Comparative Efficacy of Dual and Single Initiation of Add-On Oral Antihyperglycemic Agents in Type 2 Diabetes Uncontrolled on Metformin Alone: A Systematic Literature Review and Network Meta-Analysis

Abstract

Introduction Current guidelines recommend adding an oral antihyperglycemic agent (AHA) to metformin in patients with type 2 diabetes mellitus (T2DM) uncontrolled on metformin. Recent randomized clinical trials (RCTs) have demonstrated that adding dual AHAs instead of a single AHA provided more effective glycemic control. However, the comparative efficacy of approved single and dual initiation strategies is unknown. Therefore, we conducted a Bayesian network meta-analysis to compare the efficacy of dual and single add-on oral AHAs in patients uncontrolled on metformin. Methods A systematic literature review of RCTs was conducted following Cochrane and ISPOR guidelines. MEDLINE, Embase, and CENTRAL were searched from inception to November 19, 2019. Approved oral doses of sodium–glucose co-transporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in single or dual initiation therapies were indirectly compared. Outcomes focused on efficacy and included mean change from baseline in hemoglobin A1c (HbA1c), weight, systolic blood pressure (SBP), diastolic blood pressure, and achieving HbA1c target < 7% at 24–26 weeks. Fixed and random effects models with Markov chain Monte Carlo simulations were used. Results Of 1955 unique records screened, 25 RCTs (14,264 participants) were included. In patients uncontrolled on metformin, dual AHA added to metformin had statistically significant or a trend of greater reduction in HbA1c compared to single AHAs, with ertugliflozin + sitagliptin showing the greatest improvement. Statistically significant reductions in weight and SBP were observed with ertugliflozin + sitagliptin, ertugliflozin, or canagliflozin compared to single initiation DPP-4 inhibitors. Conclusion For reduction of HbA1c, weight, and SBP in patients uncontrolled on metformin, add-on dual AHAs showed greater improvement compared to single AHAs. These findings can further inform the treatment of T2DM patients uncontrolled on metformin. Supplementary Information The online version of this article (10.1007/s13300-020-00975-y) contains supplementary material, which is available to authorized users.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience

“…As shown in various studies, canagliflozin use was associated with the maximum HbA1c reduction compared to the other 2 SGLT-2i agents in our study[ 15 , 29 , 30 ]. However, the median HbA1c reduction was higher than that observed in clinical trials and meta-analyses presumably from the reasons as mentioned above (see dapagliflozin section).…”

Adherencia terapéutica en pacientes con diabetes tipo 2 en tratamiento con metformina y sitagliptina

“…Asimismo, es importante valorar si esta persistencia se encuentra relacionada con la disminución en el porcentaje de hemoglobina glucosilada como se ha reportado en otros estudios. 20 En Malasia, se llevó a cabo un estudio que incluyó a 497 pacientes con dm2 y se utilizó la escala mmas-8, de acuerdo con los resultados se reportó un predominio de adherencia media. 21 En cuanto a la primera pregunta de la escala, dicho estudio reportó que cerca de la mitad de los pacientes no olvidaba tomar sus medicamentos.…”

Cardiovascular and mortality benefits of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists as third-step glucose-lowering medicine in patients with type 2 diabetes: a retrospective cohort analysis

“…A recent network meta-analysis demonstrated similar HbA1c reductions for different combinations of dual therapy added to metformin. 31 Outcomes All patients in each subgroup were included in the model for the mortality outcome, but patients were excluded from the models for other outcomes if they had an event in the year before starting third-step treatment or if they had only 1 month of exposure time. Overall patient counts and unadjusted rates for the mortality, MACE, and HF hospitalization outcomes are displayed in table 2.…”