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

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.

Introduction

Type 2 diabetes (T2D) is commonly complicated by atherosclerotic cardiovascular disease (ASCVD), heart failure, and chronic kidney disease.[1,2,3,4] The proven efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor class of medications has led to professional cardiology and endocrinology society consensus recommendations and guidelines[5,6,7,8,9,10] endorsing their use and supported by regulatory product labeling.

The objective of the present study is to update previous meta-analyses,[11,12,13] adding data from the sixth completed placebo-controlled cardiovascular (CV) and kidney clinical outcomes trial of an SGLT2 inhibitor in patients with T2D, the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS CV) trial.[14] The VERTIS CV trial assessed the effects of ertugliflozin vs placebo in patients with T2D and prevalent ASCVD.[15,16] Our study results represent the totality of CV outcomes trial data for the 4 SGLT2 inhibitors available in the United States and many other countries. These trials were conducted in accordance with regulatory guidance requiring CV outcomes assessment of drugs for T2D; furthermore, our study refined estimates of drug outcomes in patients with T2D and explored the heterogeneity of outcomes assessed by individual drugs in the overall class and within selected subgroups.

Methods

Search Strategy and Selection Criteria

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.[17] A systematic literature search of randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with T2D published from January 1, 2015, to January 31, 2020, was conducted in PubMed (eFigure 1 in the Supplement). 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 trials were identified, with contributory data from 9 publications. Trial eligibility was confirmed by 2 independent reviewers (M.G., S.W.); data extraction was performed by S.W. Study quality (performed by M.G., U.M., S.W.) was evaluated using the Cochrane Risk of Bias Tool[18] (eTable 1 in the Supplement).

Patient Population

All analyses were primarily conducted on the total patient population of each of the 6 trials identified: Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME)[19]; the CANVAS Program, consisting of 2 trials: the Canagliflozin Cardiovascular Assessment Study (CANVAS) and A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R)[20]; the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI 58)[21]; Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE)[22]; and VERTIS CV.[16] Secondary analyses were performed to assess heterogeneity of associations with outcomes of interest according to prespecified baseline characteristics including (1) ASCVD or multiple ASCVD risk factors; (2) history of heart failure; (3) estimated glomerular filtration rate (eGFR); (4) glycated hemoglobin (HbA1c); and (5) albuminuria (eTable 2 in the Supplement). For all outcomes, sensitivity analyses were performed omitting the data from CREDENCE, which was primarily a kidney outcomes trial.

Outcomes

The primary outcome in all trials except CREDENCE was the time to first major adverse cardiovascular event (MACE) of myocardial infarction, stroke, or CV death. The primary outcome in CREDENCE was a composite kidney disease outcome with MACE as a prioritized secondary outcome. For the present meta-analysis, the primary outcome was time to first MACE, with secondary outcomes including time to first event for each component of MACE, the composite of hospitalization for heart failure (HHF) or CV death and each component outcome, all-cause mortality, and a composite of kidney outcomes. The composition of the principal kidney composite outcomes varied across trials (eAppendix 1 in the Supplement) and included in various permutations worsening eGFR or creatinine, end-stage kidney disease with or without requirement for kidney replacement therapy or transplant, kidney death, or CV death. In CREDENCE,[22] the kidney composite was the primary outcome. In DECLARE-TIMI 58 and VERTIS CV, analyses of kidney composite outcomes were prespecified in the primary analysis hierarchy.[15,16,23,24] In EMPA-REG OUTCOME and the CANVAS program trials, analysis of the kidney composite outcome was prespecified as exploratory.[20,25,26]

Statistical Analysis

A fixed-effect meta-analysis approach was used, with heterogeneity assessed using the Cochran Q test statistic and Higgins and Thompson I2.[27,28] Heterogeneity was considered to be low, moderate, or high if I2 was less than 25%, 25% to 75%, or greater than 75%, respectively. The hazard ratio (HR) and its 100 × (1 – α)% CI was extracted from the publications of each individual study and converted to log(HR) and its SE before the meta-analysis. The meta-analysis was directly implemented on the natural log HR scale, with results exponentiated and reported on the original HR scale. For analyses of heterogeneity of association between treatment and outcomes among subgroups, a random-effects meta-regression approach using restricted maximum likelihood with Hartung and Knapp adjustment was used to obtain the F test statistic and P value of the interaction term for each subgroup.[29] The R package, metafor, version 3.6.2 (R Foundation) was used for all analyses and for forest plot generation. Statistical analyses were conducted from April 13, 2020, to April 27, 2020. Two-sided P values <.05 were considered significant.

