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Meta-Analysis
. 2021 Feb 1;6(2):148-158.
doi: 10.1001/jamacardio.2020.4511.

Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis

Darren K McGuire  1 , Weichung J Shih  2   3 , Francesco Cosentino  4 , Bernard Charbonnel  5 , David Z I Cherney  6 , Samuel Dagogo-Jack  7 , Richard Pratley  8 , Michelle Greenberg  9 , Shuai Wang  9 , Susan Huyck  10 , Ira Gantz  10 , Steven G Terra  11 , Urszula Masiukiewicz  9 , Christopher P Cannon  12
Affiliations
Meta-Analysis

Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis

Darren K McGuire et al. JAMA Cardiol. .

Abstract

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain.

Objective: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes.

Data sources: A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020.

Study selection: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials.

Data extraction and synthesis: Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model.

Main outcomes and measures: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials.

Results: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction).

Conclusions and relevance: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McGuire reported receiving honoraria for clinical trial leadership from AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck, Novo Nordisk, and Sanofi, and consultancy fees from Afimmune, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Pfizer, Novo Nordisk, Metavant, and Sanofi outside the submitted work. Dr McGuire reported receiving personal fees and nonfinancial support from Merck and nonfinancial support from Pfizer outside the submitted work. Dr Cannon reported receiving grants and personal fees from Merck and Pfizer during the conduct of the study; grants from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Pfizer; and personal fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, Rhoshan, and Sanofi outside the submitted work. Dr Cosentino reported receiving fees from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Novo Nordisk, and Pfizer; research grants from Swedish Research Council, Swedish Heart & Lung Foundation, and the King Gustav V and Queen Victoria Foundation; nonfinancial support from Merck Sharp & Dohme and Pfizer; and personal fees from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Novo Nordisk, and Pfizer outside the submitted work. Dr Charbonnel reported receiving personal fees from Merck, Pfizer, AstraZeneca, Sanofi, Novo Nordisk, MundiPharma, and Lilly and fees from AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, and Takeda during the conduct of the study. Dr Cherney reported receiving personal fees from Boehringer Ingelheim-Eli Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, Bristol Myers Squibb, and Novo Nordisk; and operating grants from Boehringer Ingelheim-Eli Lilly, Merck, Janssen, Sanofi, AstraZeneca, and Novo Nordisk outside the submitted work. Dr Dagogo-Jack reported leading clinical trials for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck, and Sanofi; and equity interests in Jana Care Inc and Aerami outside the submitted work. Dr Pratley reported receiving research grants, consulting, or speaker fees (directed to AdventHealth) from Hanmi Pharmaceutical Co Ltd, Janssen, Merck, Novo Nordisk, Pfizer, Poxel SA, Sanofi, Scohia Pharma, and Sun Pharmaceutical Industries; publication support from Merck; speaker and consulting fees from AstraZeneca; consulting fees from GlaxoSmithKline, Glytec, and Janssen; grants from Lexicon Pharmaceuticals; and grants and consulting fees from Ligand Pharmaceuticals, Lilly, Sanofi, and Merck outside the submitted work. All payments for Dr Pratley's services were made directly to AdventHealth, a nonprofit organization. Dr Shih reported serving as consultant to the scientific advisory committee of Merck. Drs Gantz and Huyck reported being employees of Merck & Co, Inc, Kenilworth, New Jersey, and own stock in the company. Ms Greenberg and Drs Wang, Terra, and Masiukiewicz reported being employees and shareholders of Pfizer. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Major Adverse Cardiovascular Events—Composite of Myocardial Infarction, Stroke, or Cardiovascular Death
ASCVD indicates atherosclerotic cardiovascular disease; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; DECLARE-TIMI 58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; MACEs, major adverse cardiovascular events; NA, not available; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.
Figure 2.
Figure 2.. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Death
ASCVD indicates atherosclerotic cardiovascular disease; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; CV, cardiovascular; DECLARE-TIMI 58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; NA, not available; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.
Figure 3.
Figure 3.. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Hospitalization for Heart Failure
ASCVD indicates atherosclerotic cardiovascular disease; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; DECLARE-TIMI 58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HHF, hospitalization for heart failure; NA, not available; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.
Figure 4.
Figure 4.. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Kidney-Related Outcomes
ASCVD indicates atherosclerotic cardiovascular disease; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; DECLARE-TIMI 58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; NA, not available; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.
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