Cardiovascular and renal outcomes of initial combination therapy with glucose‐lowering agents versus a stepwise approach in newly diagnosed or treatment‐naïve type 2 diabetes: A systematic review and meta‐analysis

Abstract Aim To evaluate the efficacy and safety of the initial combination therapy versus a stepwise approach in newly diagnosed type 2 diabetes (T2D) by conducting a systematic review and meta‐analysis of observational cohort studies and randomized controlled trials (RCTs). Methods Studies were identified from MEDLINE, Embase, the Cochrane Library, and through search of bibliographies to January 2022. Study‐specific risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results Eight articles including four unique RCTs (n = 5527 participants) and one observational cohort study (n = 200) that compared initial combination therapy versus stepwise therapy were included. The RR for myocardial infarction comparing initial combination therapy versus stepwise therapy was 1.21 (95% CI 0.74‐2.00). Initial combination therapy reduced levels of fasting plasma glucose and glycated haemoglobin: mean differences −0.97 mmol/L (95% CI −1.41, −0.53) and −24.92 mmol/mol (95% CI −25.67, −24.27), respectively. Initial combination therapy versus stepwise therapy reduced lipid levels, blood pressure and intima media thickness, with no differences in body composition variables, neuropathy, retinopathy or adverse events. Single‐study results showed that initial combination therapy reduced creatinine levels and urine albumin excretion rate. The quality of the evidence ranged from moderate to very low. Conclusions Except for improving cardiometabolic and glycaemic variables, a limited number of studies characterized by small sample sizes show that initial combination therapy for newly diagnosed T2D may be similar in efficacy and safety to stepwise therapy with respect to cardio‐renal outcomes. There is a lack of sufficient evidence to recommend initial combination therapy with glucose‐lowering agents in newly diagnosed T2D with the aim of preventing cardio‐renal outcomes. Definitive RCTs are warranted.