One or more severe hypoglycaemic episodes affected 175 participants, while 1508 participants experienced one or more symptomatic hypoglycaemic events. We found no relationship between severe/symptomatic hypoglycaemic events and CV-specific/all-cause death. CONCLUSIONS: Ongoing poorer glucose control was associated with CV events; hypoglycaemia was not associated with CV-specific/all-cause death

An overview of insulin therapy for the non-specialist

\ua9 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley &amp; Sons Ltd.Nearly all health professionals, whatever their practice or speciality, now have contact with a significant number of insulin-using people with diabetes. People with type 1 diabetes are nearly universally managed on more complex insulin regimens, increasingly with complex support technology, and with some understanding of the concepts underlying these needed by anyone with responsibility for other aspects of their health care. People with type 2 diabetes usually come to insulin therapy in time, now with a prevalence for insulin administration of ≈50%, thanks to improved management of associated health risks giving longer life expectancy. But while some understandings have simplified the usual approach (basal insulin, self-adjustment dose algorithms), the advent of other medical products offering cardio-renal protection, the use of insulin in combination with these, and the marketing of novel insulin analogues and biosimilars, have all added complexity to clinical decision making. However for the insulin user in the mainstream of care (ambulatory diabetes services in primary and secondary care) the broad principles of choice and management of insulin therapy are fairly easily applied. In the current article, the complexity is dissected and addressed, some of the stigma around insulin therapy is neutralised, and the fundamental approach in regular care drawn into focus. Plain Language Summary: Insulin therapy is used in their diabetes lifetime by nearly all people with type 2 diabetes (T2DM), as well as in all people with type 1 diabetes (T1DM). In T2DM this is in the context of the usual progression of islet B-cell secretory failure, but also very often in the context of other conditions, from cancer or steroid therapy to acute arterial events or major surgery. Its prescription in these circumstances means that, in pharmaco-epidemiological studies, insulin use is invariably associated with poor health outcomes, but in a series of major RCTs of 5–15 years duration no excess of vascular or oncological adverse health outcomes was found. Physiologically insulin secretion occurs in two scenarios, namely basal insulin at night and between meals (≈50%), and in short (≈4 h) bursts with meals (≈50%). The former suppresses liver glucose production, which in its absence causes plasma glucose to rise threefold to around 12 mmol/l (but much higher if metabolic stress or with sugar-containing drinks). Meal-time insulin secretion in addition promotes glucose storage in skeletal muscle. People with T1DM, having no endogenous insulin secretion, thus require a multiple injection regimen (basal + meal-time), or pumped insulin, often now moderated by continuous glucose monitoring (CGM). Basal and meal-time preparations of pharmaceutical insulin analogues are also used for T2DM, with GLP-1RA and metformin usually continued. The starting regimen is normally basal only, usually with insulin glargine (100 U/ml), originator or biosimilar, while insulin degludec or glargine 300 U/ml can have advantage as basal insulins where true 24-h cover is found to be needed. Weekly insulins (developmental or marketed) may have a role in injection acceptability in T2DM, at a cost of some increase in hypoglycaemia. In ambulatory care a meal-time insulin analogue, originator or biosimilar, is added when required, often after some years on basal insulin. Meal insulins are also used in insulin pumps. Hypoglycaemia is a significant issue in T1DM, limiting insulin dosing, but can be helped by CGM, with or without pumps, and careful dose adjustment. It is a much lesser issue in T2DM, until meal-time insulins are introduced, or in people of thinner phenotype, whence again expertise in dose adjustment may be needed. Body weight gain with insulin is usually modest, particularly if basal insulin is begun appropriately before glycosuria has influenced calorie balance. In mainstream ambulatory care the broad principles of insulin therapy are fairly easily applied, the main resources being team familiarity with a basal insulin (glargine/biosimilar), a finger-prick glucose-monitoring system, basic patient education on use of these, and time to supervise dose titration. Beginning with a fixed dose (e.g. 10 U/day) and increasing by 2 U twice a week is simple, but may take months of persistent input to reach target fasting plasma glucose levels. In conclusion, insulin is a usual therapy in both T1DM and T2DM, and in the latter initially at least is fairly easily applied, in combination with other glucose-lowering agents. However it can be more challenging in the context of the technology used in T1DM, once meal-time insulin is added to basal in T2DM, and when dose requirements are complex and unstable in conjunction with other medical conditions

Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin

Aims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. Methods Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. Results Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. Conclusion/interpretation Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin

Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage

Contains fulltext : 88447.pdf (publisher's version ) (Closed access)AIMS/HYPOTHESIS: The mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy. METHODS: We conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (or=2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume. RESULTS: Thirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (DeltaTERalb: rosiglitazone +2.43 +/- 0.45%/h, placebo -0.11 +/- 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation. CONCLUSIONS/INTERPRETATION: Rosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00422955. FUNDING: GlaxoSmithKline.1 september 201

Cost-effectiveness of insulin analogs from the perspective of the Brazilian public health system

ABSTRACT Human insulin is provided by the Brazilian Public Health System (BPHS) for the treatment of diabetes, however, legal proceedings to acquire insulin analogs have burdened the BPHS health system. The aim of this study was to perform a cost-effectiveness analysis to compare insulin analogs and human insulins. This is a pharmacoeconomic study of cost-effectiveness. The direct medical cost related to insulin extracted from the Ministry of Health drug price list was considered. The clinical results, i.e. reduction in glycated hemoglobin (HbA1c), were extracted by meta-analysis. Different scenarios were structured to measure the uncertainties regarding the costs and reduction in HbA1c. Decision tree was developed for sensitivity of Incremental Cost Effectiveness Ratio (ICER). A total of fifteen scenarios were structured. Given the best-case scenario for the insulin analogs, the insulins aspart, lispro, glargine and detemir showed an ICER of R$1,768.59; R$ 3,308.54; R$11,718.75 and R$ 2,685.22, respectively. In all scenarios in which the minimum effectiveness was proposed, lispro, glargine and detemir were dominant strategies. Sensitivity analysis showed that the aspart had R$3,066.98 [95$ 6,163.97 [95% CI: 3919.29; 11401.57] for incremental costs. We concluded there was evidence that the insulin aspart is the most cost-effective

Drug safety of rosiglitazone and pioglitazone in France: a study using the French PharmacoVigilance database

International audienceBackgroundThiazolidinediones (TZDs), rosiglitazone (RGZ) and pioglitazone (PGZ) are widely used as hypoglycemic drugs in patients with type 2 diabetes mellitus. The aim of our study was to investigate the profile of adverse drug reactions (ADRs) related to TZDs and to investigate potential risk factors of these ADRs.MethodsType 2 diabetic patients were identified from the French Database of PharmacoVigilance (FPVD) between 2002 and 2006. We investigated ADR related to TZD, focusing on 4 ADR: edema, heart failure, myocardial infarction and hepatitis corresponding to specific WHO-ART terms.ResultsAmong a total of 99,284 adult patients in the FPVD, 2295 reports concerned type 2 diabetic patients (2.3% of the whole database), with 161 (7%) exposed to TZDs. The frequency of edema and cardiac failure was significantly higher with TZDs than in other patients (18% and 7.4% versus 0.8% and 0.1% respectively, p ConclusionsThiazolidinediones exposure is associated with an increased risk of edema and heart failure in patients with type 2 diabetes even when recommendations for use are respected. In contrast, the risk of hepatic reactions and myocardial infarction with this class of drugs seems to be similar to other hypoglycemic agents