Results

A total of 6 placebo-controlled clinical outcomes trials (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, CREDENCE, VERTIS CV) of 4 SGLT2 inhibitors in patients with T2D were identified, with cohort characteristics summarized in the Table, extracting data for the present analyses from the primary trial reports[16,19,20,21,22] as well as from a number of published secondary analyses.[13,24,30,31,32] Data from 46 969 patients were included for analyses, including 31 116 (66.2%) with prevalent ASCVD. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, 16 030 (34.1%) were women, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). The search and selection process is summarized in eFigure 1 in the Supplement.

Table.

Baseline Characteristics From Included Cardiovascular and Kidney Outcomes Trials With SGLT2 Inhibitors

Characteristic	No. (%)b
	EMPA-REG outcome[19] (n = 7020)	CANVAS program[20] (n = 10 142)	DECLARE-TIMI 58[21] (n = 17 160)	CREDENCE[22] (n = 4401)	VERTIS CV[16] (n = 8246)
SGLT2 inhibitor	Empagliflozin	Canagliflozin	Dapagliflozin	Canagliflozin	Ertugliflozin
Duration of follow-up, median, y	3.1	2.4	4.2	2.6	3.0
Patient characteristics
Men	5016 (71.5)	6509 (64.2)	10 738 (62.6)	2907 (66.1)	5769 (70.0)
Women	2004 (28.5)	3633 (35.8)	6422 (37.4)	1494 (33.9)	2477 (30.0)
Age, mean (SD), y	63.1 (8.6)	63.3 (8.3)	63.9 (6.8)	63.0 (9.2)	64.4 (8.1)
Race/ethnicity
White	5081 (72.4)	7944 (78.3)	13 653 (79.6)	2931 (66.6)	7240 (87.8)
Asian	1517 (21.6)	1284 (12.7)	2303 (13.4)	877 (19.9)	498 (6.0)
Black or African American	357 (5.1)	336 (3.3)	603 (3.5)	224 (5.1)	235 (2.8)
Other/missing	65 (0.9)	578 (5.7)	601 (3.5)	369 (8.4)	273 (3.3)
Diabetes characteristics
HbA1c, mean (SD), %	8.1 (0.8)	8.2 (0.9)	8.3 (1.2)	8.3 (1.3)	8.2 (1.0)
Diabetes duration, mean (SD), y	57 > 10c	13.5 (7.8)	11.8 (7.8)	15.8 (8.6)	13.0 (8.3)
Cardiovascular characteristics
Established cardiovascular disease	7020 (100)	6656 (65.6)	6974 (40.6)	2220 (50.4)	8246 (100)
History of heart failure	706 (10.1)	1461 (14.4)	1724 (10.0)	652 (14.8)	1958 (23.7)
Renal characteristics
Reduced kidney functiond	1819 (25.9)	2039 (20.1)	1265 (7.4)	2631 (59.8)	1807 (21.9)
Urine ACR≥300 mg/g	769 (11.0)	760 (7.6)	1169 (6.8)	3874 (88.0)	755 (9.2)
Cardiovascular medications
ACEI or ARB blockade	5666 (80.7)	8116 (80.0)	13 950 (81.3)	4395 (99.9)	6686 (81.1)
β-Blocker	4554 (64.9)	5421 (53.5)	9030 (52.6)	1770 (40.2)	5692 (69.0)
Statin/ezetimibe	5403 (77.0)	7599 (74.9)	12 868 (75.0)	3036 (69.0)	6790 (82.3)
Antihyperglycemic medications
Insulin	3387 (48.2)	5095 (50.2)	7013 (40.9)	2884 (65.5)	3900 (47.3)
Metformin	5193 (74.0)	7825 (77.2)	14 068 (82.0)	2545 (57.8)	6292 (76.3)
Sulfonylurea	3006 (42.8)	4361 (43.0)	7322 (42.7)	1268 (28.8)	3390 (41.1)
DPP-4 inhibitor	796 (11.3)	1261 (12.4)	2888 (16.8)	751 (17.1)	911 (11.0)
GLP-1 receptor agonist	196 (2.8)	407 (4.0)	750 (4.4)	183 (4.2)	278 (3.4)

Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ACR, albumin/creatinine ratio; ARB, angiotensin receptor blocker; 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; DPP-4, dipeptidyl peptidase-4; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; SGLT2, sodium-glucose cotransporter 2; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.

