Between September 15 and 19, the European Association for the Study of Diabetes (EASD) meeting took place in Vienna, Austria, celebrating its 50th anniversary. One of the hot topics discussed at the conference were the SGLT-2 inhibitors, with two years treatment data now providing longer-term efficacy and safety data. Another highly appreciated topic was the GLP-1 agonists; liraglutide, with its potential usage in the obese type 2 diabetes (T2D) population, and exenatide, with its long-term DURATION-1 study, both attracting a great deal of attention and a big audience. After discussing new insulin preparations and their potential to demonstrate superiority over existing combination therapies, the conference ended with a discussion about the most-used diabetes drug in the world: metformin.
To pick up only a few of those main points:
Empagliflozin's 104 week study (EMPA-REG H2H-SU)
In a randomized, double-blind, active comparator, Phase III study (EMPA-REG H2H-SU), Boehringer Ingelheim/Eli Lilly's SGLT-2 inhibitor empagliflozin demonstrated sustained reductions in HbA1c over 104 weeks as an add-on to metformin therapy, as well as reductions in body weight and blood pressure (BP). In comparison to glimepiride, empagliflozin achieved significantly greater reductions from baseline in HbA1c, body weight, and systolic BP (-0.11%, -4.5%, and -5.6%, respectively). Physicians complimented the study design in general; however, they raised concerns about the representativeness of the study, given that glimepiride had not been fully up-titrated to the maximum dose during the trial.
Fixed dose combination (FDC) therapies
Another study compared the empagliflozin/linagliptin FDC against each of the single therapies alone, showing a persistent (although not completely additive) HbA1c lowering effect. However, this was not the case for all patient populations and strengths of the drug, as the FDC with only 10 mg empagliflozin did not show significantly better results compared to 10 mg empagliflozin monotherapy in patients with HbA1c 8.5% at baseline. Nonetheless, the presenter stated that the superior efficacy results in certain subgroups opens thoughts about triple combination therapies of empagliflozin, linagliptin, and metformin. However, if we look at the recent reaction of the FDA, polypills certainly failed to impress the advisory committee: the FDA has turned down NDAs for both a combination of beta-blocker and angiotensin receptor blocker (nebivolol/valsartan) and a combination of an antihypertensive, aspirin, and a statin. In terms of insulin combinations, physicians at the EASD conference did not seem impressed about the combination injection IDegAsp (70% insulin degludec + 30% insulin aspart), despite reductions in the number of injections per day, and therefore patient burden by up to 50%.
Liraglutide 3.0 mg, the SCALE study
The GLP-1 agonist liraglutide 3.0 mg is currently being investigated in the SCALE study. After 56 weeks, liraglutide 3.0 mg showed greater improvements in glycemic control and systolic BP versus placebo, and greater improvements in HbA1c reduction than the 1.8 mg formulation. However, this reduction was not significant in patients achieving HbA1c <7.0%, and was modest in patients achieving HbA1c < 6.5%, which raised the question among physicians whether it is worth the additional anticipated cost (possibly double the price of liraglutide 1.8 mg). During the off-treatment follow-up study, weight regain occurred with both liraglutide doses, although mean weight loss from baseline remained significantly greater in the 3.0 mg group compared to placebo. In my opinion it would have been interesting to see half the patients remain on liraglutide (both doses) for the extended 12 weeks, and then compare the results to the patients off-treatment to show superiority in weight loss compared to those not on liraglutide. Also, the question remains whether the weight loss effect is not mainly induced by nausea, as physicians claim that the weight curves rise following one year of treatment, with the weight loss curve over time matching the nausea curve. Exenatide's long-term DURATION-1 study did not help to resolve those questions about weight regain, but at least 50% of the patients were able to maintain their HbA1c goal (either less than 7%, or 6.5%) over the six-year treatment period.
Some final thoughts and ideas for drug companies:
Over all, physicians were mainly concerned about safety signals such as lipase activity or pancreatitis in the GLP-1 analogues. Also, they appreciated glucagon measures during studies throughout the different drug classes. However, the majority of physicians would prefer to see trials comparing novel agents with active comparators rather than with placebo. Likewise, meta-analyses were not appreciated, as they do not provide the exact same baseline measures, durations, patient populations, and therapies, and therefore are not representative. Nonetheless, the vibe throughout the conference was positive. Physicians agreed that governments and the industry should work together to provide outcomes data and sustainable results, not just to make someone rich.