Reports

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PRIORITY PRESS - 73rd Scientific Sessions of the American Diabetes Association (ADA)

Chicago, Illinois / June 21-25, 2013

Chicago - New therapeutic options for insulin-dependent diabetes are inching closer to the ideal of predictable blood glucose control over each 24-hour dosing period, according to large trial data presented at the ADA. Relative to the standard regimens they will replace, the newer therapies reduce abnormal glycemic excursions at periods of peak risk, including hypoglycemia at night or during exercise and hyperglycemia after meals. The opportunity for improved blood glucose control is not restricted to a single class. Newer insulins are being designed to deliver flatter steady state pharmacokinetics (PK), while drugs from new therapeutic classes, particularly activators of the glucagon-like peptide-1 (GLP-1) incretin, show promise for adjunctively preserving the simplicity of a once-daily treatment regimen when insulin alone is insufficient. The ability of these therapies to sustain control, reflected in HbA_1c values, have obvious implications for circumventing micro- and macrovascular complications.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The history of insulin-dependent diabetes is marked by a series of incremental advances that have increased the predictability of control while simplifying therapy. The introduction of once-daily dosing of insulin through long-acting basal insulin analogs advanced the predictability and simplicity of blood glucose control, but subsequent advances have been focused on further reducing risk of abnormal glycemic excursions. Often, these have involved complicated combinations of short- and long-acting insulins, but new data presented at the ADA this year suggest it may be possible to keep regimens simple.

“The options continue to expand, but we continue to look for opportunities to further improve basal insulins, notably with regard to further reduction in the risk of hypoglycemia as well as more convenient dosing,” observed Dr. Matthew C. Riddle, Oregon Health & Science University, Portland, Oregon. Lead author of the latebreaking EDITION 1 trial, which was updated at the ADA, Dr. Riddle said one of the most promising areas is improving the PK of the long-acting basal insulin analogs simply because these already have a well-established efficacy and safety profile.

New Findings

The EDITION 1 trial tested this premise. In the study, a new insulin glargine formulation of 300 U/mL (Gla-300) was compared to the standard. The more favorable steady state of the Gla-300 formulation relative to the conventional 100 U/mL dose (Gla-100), has been demonstrated in several studies, most recently a crossover euglycemic clamp study presented at this year’s ADA (Dahmen et al. ADA 2013; Abs 113-OR). The longer and flatter PK profile of Gla-300 relative to Gla-100 in that study of 30 patients with type 1 diabetes (DM1) was shown to exert tighter blood glucose control by greatly extending insulin concentrations in the therapeutic range for each once-daily dose.

Evaluating the clinical significance of this PK difference was the objective of the multicenter, randomized, double-blind EDITION 1 study (Riddle et al. ADA 2013; Abs 43-LB). To test the incremental advantage of a flatter but more extended PK curve, one of the key efficacy end points was the comparison of nocturnal hypoglycemic events in the last 3 months of the study. Overall efficacy, safety, and tolerability in this phase 3a trial, which randomized 807 patients in 14 participating countries to Gla-300 or Gla-100, were also monitored and compared.

The incremental advantage of the longer PK was demonstrated across multiple end points. As expected, reductions in HbA_1c at 6 months did not differ between study arms (-0.83% in both groups), but the percentage of patients reporting at least 1 severe or confirmed nocturnal hypoglycemic event from month 3 to 6 was 36.1% in the Gla-300 group and 46% in the Gla-100 group. This represented a relative risk (RR) reduction of 21% (RR 0.79; 95% CI 0.67 - 0.93; P=0.0045). The incidence of hypoglycemia was also significantly lower on the Gla-300 dose when stratifications were made for any nocturnal episode (45.3% vs. 59.7%), any daytime episode (81.2% vs. 85.8%), any severe episode (5.0% vs. 5.7%), or any hypoglycemic event (83.4% vs. 88.6%).

“The expectation was for a lower risk of hypoglycemia at night, but there was a lower risk of severe or confirmed hypoglycemia on Gla-300 at any time of the 24-hour day across the entire study period,” Dr. Riddle reported.

The concern about risk for episodes of hypoglycemia has also driven clinical studies of other long-acting insulin analogs, such as detemir and degludec. Degludec, in particular, has an ultra long-acting profile that offers the potential for infrequent dosing but at the potential cost of unfavorable blood glucose excursions with changes in activity and energy demand. However, a meta-analysis of 7 randomized treat-to-target trials directly comparing this agent to Gla-100 regarding risk of exercise-related hypoglycemic episodes was reassuring (Heller et al. ADA 2013 Abs 742-P). The cumulative data with more than 4500 patients and more than 3000 confirmed hypoglycemic episodes found relative risk of events to be comparable on both long-acting agents.