Adapted from Arnott et al, 2020.[12]

Values written as No. (%) unless otherwise specified.

Approximately 57% more than 10 years.

Estimated glomerular filtration rate <60 mL/min per 1.73 m2 based on the Modification of Diet in Renal Disease equation in EMPA-REG OUTCOME, the CANVAS Program, and VERTIS CV, and the Chronic Kidney Disease Epidemiology Collaboration equation in DECLARE-TIMI 58 and CREDENCE.

Across the 6 trials, median follow-up ranged from 2.4 to 4.2 years, T2D duration ranged from 11.8 to 15.8 years, and average baseline HbA1c ranged from 8.1% to 8.3% (Table). The proportion of patients with prevalent ASCVD ranged from 40.6% in DECLARE-TIMI 58 to 100% in EMPA-REG OUTCOME and VERTIS CV. The proportion of patients with baseline eGFR less than 60 mL/min/1.73 m2 ranged from 7.4% in DECLARE-TIMI 58 to 59.8% in CREDENCE. History of heart failure ranged from 10.0% in DECLARE-TIMI 58 to 23.7% in VERTIS CV (Table).

Overall, 4931 patients experienced a MACE, with 4024 (81.6%) of the MACE outcomes occurring in the subset of patients with prevalent ASCVD. Analyses of associations between SGLT2 inhibitors and outcomes on the hazard for MACE overall and by ASCVD status at baseline are presented in Figure 1. Overall, SGLT2 inhibitors significantly reduced the hazard for MACE (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27); the presence or absence of ASCVD did not modify the treatment outcome on MACE (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07; P = .63 for interaction). Similar findings were observed in additional prespecified subgroup analyses by baseline HbA1c, albuminuria, eGFR, and history of heart failure (eFigure 2 in the Supplement).

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.

Overall, 2031 CV death events occurred, including 1680 (82.7%) of CV deaths in the subset of patients with prevalent ASCVD. Associations of SGLT2 inhibitors on the hazard for CV death overall and by ASCVD status are presented in Figure 2. Overall, the SGLT2 inhibitors significantly reduced the hazard for CV death (HR, 0.85; 95% CI, 0.78-0.93), with moderate heterogeneity observed across the trials (Q statistic, P = .02; I = 64.3%), with no interaction of outcome observed for those with vs without ASCVD (HR, 0.83; 95% CI, 0.76-0.92 and HR, 0.95; 95% CI, 0.77-1.17, respectively; P = .41 for interaction). Similar findings were observed in additional prespecified subgroup analyses by baseline HbA1c, albuminuria, eGFR, and history of heart failure (eFigure 3 in the Supplement). In analyses of all-cause mortality occurring in 3339 patients, SGLT2 inhibitors were associated with a reduced risk overall, with moderate heterogeneity of outcome (HR, 0.87; 95% CI, 0.81-0.93; Q statistic P = .06; I2 = 56.5%), with no significant interaction by ASCVD status (P = .64 for interaction; eFigure 4 in the Supplement).

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.

Overall, 3154 HHF/CV death composite events occurred, including 2560 (81.2%) of these events occurring in the subset of patients with prevalent ASCVD. Associations between SGLT2 inhibitors and outcomes on the hazard for HHF/CV death overall and analyses by prevalent ASCVD are presented in eFigure 5A and 5B in the Supplement. Overall, SGLT2 inhibitors were associated with a significant reduction in the hazard for HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84), with moderate heterogeneity of associations with outcomes across trials (Q statistic P = .09; I2 = 50.6%). There was no interaction of outcome observed for those with vs without ASCVD (HR, 0.77; 95% CI, 0.72-0.84 and HR, 0.81; 95% CI, 0.69-0.95, respectively; P = .62 for interaction). Similarly, no modification of treatment outcome was observed for HHF/CV death in prespecified analyses by baseline eGFR categories or history of heart failure (eFigure 5C and 5D in the Supplement).

