The present meta-analysis was conducted as part of the process of updating the Italian guidelines for the treatment of type 2 diabetes, to evaluate the cardiovascular and renal effects of glucose-lowering drugs, with studies limited to those randomised controlled trials that had externally adjudicated event outcomes. Data from 260 trials of eight drug classes (metformin, pioglitazone, alpha-glucosidase inhibitors, insulin secretagogues, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors and insulin) were analysed.
When compared with other treatments, including placebo, GLP-1 RAs (odds ratio [OR], 0.88) and SGLT2 inhibitors (OR, 0.85) were associated with significant reductions in all-cause mortality, while metformin showed a non-significant trend towards reduced mortality (OR, 0.82; 95% CI, 0.63–1.01). Insulin secretagogues were associated with increased risk (OR, 1.12), while the other agents were neutral in terms of risk.
Metformin (OR, 0.60), GLP-1 RAs (OR, 0.89), SGLT2 inhibitors (OR, 0.90) and pioglitazone (OR, 0.85) were all significantly associated with reduced risk of 3-point major adverse cardiovascular events, while insulin secretagogues were associated with an increased risk (OR, 1.19); however, this increase was no longer significant once comparisons with metformin, GLP1-RAs, SGLT2 inhibitors and pioglitazone were excluded. There was no data on alpha-glucosidase inhibitors.
Regarding hospitalisation for heart failure (HHF), only SGLT2 inhibitors were associated with reduced risk (OR, 0.68), while pioglitazone was associated with increased risk (OR, 1.30). There was no data on alpha-glucosidase inhibitors. Regarding renal outcomes, SGLT2 inhibitors were associated with reduced risk of progression of albuminuria (OR, 0.67) and serum creatinine levels (doubling of creatinine; OR, 0.58). No significant effects were observed for the other drug classes.
The authors acknowledge limitations in their study design, including the fact that many of the trials enrolled participants with very high cardiovascular risk, and thus the results might not be fully generalisable to the typical population with type 2 diabetes seen in clinical practice. On the other hand, it strengths lie in the inclusion of studies with externally adjudicated events only, as this avoids potentially misleading misclassifications of events.
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