Two recent studies provided results from the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness (GRADE) Study, which randomized 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 to the addition of insulin glargine U-100, the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase-4 inhibitor sitagliptin. One study reported on the trial's primary metabolic outcome of HbA1c levels of 7.0% or higher, while the other looked at microvascular and cardiovascular (CV) outcomes with the four drug classes.
The two studies were published by the New England Journal of Medicine on Sept. 22, 2022, and were summarized in the October 2022 ACP Diabetes Monthly. The following commentary by Krysta Brown, DO, FACP, and Anthony A. Donato, MD, MHPE, MACP, was published in the ACP Journal Club section of Annals of Internal Medicine on Jan. 3.
The GRADE comparative effectiveness trial evaluated 4 commonly used glycemic-lowering medications added to metformin in patients with type 2 diabetes. Patients received maximum-dose metformin in keeping with established guidelines, broadening the trial's applicability. The trial included a diverse population (19.8% Black, 18.6% Hispanic), attempting to replicate the large incidence of diabetes in these real-world populations. Patients had a mean baseline HbA1c level of 7.5%, representing a population with fairly well-controlled and relatively recently diagnosed (mean 4.2 y since diagnosis) diabetes, and a mean body mass index of 34 kg/m2. They also had overall low CV risk—only 6% had previous CV disease. The choice of metformin plus study drug fit well with the goal of reducing HbA1c level to <7% in this population.
The authors concluded that “microvascular complications and death were not materially different among the four treatment groups.” Although liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduced CV disease events compared with other drugs, the study was not powered to detect this difference. Fewer moderate albuminuria events occurred than expected in the trial's initial power calculations, opening the possibility for a type II error. Although outcomes were meticulously measured and loss to follow-up was low (6.2%), differences in complication rates could take >5 years to become apparent.
The GRADE trial allows us to make inferences about the role of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors in practice. 77% of the sitagliptin (DPP-4 inhibitor) group did not attain an HbA1c level <7.0%, the poorest performance of the 4 trial groups, with a higher failure rate than the other 3 groups in the first year (55% vs. <40%). Given lackluster glycemic control, no benefit for CV or microvascular outcomes, and a price of about $500/mo, the utility of DPP-4 inhibition over other study medications or newer agents is questionable. Liraglutide had better glycemic control, more weight loss, and a CV benefit, making it our preferred choice for any well-insured patient willing to consider an injection. Glimepiride, a sulfonylurea, failed to attain HbA1c goals for 72% of patients, which was slightly better than sitagliptin, but it had the highest rate of severe hypoglycemia, albeit the rate was low at 2.2%. Over 4 years, patients receiving glimepiride lost 0.73 kg, which is counter to clinical observations. Sulfonylureas are low cost and widely available. With modest efficacy and no substantial harm, they remain useful for patients who lack access to more efficacious medications with secondary benefits.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors were not included in the GRADE trial because they received U.S. Food and Drug Administration approval after trial planning was underway. U.S. guidelines recommend SGLT2 inhibitors plus metformin alongside GLP-1 receptor agonists as initial agents for patients with CV or chronic kidney disease (grade A recommendation). The GRADE trial findings are not applicable to patients with poorly controlled diabetes (e.g., with symptoms, HbA1c level >10%, or blood glucose >300 mg/dL [16.7 mmol/L]), for whom guidelines recommend insulin first (grade E recommendation).
The GRADE trial provides useful data to help clinicians compare glycemic-lowering agents for patients with early diabetes and low CV risk. It also shows the sobering nature of diabetes progression. 71% of patients did not meet or maintain HbA1c levels <7.0% despite regular visits and the addition of insulin and nonstudy drugs. Additional comparative effectiveness trials are needed to determine which medications provide greatest benefit for reducing the complications of diabetes.