The challenges and pitfalls of incorporating evidence from cardiovascular outcomes trials in health economic modelling of type 2 diabetes.

The clinical evidence base for evaluating modern type 2 diabetes interventions has expanded greatly in recent years, with numerous efficacious treatment options available (including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors). The cardiovascular safety of these interventions has been assessed individually versus placebo in numerous cardiovascular outcomes trials (CVOTs), statistically powered to detect differences in a composite endpoint of major adverse cardiovascular events. There have been growing calls to incorporate these data in the long-term modelling of type 2 diabetes interventions because current diabetes models were developed prior to the conduct of the CVOTs and therefore rely on risk equations developed in the absence of these data. However, there are numerous challenges and pitfalls to avoid when using data from CVOTs. The primary concerns are around the heterogeneity of the trials, which have different study durations, inclusion criteria, rescue medication protocols and endpoint definitions; this results in significant uncertainty when comparing two or more interventions evaluated in separate CVOTs, as robust adjustment for these differences is difficult. Analyses using CVOT data inappropriately can dilute clear evidence from head-to-head clinical trials, and blur healthcare decision making. Calibration of existing models may represent an approach to incorporating CVOT data into diabetes modelling, but this can only offer a valid comparison of one intervention versus placebo based on a single CVOT. Ideally, model development should utilize patient-level data from CVOTs to prepare novel risk equations that can better model modern therapies for type 2 diabetes.

A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine Hagedorn in type 1 diabetes.

OBJECTIVE: This randomized controlled trial aimed to compare the efficacy and safety of insulin detemir (IDet) with neutral protamine Hagedorn (NPH), both with insulin aspart, in pregnant women with type 1 diabetes. The perinatal and obstetric pregnancy outcomes are presented. METHODS: Subjects were randomized to IDet (n = 152) or NPH (n = 158) ≤12 months before pregnancy or at 8-12 gestational weeks. RESULTS: For IDet and NPH, there were 128 and 136 live births, 11 and 9 early fetal losses, and two and one perinatal deaths, respectively. Gestational age at delivery was greater for children from the IDet arm than the NPH arm (treatment difference: 0.49 weeks [95% CI 0.11;0.88], p = 0.012, linear regression). Sixteen children had a malformation (IDet: n = 8/142, 5.6%; NPH: n = 8/145, 5.5%). The incidence of adverse events was similar between treatments. CONCLUSION: IDet is as well tolerated as NPH as regards perinatal outcomes in pregnant women with type 1 diabetes and no safety issues were identified.

Safety of once-daily insulin detemir in patients with type 2 diabetes treated with oral hypoglycemic agents in routine clinical practice.

BACKGROUND: The aim of the present study was to identify demographic and treatment factors that were predictive of hypoglycemia in a large cohort of type 2 diabetic patients initiating insulin detemir. METHODS: The present 24-week observational study of insulin initiation included 17 374 participants from 10 countries. Severe hypoglycemia was defined as an event requiring third party assistance; minor hypoglycemia was defined as a daytime or nocturnal glucose measurement <3.1 mmol/L. RESULTS: Prior to initiating insulin therapy, 4.9% of the cohort reported hypoglycemia (pre-insulin hypoglycemia), with most (94.2%) reporting minor events and 9.6% reporting severe events. Compared with patients without pre-insulin hypoglycemia, those with pre-insulin hypoglycemia had a higher incidence of events of minor hypoglycemia (1.72 vs 4.46 events per patient-year [ppy], respectively), nocturnal hypoglycemia (0.25 vs 1.09 events ppy, respectively), and severe hypoglycemia (<0.01 vs 0.04 events ppy, respectively) at final visit. Age (P < 0.047), body mass index (P < 0.001), a prior history of microvascular disease (P < 0.001), pre-insulin hypoglycemia (P < 0.001), increased number of oral hypoglycemic agents (OHAs; P < 0.001), OHA intensification (P < 0.001), and the use of glinides (P = 0.004) were all found to be independently associated with the occurrence of hypoglycemia during the study. CONCLUSIONS: Once-daily insulin detemir therapy was safe and effective, and rates of hypoglycemia were low. Concerns about hypoglycemia should not deter the initiation of basal insulin analogs.

Diversity in diabetes: the role of insulin aspart.

Diabetes management is changing not only with novel treatments but also in patient demography. This presents clinical challenges and influences our view of diabetes therapies. Insulin analogues have been developed to overcome some of the limitations of traditional human insulins, with the aim of providing a more physiological pharmacokinetic/pharmacodynamic profile. The rapid-acting insulin analogue insulin aspart has been investigated in many clinical trials over the past 10 years and the aim of this review is to present the insulin aspart clinical trial data from across the spectrum of patients with diabetes. Five studies have looked at insulin aspart use (including continuous subcutaneous insulin infusion) in children and adolescents, where the analogue was as effective and well tolerated as soluble human insulin. One large-scale, randomized, controlled trial in pregnant women with type 1 diabetes observed trends towards a reduction in major hypoglycaemia, fewer preterm deliveries and lower birthweight with insulin aspart compared with soluble human insulin. Two 6-month, randomized, controlled, multicentre, multinational, parallel-group, open-label trials reported significant reductions in haemoglobin A(1c) and major nocturnal hypoglycaemia with insulin aspart compared with soluble human insulins in patients with type 1 diabetes. There are fewer data involving insulin analogue use in hospitals and in elderly patients with diabetes, but some recent studies have investigated insulin aspart in the emergency department, intensive/non-intensive care setting and in a pharmacokinetic/pharmacodynamic study in patients aged ≥ 65 years. In summary, the evidence would suggest that insulin aspart is suitable for use in a variety of patients with diabetes.