Overall, 1430 HHF events occurred, including 1151 (80.5%) in the subset of patients with prevalent ASCVD. Associations between SGLT2 inhibitors and outcomes on the hazard for HHF overall and by ASCVD status are presented in Figure 3. The SGLT2 inhibitors were associated with a significant reduction in the hazard for HHF (HR, 0.68; 95% CI, 0.61-0.76), with consistency of effectiveness across the trials (Q statistic P = .85; I2 = 0.0%), and similarly in those with vs without prevalent ASCVD (HR, 0.70; 95% CI, 0.62-0.78 and HR, 0.63; 95% CI, 0.50-0.80, respectively; P = .26 for interaction).

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.

Overall, 1426 kidney composite outcome events occurred. Outcomes of SGLT2 inhibitors on the hazard for progression of kidney disease overall and by ASCVD status are presented in Figure 4. Overall, the SGLT2 inhibitors were associated with a significant reduction in the hazard for progression of kidney disease (HR, 0.62; 95% CI, 0.56-0.70) with moderate heterogeneity across the trials (Q statistic P = .09; I2 = 49.7%). There was no interaction of outcome on progression of kidney disease observed for those with vs without ASCVD (HR, 0.64; 95% CI, 0.56-0.72 and HR, 0.60; 95% CI, 0.50-0.73, respectively; P = .73 for interaction). Similarly, no interaction of effectiveness was observed for outcomes of SGLT2 inhibitors on the kidney composite outcome in prespecified analyses by baseline albuminuria or history of heart failure (eFigure 6 in the Supplement).

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.

Results of additional analyses overall and by predefined subgroups for myocardial infarction and stroke are presented in eFigures 7 and 8 in the Supplement. The results of the sensitivity analyses that excluded CREDENCE are presented in eFigures 9 to 16 in the Supplement. For completeness, trial level summaries of adverse events of special interest including severe diabetic ketoacidosis, bone fractures, amputations, genital mycotic infections, and acute kidney injury events are presented in eTable 3 in the Supplement; however, broad differences across trials in definitions, ascertainment, and reporting of such events preclude meaningful meta-analyses.

Discussion

The present meta-analysis includes clinical outcomes data among patients with T2D for all 4 SGLT2 inhibitors in clinical use in the United States and many other countries. Compared with previous meta-analyses of cardiorenal outcomes of SGLT2 inhibitors,[12,13] similar search methods and statistical methodology were used in the present study. One difference in the present analyses includes the extraction of HR and 100 × (1 – α)% CI for all eligible trials, whereas previous meta-analyses limited extraction to analyses reporting HR and 95% CI[13] or pooled different outcome metrics (eg, relative risk, odds ratio, HR) in the same analysis.[12] The present meta-analysis adds to those previously published not only by the inclusion of data from the VERTIS CV trial but also with the inclusion of additional subgroup analyses (eg, baseline albuminuria level, baseline HbA1c level) where data were published for 2 or more trials.

The present results augment the growing evidence base that SGLT2 inhibitors in general are associated with favorable CV and kidney outcomes; in addition, the present study refines understanding of important differences in outcomes associated with drugs within the class. The trials completed to date assessing the CV safety and effectiveness of SGLT2 inhibitors in patients with T2D have predominantly focused on ASCVD-related outcomes. In this context, it is key to note that in the overall pooled estimate, the beneficial outcome of SGLT2 inhibitors on MACE is rather modest and is demonstrated within trials only for empagliflozin and canagliflozin. Likewise, only empagliflozin has demonstrated significant outcomes for CV death risk reduction,[19] with moderate heterogeneity across the class. Notably, the predominant CV outcome of the SGLT2 inhibitors is an associated reduction in HHF, highly consistent across the class achieving nominal significance in each of the trials, with similar consistency across the class for improving kidney outcomes, with ertugliflozin being the only SGLT2 inhibitor without this demonstrated benefit.

