Comparing the effectiveness of glucose-lowering agents: real-world data to emulate a four-arm target trial

We read the study by Yan Xie and colleagues1Xie Y Bowe B Xian H Loux T McGill JB Al-Aly Z Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.Lancet Diabetes Endocrinol. 2023; 11: 644-656Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar with great interest. The study filled a gap in the evidence for the cardiovascular effects of diabetes medications by using an original method of emulation of a randomised pragmatic clinical trial. The findings of the study showed that SGLT2 inhibitors and GLP-1 receptor agonists were superior to DPP-4 inhibitors in reducing major adverse cardiovascular events (MACE) and that DPP-4 inhibitors reduced MACE more than sulfonylureas. Since the effects of four different agents on MACE were compared with themselves, no judgment can be made as to how much they reduce MACE compared with placebo. The general perception in the interpretation of this study1Xie Y Bowe B Xian H Loux T McGill JB Al-Aly Z Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.Lancet Diabetes Endocrinol. 2023; 11: 644-656Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar is that sulfonylureas are neutral, DPP-4 inhibitors are more favourable than sulfonylureas, and SGLT2 inhibitors and GLP-1 receptor agonists are superior. From another perspective, the results of large-scale placebo-controlled cardiovascular outcome studies of DPP-4 inhibitors are conclusive.2Lin DS Lee JK Hung CS Chen WJ The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials.Diabetologia. 2021; 64: 2676-2686Crossref PubMed Scopus (37) Google Scholar All studies have shown that DPP-4 inhibitors are non-inferior compared with placebo, except for the study showing that saxagliptin increased hospitalisations due to heart failure.3Scirica BM Bhatt DL Braunwald E et al.Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.N Engl J Med. 2013; 369: 1317-1326Crossref PubMed Scopus (2864) Google Scholar However, the cardiovascular endpoint studies with sulfonylureas resulted in conflicting findings, either neutral or negative.4Cushman WC Evans GW Byington RP et al.Effects of intensive blood-pressure control in type 2 diabetes mellitus.N Engl J Med. 2010; 362: 1575-1585Crossref PubMed Scopus (2887) Google Scholar We want to bring attention to a pivotal message conveyed in this study1Xie Y Bowe B Xian H Loux T McGill JB Al-Aly Z Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.Lancet Diabetes Endocrinol. 2023; 11: 644-656Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar that could be overlooked. As DPP-4 inhibitors have proven to be neutral in cardiovascular protection, the higher MACE rate of sulfonylureas than DPP-4 inhibitors in this study supports the concern that sulfonylureas are not neutral and might even be detrimental to cardiovascular outcomes. With the results of this study, we believe that the possibility of sulfonylureas increasing cardiovascular risk should be noted. MK has received lectures or speaker's bureau from AstraZeneca, Novartis, NovoNordisk, Pfizer, Boehringer Ingelheim, and MSD. AO has received honoraria for consultancy or lectures or speaker's bureau from Sanofi, Bayer, AstraZeneca, Novartis, NovoNordisk, Pfizer, Boehringer Ingelheim, and MSD. OC declares no competing interests. Comparing the effectiveness of glucose-lowering agents: real-world data to emulate a four-arm target trialWe read the study by Yan Xie and colleagues1 with interest. Findings of this observational retrospective cohort study suggest that both SGLT2 inhibitors and GLP-1 receptor agonists are associated with a lower risk of major adverse cardiovascular events compared with DPP-4 inhibitors or sulfonylureas. The authors concluded that these “results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy.”1 Full-Text PDF Comparing the effectiveness of glucose-lowering agents: real-world data to emulate a four-arm target trial – Authors' replyWe thank Ali Ahmed and colleagues for their interest in our study of the comparative effectiveness of four antihyperglycaemics on the risk of major adverse cardiovascular events (MACE).1 However, they do not seem to appreciate the merit of the target trial emulation approach in general and that we leveraged this approach to address a major knowledge gap that has not been answered by any randomised controlled trial (RCT).2,3 Target trial emulation is a novel approach in pharmacoepidemiology that seeks to replicate the design of an RCT using observational data. Full-Text PDF Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health recordsBoth SGLT2 inhibitors and GLP-1 receptor agonists were associated with reduced risk of MACE compared with DPP-4 inhibitors or sulfonylureas. DPP-4 inhibitors were associated with reduced risk of MACE compared with sulfonylureas. There was no statistically significant difference in risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists. The results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy. Full-Text PDF Comparing the effectiveness of glucose-lowering agents: real-world data to emulate a four-arm target trialSGLT2 inhibitors have a protective effect for the cardiovascular system and for the kidney.1 It is recommended to add these drugs in the treatment of type 2 diabetes when cardiovascular disease or kidney disease is prevalent. However, a matter of debate is the possible usefulness of using this class of drugs in the absence of such conditions, especially in people with a recent diagnosis of type 2 diabetes. Full-Text PDF