Dose-escalated oral antidiabetic drug therapy effect may be less potent than reported

In the real-world treatment of Asian patients with type 2 diabetes mellitus (T2DM), the blood glucose-lowering benefit following oral antidiabetic drug (OAD) dose escalation is lesser than what has been reported in clinical trials, according to a study from Singapore.

“In this study, any OAD initiation … does not result in the expected magnitude of HbA1c reduction, being 3–12 mmol/mol (0.3–1.1 percent) lower compared to results from clinical trials. A review of clinical trials published [previously] found that most OADs lowered HbA1c levels by 6–14 mmol/mol (0.5–1.25 percent),” as noted by a team of investigators from the National University of Singapore (NUS). [Diabetes Care 2012;35:446-454; Diabetologia 2013;56:973-984; Clin Ther 2014;36:84-100.e9; Diabetes Care 2010;33:1859-1864]

The current analysis was conducted on 54,744, 32,262, and 7,7016 HbA1c pairs in the “no-OAD,” “nontitrator,” and “titrator” cohorts, respectively. The mean age ranged 64.0–71.9 years across the three cohorts, with slight female predominance (51.4–57.1 percent). Most patients in each cohort had hypertension (87.5–91.0 percent) and dyslipidaemia (93.5–94.0 percent).

The change in HbA1c levels due to up-titration, down-titration, and discontinuation of OADs were −1 to −8 mmol/mol (−0.1 to −0.7 percent), 1–7 mmol/mol (0.1–0.6 percent), and 2–11 mmol/mol (0.2–1.0 percent), respectively. [BMC Med 2022;doi:10.1186/s12916-021-02221-z]

Meanwhile, the HbA1c-lowering effect of initiating newer OADs, namely dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, was 8–11 mmol/mol (0.7–0.9 percent) and 7–11 mmol/mol (0.6–1.0 percent), respectively.

“One possible reason for this discrepancy is due to suboptimal medication adherence among patients in the real world. This is supported by the fact that newer single daily dose of OADs (DPP-4 inhibitors and SGLT-2 inhibitors) achieve comparable HbA1c reduction with those from clinical trials,” according to the investigators. [BMJ Open 2017;7:e016317; J Diabetes Investig 2016;7:555-564; Diabetes Obes Metab 2015;17:936-948; Diabetologia 2006;49:2564-2571]

“The simplified dosing of newer OADs is postulated to result in better medication adherence and maintain its effectiveness in real-world setting vis-à-vis to clinical trials. In contrast, patients taking multiple doses of metformin and sulphonylurea are often associated with poorer medication adherence and consequently attain lower HbA1c decline than expected,” they added. [Diabetes Ther Res Treat Educ Diabetes Relat Disord 2013;4:175-194; Diabetes Care 2012;35:446-454; Diabetologia 2013;56:973-984]

Overall, the present real-world data on Asians with T2DM in this study show that the magnitudes of OAD initiation and dose titration are marginally lower than the results from clinical trials. The investigators expect that the results will enable physicians to communicate realistic expectation of the effect of oral medications on the glycaemic control of their patients in primary care during shared decision-making in selecting treatment options.