Combined sulphonylurea and insulin treatment for type 2 diabetes mellitus : metabolic and electrophysiological studies

Type 2 diabetes is a prevalent disorder characterized by elevated blood glucose levels and associated with increased morbidity from micro- and macrovascular complications. Lowering of blood glucose has been shown to reduce the incidence of such complications. Since the patient population is heterogeneous and the disease progresses with time, multiple therapies become necessary in the long-term. Combining sulphonylurea (SU) with insulin is one option, and various aspects of such therapy were studied in this thesis. Study I was a double-blind randomized study where 175 patients with secondary failure to oral agents were started on insulin in addition to oral glibenclamide. Glycaemic control improved, mean HbA1c 9.65% to 7.23% at four months. A high HbA1c and preserved insulin sensitivity at baseline were associated with a greater response to insulin combined with SU. Thereafter SU was, replaced by placebo in a majority of the patients, while a smaller control group continued on SU. the placebo/SU withdrawal group, fasting blood glucose (FBG) increased >10% in 79% within weeks, and 60% of the group were classified as SU responders, defined as >40% increase in FBG. Multivariate logistic regression analyses showed no clinically useful patient characteristics that identified SU responders at baseline, but long diabetes duration and absence of GAD antibodies were associated with beneficial response. A short period of SU withdrawal appeared as a useful test to determine whether a patient still benefits from SU. In Study II 80 patients with secondary SU failure were randomized to two principally different insulin regimens - bedtime NPH or preprandial regular insulin - in addition to SU. Both regimens had similar effects on HbA1c but weight gain was more pronounced in patients on pre-prandial insulin. Patients who participated in Studies I and 11 at Danderyd Hospital were included in a follow-up over a median of 69 months (Study III). During this time four patients died and six were reclassified as having type I diabetes. Glycaemic control was maintained at an improved level with mean HbA1c 7.4% (SD 1.1) and weight stabilized after an initial gain of approximately 5 kg the first year. When necessary metformin was added to SU and insulin, and at 54 months about half were on such triple therapy. Hypoglycaemia is a limiting factor in attaining glycaemic goals in diabetes. Physiological responses to low blood glucose include decrease of insulin secretion and increase of counterregulatory hormones, the most important being glucagon and adrenaline. Study IV showed that glibenclamide affected these responses during insulin-induced hypoglycaemic clamp experiments in 13 patients with type 2 diabetes. When SU was present, insulin secretion was less suppressed and the glucagon response to hypoglycaemia was blunted. In Study V measurements of QT intervals were used to study the effects of hypoglycaemia on cardiac repolarization in 13 patients. Mean QT intervals and QT dispersion increased significantly during hypoglycaemia, indicating an increased risk of arrhythmia at low blood glucose values. No significant changes were seen between the two experiments with or without glibenclamide but the number of patients was too small to give conclusive data regarding this issue. In summary, more studies regarding SU effects on glucagon secretion and cardiac repolarization are needed and should include comparisons of different SU derivatives. The present studies provide both pros and cons for combining glibenclamide with insulin in patients with type 2 diabetes who no longer can attain glycaemic goals on oral therapy alone; but the advantages seem to outweigh the possible disadvantages

Cost-effectiveness of switching to insulin degludec from other basal insulins: evidence from Swedish real-world data

<p><b>Objectives:</b> Health economic analysis from a healthcare and societal point of view was conducted to assess the cost-effectiveness of insulin degludec (IDeg) after switching from other basal insulins in people with type 1 diabetes.</p> <p><b>Material and methods:</b> This was a prospective, open-label, single arm, observational follow-up from August 2013 to October 2015 of 476 consecutive patients at Danderyd Hospital (Stockholm, Sweden) who switched to IDeg from other basal insulins (99% basal insulin analogs). The IMS CORE Diabetes Model (CDM) was used to predict the cost-effectiveness of life-long treatment with IDeg vs. other basal insulins, based on a Swedish setting.</p> <p><b>Results:</b> Mean (SD) duration of follow-up was 21.7 (6.0) weeks. Mean HbA_1c decreased by 2.7 mmol/mol, mean basal insulin dose decreased by 13.1% (<i>p</i> < .0001), and mean bolus insulin dose decreased by 7.5% (<i>p</i> < .0001) after switching. Frequencies of non-severe daytime hypoglycemia and non-severe nocturnal hypoglycemia decreased by 12% (<i>p</i> = .0127) and 53% (<i>p</i> < .0001) respectively and severe hypoglycemia was reduced by 62% (<i>p</i> = .0225). The CDM predicted a gain in life expectancy of 0.33 years, a discounted gain in quality-adjusted life-years (QALYs) of 0.54, and lower estimated direct lifetime healthcare costs of SEK 22,757 for patients switching to IDeg. The incremental cost-effectiveness ratio (ICER) showed IDeg as dominant (i.e. higher effectiveness with a lower cost). Sensitivity analyses confirmed the results.</p> <p><b>Conclusion:</b> Based on this prospective, real-world, follow-up and using the CDM, it was estimated that switching to IDeg from other basal insulins translated into QALY gains including improved life expectancy and health-related quality of life, as well as dominant ICER, meaning cost-savings for the healthcare system. However, the study is limited by its observational design. Extrapolation into the future is only estimated since the actual treatment effect cannot be projected with certainty.</p

Clinical use of insulin degludec

The limitations of current basal insulin preparations include concerns related to their pharmacokinetic and pharmacodynamic properties, hypoglycaemia, weight gain, and perception of management complexity, including rigid dosing schedules. Insulin degludec (IDeg) is a novel basal insulin with improved pharmacokinetic and pharmacodynamic properties compared to insulin glargine (IGlar) including a long half-life of ∼25 h and a duration of action >42 h at steady state, providing a flat and stable blood glucose-lowering effect when injected once daily. Evidence from phase 3a clinical trials with a treat-to-target design in patients with type 1 and type 2 diabetes has shown that IDeg has similar efficacy to IGlar, with a 9% and 26% reduction in risk of overall and nocturnal hypoglycaemia, respectively (in the pooled population) during the entire treatment period, and a 16% and 32% reduction during the maintenance period, respectively. Given its pharmacodynamic properties, IDeg offers a broad dosing window, allowing for flexible dose administration, if required. Two different formulations of IDeg are available (100 units/mL [U100] and 200 units/mL), the latter providing the same IDeg dose as the U100 formulation in half the injection volume. The unique pharmacokinetic profile of IDeg facilitates glycaemic control while minimising the risk of nocturnal hypoglycaemia