The “Old” Oral Antidiabetics

Abstract

Treatment of patients with type 2 diabetes aims to avoid acute symptoms of hyperglycemia and to prevent macro- and microvascular complications. In recent years, the number of glucose-lowering drugs increased to unprecedented levels. The American Diabetes Association (ADA) lists seven drug classes of available glucose-lowering agents in the last edition of their standards of medical care in diabetes (American Diabetes Association, Diabetes Care 44(Suppl 1):S111–S124, 2021). All are proven to decrease HbA1c-levels or postprandial glucose excursions, but evidence on patient-relevant outcomes, such as cardiovascular mortality, amputations, or retinopathy, is sparse. Reduction of HbA1c-values is often used as a surrogate outcome measure to assess the efficacy of antidiabetic medication. However, its appropriateness has been disproven (Buhse et al., Novelties in diabetes, endocrine development, Karger, Basel, 2015; Bousageon, Br J Clin Pract 67:85–87, 2017). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (Gerstein et al., N Engl J Med 358: 2545–2559, 2008; Tian et al., Diabetes Care 43:1293–1299, 2020) and the Veterans Affairs Diabetes Trial (VADT) (Duckworth et al., N Engl J Med 360:129–139, 2009; Reaven et al., N Engl J Med 380:2215–2224, 2019), a rigid treatment regime with low HbA1c-targets did not result in better patient-relevant outcomes. Patients in the intervention arm of the ACCORD study even had a higher risk of mortality, and consequently, the study was terminated earlier (Gerstein et al., N Engl J Med 358: 2545–2559, 2008). Other drugs have been withdrawn from the market because of a negative benefit-risk ratio, for example, phenformin, which increased the risk of lactic acidosis or rosiglitazone that reduced HbA1c-values but increased cardiovascular risk (Wallach et al., BMJ 368:I7078, 2020). In recent years, pharmaceutical companies decided to withdraw several new antidiabetic agents from the German market, such as vildagliptin and canagliflozin, because no additional benefit over usual care could be demonstrated and therefore health insurances would not have covered additional costs.