Sulfonylureas: Scoring beyond START STUDY.

Sir,

I read with great interest the article published in your journal titled “Comparative Evaluation of Safety and Efficacy of Glimepiride and Sitagliptin in Combination with Metformin in Patients with Type 2 Diabetes Mellitus: Indian Multicentric Randomized Trial - START Study.” This article is an eye opener for all the physicians making a key mark on the role of SUs in the management of type 2 diabetes mellitus (T2DM). For the last 60 years, sulfonylureas (SUs) have remained the mainstay of pharmacotherapy in the management of T2DM. Despite their well-established benefits, their place in therapy was inappropriately being overshadowed by newer therapies. There was a need to relook at the data on SUs and put it has a perspective to address the concerns of the treating physician.

As concluded in the published study that In T2DM patients, glimepiride/metformin combination exhibited a significant reduction in glycemic parameters as compared to sitagliptin/metformin combination. Both glimepiride and sitagliptin were well tolerated with no significant between group difference in weight and low propensity for hypoglycemia. Hence, given the good efficacy, safety profile, less hypoglycemic risk, weight neutrality, extrapancreatic effects, and many pleiotropic benefits, glimepiride is still a rational choice as an add on to metformin in T2DM patients.

I would like to share few more points regarding the same. Both metformin and SUs may reduce hepatic glucose overproduction by decreasing hepatic gluconeogenesis and glycogenolysis; however, the relative contribution of gluconeogenesis and glycogenolysis by metformin remains controversial.[12] SUs may inhibit secretion of glucagon from islets cells[3] and also stimulates glycogen synthesis in the liver.[2] A combination of two drugs with the complementary mechanism of action helps in addressing multiple etiologies of hyperglycemia.

Even SUs are associated with less risk of therapy failure than dipeptidyl peptidase-4 inhibitor (DPP-4i)[4] (adjusted hazard ratio, 1.58; 95% confidence interval: 1.48–1.68). However, SUs have been associated with higher rates of overall and cardiovascular (CV)-related mortality and CV events than Incretin mimetics. By keeping metformin + SU as reference, a significantly decreased risk of death was found among metformin + DPP-4i users (n = 11,138) with a relative risk of 0.65 (0.54–0.80) for mortality, 0.57 (0.40–0.80) for CV mortality, and 0.70 (0.57–0.85) for the combined end point.[5]

The association of glimepiride/metformin, both due to cost as well as effectiveness and safety, may be the preferential treatment for most T2DM patients, and it offers a potential advantage in refractory hyperglycemic populations, tolerant to treatment.[6] There is evidence that the effect of DPP-4i on HbA1c in Type 2 diabetes significantly declines during the second year of treatment.[7]

Given the plethora of evidence favoring modern over the older SUs, it is now time to rest the older SUs such as glibenclamide. Even as per SAFES[8] recommendation which is a consensus statement made by recommendations of 20 experts from 15 countries based on the available evidence about SUs, especially modern SUs, compared to DPP-4i, SUs demonstrate better and more durable glucose lowering efficacy; however, likelihood of body weight increase and hypoglycemia risk should be taken into consideration (Grade A, EL 1).

Hence, modern SUs (such as glimepiride and gliclazide) are backed by a large body of evidence, experience, and outcome data, which supports their role in managing patients with diabetes. Person-centered care - careful choice of SU, appropriate dosage, timing of administration, and adequate patient counseling, will ensure that deserving patients are not deprived of the advantages of this well-established class of antidiabetic agents.

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Conflicts of interest

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