The present network meta-analysis included the most recent published CVOTs, thus providing the most contemporary assessment of the total available evidence for DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors and their cardiorenal outcomes. The results of our analysis confirm the lack of any benefit by DPP-4 inhibitors on cardiorenal outcomes in people with type 2 diabetes (23). Although past meta-analyses reported substantial reductions in MACE with DPP-4 inhibitors (24), their conclusions were based on studies with small sample sizes and limited numbers of cardiovascular events, which have not been confirmed by the four CVOTs specifically designed to assess the CV safety of DPP-4 inhibitors. Our analysis also confirms that GLP-1RA, when compared with placebo, reduce the risk of MACE, total death, HHF, and the composite renal outcome (12). Finally, when compared with placebo, SGLT-2 inhibitors are associated with a robust reduction of hospitalization for HHF and renal outcome, and a moderate reduction of CV and total death, and MACE (13).
As for the network meta-analysis, Fig. 4 shows an “at glance” summary of the results obtained. According to our data, SGLT-2 inhibitors show the highest probability to be superior to GLP-1RA and DPP-4 inhibitors in terms of HHF and the composite renal outcome, while GLP1-RA are superior to DPP-4 inhibitors for both outcomes. These results are based on 22 comparisons for HHF and 18 comparisons for the renal outcome. As for mortality, both SGLT-2 inhibitors and GLP-1RA are similar in reducing both total and CV deaths, but SGLT-2 inhibitors only are superior to DPP-4 inhibitors for both deaths, whereas GLP-1RA are superior to DPP-4 inhibitors for total death, but equal for CV death. These results are based on all 23 comparisons. As for nonfatal stroke, GLP-1 RA are the only drug class that significantly reduces nonfatal stroke, as compared with placebo, without any difference among the three classes of drugs. These results, as those for nonfatal MI and MACE, are based on 18 comparisons. As for nonfatal MI, both SGLT-2 inhibitors and GLP-1RA are similar, but SGLT-2 inhibitors only are superior to DPP-4 inhibitors. Finally, for the primary endpoint MACE, both SGLT-2 inhibitors and GLP-1RA are similar and both are superior to DPP-4 inhibitors. For the first time, clinicians have the option to save lives with antidiabetic drugs in certain groups of patients with type 2 diabetes.
The inclusion in our network analysis of the AMPLITUDE-O and EMPEROR-P data have modified the conclusions of the most recent similar analysis (15) indicating that SGLT-2 inhibitors increased the risk of stroke as compared with GLP-1RA and that GLP-1RA are superior to DPP-4 inhibitors as for nonfatal MI. Although EMPEROR-R enrolled patients with and without type 2 diabetes, the primary outcome of the trial (a composite of CV death and hospitalization for HF) was almost identical in both groups, suggesting that the different population didn’t affect the results, at least for the primary outcome.
Owing to intrinsic limitations of network meta-analysis, we avoided to analyze the effects of these drugs in several subgroups – e.g., as stratified by age or the presence of CV disease or type 2 diabetes – to avoid type 1 error due to the many subgroup analyses. Moreover, these analyses have already been done in conventional meta-analyses, showing for SGLT-2 inhibitors the lack of significant difference in the reduced risk of the composite outcome (CV death + HHF) in patients with or without type 2 diabetes or in subjects of 65 years of age or younger vs those older than 65 years of age (13). Moreover, GLP-1RA reduced the risk of MACE by 14% in the overall diabetic population, with an apparent greater effect in patients with established CV disease (16% vs 6% reduction, respectively), although the lack of significant interaction between subgroups does not allow to separate them (12).
As evidence of the efficacy of SGLT-2 inhibitors continued to grow, trials on these drugs have expanded their study populations from diabetes patients only to also include patients with HF or CKD in the absence of diabetes. On the basis of results of the most recent CVOTs (DAPA-HF, DAPA-CKD, EMPEROR-R), the FDA has approved dapagliflozin (2020) and empagliflozin (2021) to reduce risk for CV death and HF hospitalization in adults with HF and reduced ejection fraction regardless of whether they have diabetes (25,26). FDA has also approved dapagliflozin for treatment for CKD (2021) (27) and has given priority review for empagliflozin to potentially treat heart failure not associated with left ventricular ejection fraction (28). SGLT-2 inhibitors and GLP-1RA should, therefore, be considered evidence-based treatments for patients with type 2 diabetes after metformin. In theory, SGLT-2 inhibitors should be considered before GLP-1RA because of the reduction in both CV and total deaths associated with their use. In practice, it seems better to tailor the choice to different patients, depending on the preference of the route of administration (oral vs injectable), the presence of intolerance or side-effects, and contraindications; in these cases, one can be switched to another, or they can both be given, if the glycemic target is not attained.
To confirm that CVOTs findings are consistent in more diverse populations reflective of patients in the clinical practice, we may need to look beyond clinical trials to real-world evidence studies. In a meta-analysis evaluating the real-world effect of SGLT-2 inhibitors on cardiovascular outcome in patients with type 2 diabetes, Li et al (29) included fourteen trials enrolling 3,157,259 patients. They found that the predominant impact of SGLT-2 inhibitors is on cardiovascular outcome was driven predominantly by reduction in MACE, total death, HHF, MI, stroke, and CV death. These results were even greater than those recorded in CVOTs. Quite similar results, although of lesser extent and for lesser outcomes, have been observed with GLP-1RA (30).
Our network meta-analysis has certain limitations. Firstly, there was no head-to-head CVOT directly comparing these antidiabetic drug classes; therefore, the comparative effects were generated with indirect evidence, and caution must be exercised when interpreting data from indirect comparison of CVOTs. Moreover, different drugs were used within each drug class, and there could be within-class differences. However, there are on the horizon no cardiorenal outcome studies comparing SGLT-2 inhibitors with GLP-1RA, so it is likely that we must rely on indirect comparisons. Secondly, as for most meta-analyses, we did not have patient-level data, limiting the scope for adjustments. Finally, there were differences in trial designs, patient characteristics, background therapy, and endpoint definitions, especially for the renal outcome. Strengths of the present meta-analysis are the inclusion of all CVOTs published by 10 December 2021, the very large number of participants, the high quality of the trials which minimizes the risk of bias, and the absence of significant heterogeneity in most analyses, which ranged from absent to low or moderate. The clinical relevance of these results seems also highlighted by the evidence that for some outcomes the clinical benefit is consistent irrespective of the presence of type 2 diabetes (13), advanced age (13,31), and the background cardiorenal disease (12,15,32). Accordingly, people with type 2 diabetes, cardiovascular disease, heart failure, or chronic kidney disease should be treated appropriately with an SGLT-2 inhibitor or GLP-1RA, even because more adults with type 2 diabetes in the US have suboptimal glycemic control now compared to 10 years ago, associated with a resurgence in vascular diabetic complications (33).