Improving Control

The issue of inadequate control of blood sugar as insulin-dependent diabetes progresses was also addressed in new data presented at the ADA. Not unsurprisingly, the steady-state effect of long-acting basal insulin analogs is typically challenged by meal-related hyperglycemia. Of new classes of agents, GLP-1 receptor agonists may represent the most attractive adjunctive agents for those experiencing postprandial hyperglycemia on their current insulin regimen. Several agents in this class, including exenatide, dulaglutide, lixisenatide, and albiglutide, are available or in late stages of clinical testing. As a class, these drugs are associated with a low risk of hypoglycemia and have favorable metabolic effects, such as improving satiety and opposing weight gain.

GLP-1 receptor agonists have been most widely studied in type 2 diabetes (DM2) as add-ons to oral therapies such as metformin, but new data at the ADA document a benefit as adjunctive therapy in the management of insulin-dependent diabetes. There is now a large experience with lixisenatide, a relatively short-acting but once-daily GLP-1 receptor agonist now marketed in Europe. In initial studies with oral antidiabetic combinations, this agent repeatedly demonstrated particular efficacy in control of postprandial hyperglycemia. The potential for therapeutic gain in insulin-dependent patients was tested in post-hoc analyses pooled phase 3 data presented at the ADA (Riddle et al. ADA 2013; Abs. 941-P).

The 24-week, placebo-controlled phase 3 studies were similarly designed. Insulin-dependent DM2 patients with insufficiently controlled HbA_1c (>7%) were randomized to receive once-daily lixisenatide or placebo in addition to their insulin. Patients on insulin already on oral antidiabetic therapies were included. The efficacy end points included HbA_1c as well as the 7-point structured self-monitoring blood glucose (SMBG) profile, which captures postprandial hyperglycemic excursions.

An improvement in HbA_1c was associated with lixisenatide, but the advantage, as predicted by the study hypothesis, was exerted almost entirely through improved control of postprandial hyperglycemia. Overall, the HbA_1c levels were reduced from baseline by 0.77% in the lixisenatide arm and 0.29% (P<0.0001) in the placebo arm. In the SMBG analysis, the advantage of lixisenatide on basal exposure, unlike the advantage on postprandial exposure (P<0.0001 vs. placebo), did not reach significance. 

A meta-analysis of the same data presented with a more global summary of outcomes emphasized the same postprandial effect (Charbonnel et al. ADA 2013; Abs 1047-P). According to Dr. Bernard Charbonnel, the lead author, those randomized to lixisenatide were more likely overall to reach HbA_1c <7% without weight gain and with no episodes of symptomatic hypoglycemia relative to basal insulin alone, but the relative improvement in postprandial blood glucose control is the noteworthy finding of the trial.

“The different target of activity of lixisenatide makes this add-on ideal for intensification for patients insufficiently controlled with basal insulin alone,” Dr. Charbonnel reported.

The same strategy is being evaluated with the GLP-1 agonist exenatide. In a randomized non-inferiority trial evaluating this GLP-1 agonist, 637 patients with uncontrolled postprandial hyperglycemia on basal insulin glargine were randomized to exenatide twice daily or the short-acting insulin lispro three-times daily (Diamant et al. ADA 2013; Abs 70-OR). At the end of 12 weeks, the 1.1% HBA_1c reduction from baseline on exenatide reached superiority relative to the 1.0% reduction (P=0.03) on insulin lispro. Although GI adverse events were more frequent on exenatide, there were fewer hypoglycemic excursions and greater weight loss in this group. The authors concluded that exenatide is an attractive alternative adjunctive to bolus insulin for insulin-dependent patients requiring postprandial blood glucose control.

With an expanding array of therapeutic options for control of insulin-dependent diabetes, the goal will be to identify these types of combinations which provide added value on a simple dosing scheme to achieve the goals of tight blood glucose control with a low risk of hypoglycemia. Even among insulin-dependent patients, the optimal combination is not likely to be uniform but influenced by lifestyle considerations. Yet, trials presented at the 2013 ADA suggest the optimal characteristics of antidiabetic drugs alone or in combination are being increasingly well described.

Conclusion

New data presented at ADA define strategies that were associated with incremental gains in the management of insulin-dependent diabetes relative to standard approaches. While long-acting basal insulins are an attractive choice in many such patients, these studies document efforts to employ favorable changes in PK to improve the predictability of drug effects. When combined with simple strategies to boost control as insulin therapy fails, these strategies address efficacy and risk simultaneously.