Observed heterogeneity across the class for selected outcomes, specifically for MACE, CV death, and composite kidney outcomes, requires further exploration. Whether this is due to differences in the populations studied and their risk profiles, differences in capture or definition of outcomes, or differences in the drugs requires further evaluation. Pharmacologically, ertugliflozin is most similar to empagliflozin with regard to selectivity for SGLT2, with dapagliflozin slightly less selective and canagliflozin the least selective of the 4 drugs,[33] yet only empagliflozin was associated with an improved risk for CV death, and ertugliflozin is the only SGLT2 inhibitor of the 4 studied that failed to reach statistical significance on the prespecified kidney composite end point, although analysis of eGFR change was associated with a significant improvement by ertugliflozin. The definition of events comprising the renal composite end point differed from that of the other CV and renal outcomes trials. These discordant observations do not seem attributable to differences in the doses studied, as pharmacodynamic outcomes on HbA1c, blood pressure, and body weight were similar across the trials. This finding amplifies the possibility that CV and kidney benefits are due to mechanisms other than SGLT2. For example, off-target effects of SGLT2 inhibitors have been proposed, including the direct effect on the sodium-hydrogen exchanger 1 (NHE1) in the heart, NHE3 in the kidney, and NHE9 in inflammatory cells that could influence MACE, heart failure, and kidney outcomes.[34] In addition, effects of selected SGLT2 inhibitors on myocardial sodium, calcium, and potassium channels have been demonstrated in preclinical models,[35,36] raising the possibility of the drugs having effects on myocardial function and rhythm stability independent of SGLT2 engagement. Continued investigation into the potential clinical relevance of such observations and to what degree these effects differ between members of the class is of utmost importance.

The benefits on risk for HHF and related outcomes apply broadly to the class, independent of baseline ASCVD and prior heart failure and across the spectrum of baseline eGFR. These observations provide strong support for contemporary guidelines and medical society recommendations supporting the use of SGLT2 inhibitors, regardless of glucose control, for patients with T2D with prevalent ASCVD and with or at high risk of heart failure.[5,6,7,9,10] This guidance prioritizes the use of SGLT2 inhibitors with proven efficacy (empagliflozin or canagliflozin for MACE; empagliflozin, canagliflozin, or dapagliflozin for kidney outcomes; all 4 drugs for heart failure), independent of glucose control considerations, in patients with T2D with or at high risk for CV and kidney complications.

Although the mechanisms underpinning the CV and kidney outcomes of SGLT2 inhibitors remain uncertain, it is clear that the benefits are not attributable to glucose control per se. For example, there was no association between baseline or achieved glucose and CV or kidney outcomes in the EMPA-REG OUTCOME trial supported by only modest association between HbA1c and outcomes in mediation analyses from that trial.[37,38,39] Similarly, in CREDENCE, whereas the between-group contrast in HbA1c was the smallest of reported trials as expected with lower eGFR by the glucose-lowering mechanism of action, the magnitude of benefits for MACE and for HHF were numerically the largest across the trials. Although not specifically analyzed in the DAPA-HF (Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction) trial of dapagliflozin vs placebo, a patient population that included patients with or without diabetes, benefits on CV death, HHF, and their composite were no different in those with or without diabetes, providing additional evidence discounting the role of the glucose-modifying effects of the SGLT2 inhibitors accounting for their benefit in CV disease. Outcomes trials are under way to assess the use of empagliflozin and dapagliflozin for CV and kidney disease in extended patient populations independent of diabetes status in patients with heart failure with reduced and preserved[40,41,42] ejection fraction and chronic kidney disease of diverse diabetic and nondiabetic kidney disease etiologies.[43,44] The first of these 2 latter trials, DAPA-CKD trial of dapagliflozin vs placebo, was stopped early for efficacy outcome, with results presented at the 2020 European Society of Cardiology Scientific Sessions but not yet published.[45]

