Abstract
Background and Aims
The latest consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends metformin and lifestyle intervention as first-line therapy for type 2 diabetes. Second-line therapy recommendation is the use sodium-glucose cotransporter 2 (SGLT 2) inhibitors (if estimated glomerular filtration rate [eGFR] is adequate) or GLP-1 receptor agonists if eGFR is inadequate (or SGLT-2 inhibitors not tolerated). No recommendation is made for dipeptidyl peptidase-4 (DPP-4) inhibitors. Therapy choices are limited for patients with both type 2 diabetes and moderate-to-severe chronic kidney disease (CKD) and it is unclear from published data if observed cardiovascular benefits of new anti-diabetic agents extend to the CKD cohort. The aim of this study was to undertake a systematic review of all published CVOT trials using new anti-diabetic agents (GLP-1 receptor agonist, DPP-4 inhibitor, SGLT 2 inhibitor).
Method
We searched MEDLINE (via PubMed and the Cochrane Central Register of Controlled Trials) up to 1st December 2019. Data was stratified by trial entry eGFR into normal (eGFR ≥60 ml/min) and CKD (eGFR <60 ml/min), with data extracted for primary major cardiovascular event (MACE) rates such as cardiovascular death, stroke and/or myocardial infarct. A meta-analysis with random effects model was performed to estimate overall hazard ratios (HRs) for MACE with new anti-diabetic agents stratified by eGFR. Inter-study heterogeneity was assessed with the I2 index and Cochran’s Q test.
Results
We analysed 13 studies from 16 that were eligible after our search strategy, with 2 excluded due lack of data stratified by eGFR and 1 excluded due to combined MACE/renal outcomes. The studies (GLP-1 agonists, n=6; DPP-4 inhibitors, n=4; SGLT 2 inhibitors, n=3) had a combined total of 128,266 participants (22.1% with eGFR <60 ml/min). HR for MACE with GLP-1 agonists for participants with eGFR ≥60 ml/min was 0.87 (95% CI 0.77-0.98; p=0.02) and for participants with eGFR <60 ml/min was 0.90 (95% CI 0.78-1.04; p=0.14). HR for MACE with DPP-4 inhibitors for participants with eGFR ≥60 ml/min was 0.99 (95% CI 0.92-1.07; p=0.86) and for participants with eGFR <60 ml/min was 0.99 (95% CI 0.91-1.08; p=0.86). HR for MACE with SGLT 2 inhibitors for participants with eGFR ≥60 ml/min was 0.98 (95% CI 0.88-1.10; p=0.78) and for participants with eGFR <60 ml/min was 0.82 (95% CI 0.70-0.96; p=0.01). Significant heterogeneity was observed in the meta-analyses for each new anti-diabetic therapy drug class stratified by eGFR.
Conclusion
Among the new anti-diabetic agents, our study suggests efficacy for prevention of MACE in the setting of CKD exists only for SGLT 2 inhibitors and not with GLP-1 receptor agonists or DPP-4 inhibitors. Targeted CVOT studies incorporating participants with diabetes and CKD are critical to guide glycaemic management in these high-risk patients. Until then, we suggest recommendations for second-line therapy in patients with type 2 diabetes and renal impairment should be amended to reflect the current evidence base supporting prevention of MACE with SGLT 2 inhibitors versus other new anti-diabetic agents.
Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials
