Spotlight on diabetes drug class comparisons

A large trial compared insulin, a sulfonylurea, a glucagon-like peptide-1 (GLP-1) receptor agonist, and a dipeptidyl peptidase-4 inhibitor as second-line therapy, while a modeling study considered GLP-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors as first-line agents.

Recent studies compared drugs for type 2 diabetes on glycemic control, cardiovascular and microvascular outcomes, and cost.

Two reports from the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness (GRADE) Study were published by the New England Journal of Medicine on Sept. 22. That trial included 5,047 patients with type 2 diabetes of less than 10 years' duration who had HbA1c levels of 6.8% to 8.5% and were taking metformin. They were randomized to the addition of insulin glargine U-100, the sulfonylurea glimepiride, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, or the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin. A noted limitation of the trial was the exclusion of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, due to the timing of their FDA approval. Patients were followed for a mean of 5.0 years.

One study reported on the trial's primary metabolic outcome of an HbA1c of 7.0% or higher, finding that insulin and liraglutide performed better than glimepiride and sitagliptin (26.5, 26.1, 30.4, and 38.1 outcomes per 100 participant-years, respectively). The same trend was seen on the secondary outcome of an HbA1c level of 7.5% or above. Severe hypoglycemia was significantly more common with glimepiride (2.2%) than with insulin (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Patients assigned to liraglutide reported more gastrointestinal side effects and lost more weight than those in the other groups. The authors concluded that all four medications decreased HbA1c levels but that insulin and liraglutide were “significantly, albeit modestly, more effective” at achieving and maintaining glycemic control. “The major implication of the current trial is that maintenance of target glycated hemoglobin levels is challenging, even in a clinical trial in which all care is provided free of charge. The data highlight the need for more effective interventions for long-term control of glycemia in persons with type 2 diabetes,” they wrote.

The other study of the same trial looked at microvascular and cardiovascular outcomes with the four drug classes. It found no material differences among the groups in development of hypertension or dyslipidemia or microvascular complications. The treatment groups also had similar rates of major cardiovascular events, hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality. There were small differences in the development of any cardiovascular disease, with the liraglutide group having a slightly lower rate of events per 100 participant-years (1.4 vs. 1.9 in the insulin and glimepiride groups and 2.0 in the sitagliptin group). Overall, the results show that these secondary outcomes did not differ materially among the medication classes, the authors said. “These results should not be viewed as definitive proof that GLP-1 receptor agonists reduce the incidence of cardiovascular disease in low-risk populations. However, our results parallel the benefits with respect to cardiovascular disease that have been reported in populations with type 2 diabetes mellitus and higher cardiovascular risk at baseline than the population in the current trial,” they added.

An accompanying editorial noted that “it is not surprising that insulin glargine was efficient” and that the potency of liraglutide had already been shown in a trial. The study population was at relatively low risk for hypoglycemia and thus the findings on that outcome may not be generally applicable, the editorialist added. “The mean 5-year follow-up was presumably too short to expect robust effects on cardiovascular outcomes in the low-risk trial population, so there are unanswered questions beyond those related to microvascular outcomes,” said the editorial. “The data confirm that older generic or biosimilar low-cost agents still have a role in the treatment of persons with early type 2 diabetes who are at low cardiovascular risk.”

Finally, another recent study, published by Annals of Internal Medicine on Oct. 4, considered the use of SGLT-2 inhibitors and GLP-1 receptor agonists as first-line therapies for diabetes. Compared to metformin, SGLT-2 inhibitors and GLP-1 receptor agonists would lead to lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke, according to the study's Markov modeling. However, SGLT-2 inhibitors cost $43,000 and added 1.8 quality-adjusted months ($478,000 per quality-adjusted life-year [QALY]). GLP-1 receptor agonists actually reduced QALYs compared with metformin because of the impact of injections, “a nontrivial source of concern from the patients' perspective,” said the authors. Even removing that factor, injectable GLP-1 receptor agonists cost $327,000 per QALY and oral versions cost $823,000 per QALY. To be cost-effective (<$150,000 per QALY), SGLT-2 inhibitors would need to cost under $5 per day and oral GLP-1 receptor agonists under $6 per day, reductions of 70% and 90%, respectively, from current prices, the authors said. “In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT-2 inhibitor and GLP1 receptor agonist medication costs substantially for patients with type 2 to improve health outcomes and prevent exacerbating diabetes health disparities,” they wrote.