When initially approved for clinical use, SGLT2 inhibitors had product-labeled cautions or contraindications for use in patients with reduced eGFR, based exclusively on the attenuation of glycemic efficacy as eGFR wanes and without specific safety concerns that typically underpin eGFR-based prescriptions. However, with the demonstration of CV and kidney benefits across the spectrum of kidney function in patients enrolled in trials to date, an eGFR as low as 30 mL/min/1.73 m2 in EMPA-REG OUTCOME, the CANVAS trials, VERTIS CV, and CREDENCE, liberalization of these restrictions is now justified. For example, based on the results from CREDENCE,[22] canagliflozin has a product-labeled indication to reduce the incidence and progression of kidney disease, approved for initiation down to an eGFR of 30 mL/min/1.73 m2, with use allowed to continue in patients taking canagliflozin until initiation of dialysis. Similarly, society recommendations and guidelines endorse the use of all SGLT2 inhibitors for patients with an eGFR of 30 mL/min/1.73 m2 or higher, independent of glucose considerations and based wholly on the CV and kidney benefits as supported by the present meta-analyses.[5,10]

The safety profile of the SGLT2 inhibitors is firmly established, and the addition of the VERTIS CV data did not materially alter risk considerations for any specific adverse event. The most common adverse effect is mycotic genital infections,[16,19,20,21,22] typically mild and most often treated with over-the-counter therapies. With regard to diabetic ketoacidosis, unlike the situation in patients with type 1 diabetes treated with SGLT2 inhibitors, where the relative risk and absolute risk increment for diabetic ketoacidosis is much greater,[46] the present summary of reports from outcomes trials of patients with T2D demonstrates a much lower incidence and a much more modest incremental absolute risk for diabetic ketoacidosis. Risk mitigation strategies for SGLT2 inhibitor-associated diabetic ketoacidosis focusing largely on type 1 diabetes have been published by international authorities in the field, and probably can also be applied to patients with T2D.[46] Specifically, patients are advised to not take the medication on days with diminished oral intake and, when feeling generally unwell, to monitor ketones with either urine dipsticks or point-of-care blood monitoring of beta-hydroxybutyrate.[46,47] With regard to amputation risk, there is significant variability across the trials, with a significant increase only observed in the CANVAS program with canagliflozin. Of note, in the CANVAS program and in EMPA-REG OUTCOME, amputation events were captured through adverse event reporting without dedicated prospective event capture and source document collection, except during the final few months of the CANVAS program when systematic data capture for amputations was implemented. All subsequent trials have prospectively captured amputation events as an adverse event of special interest with no evident incremental risk noted, including in the CREDENCE trial of canagliflozin.[22] In CREDENCE, investigators were instructed to examine participants’ feet at every study visit, and the investigational product was withheld during incident diabetic foot complications. Therefore, it remains unclear whether the amputation risk observed with canagliflozin in the CANVAS trials was a spurious finding or attributable to different populations studied, or whether avoidance in the setting of diabetic foot complications mitigated the associated risk.

Limitations

A number of limitations are acknowledged. Differences in eligibility criteria, cohort characteristics, and trial duration may have affected the meta-analysis. For example, in the combined data set, the majority of patients had prevalent ASCVD, advanced kidney disease, or both, so further data might help elucidate the outcomes of this class in primary prevention populations. Although the CV outcomes were very similarly defined across the trials, there were notable differences in the components comprising the composite renal outcomes. Each of these limitations may introduce bias into the analyses, and such results should be interpreted accordingly. At the review level, although incomplete retrieval of primary trial reports is unlikely given the scope of such clinical outcomes trials and their high-profile reporting, the possibility exists of incomplete retrieval of reports and results from secondary analyses and outcomes, which may introduce further bias into these results.

Conclusions

Study results suggest that the SGLT2 inhibitor class of medications favorably affects risk for CV outcomes in patients with T2D with noted heterogeneity of outcomes between specific members of the class. Furthermore, results suggest that empagliflozin is associated with reduced risk for CV death, canagliflozin with reduced risk for MACE and for the incidence and progression of kidney disease, and dapagliflozin with reduced risk for HHF; each indication is reflected in the product labeling. Beyond product labeling, across the class, there are robust and consistent associations with reduction in risk for HHF, independent of baseline ASCVD status or kidney function. These data support contemporary society recommendations to prioritize the use of SGLT2 inhibitors with demonstrated outcomes, independent of glucose control considerations, in patients with T2D with or at high risk for CV and kidney complications. The heterogeneity of the associations with outcomes of different SGLT2 inhibitors on CV death among patients with T2D and ASCVD requires further study.