Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

Figures & data

Table 1 Completed CV outcome trials of glucose-lowering drugs in patients with T2DM

Trial name (publication year)	Major inclusion criteria	Number of patients randomized	Median follow-up, years	Intervention	Primary outcome data
DPP-4 inhibitors
SAVOR-TIMI 53 (2013)^Citation13	≥40 years + history of established CVD; males ≥55 years or females ≥60 years + risk factors for vascular disease	16,492	2.1	Saxagliptin versus placebo	Composite: CV death, non-fatal MI, or non-fatal ischemic stroke; HR 1.00 (95% CI: 0.89, 1.12); p = 0.99 for superiority; p < 0.001for non-inferiority
EXAMINE (2013)^Citation14	Acute coronary event within previous 15–90 days	5380	1.8	Alogliptin versus placebo	Composite: CV death, non-fatal MI, or non-fatal stroke; HR 0.96 (upper bound of one-sided repeated CI: 1.16); p < 0.001 for non-inferiority
TECOS (2014)^Citation15	HbA1c 6.5%–8.0%; ≥50 years; established CVD	14,671	3.0	Sitagliptin versus placebo	Composite: CV death, non-fatal MI, non-fatal stroke, or hospitalization for UA; HR 0.98 (95% CI: 0.88, 1.09); p < 0.001 for non-inferiority
GLP-1 receptor agonists
ELIXA (2015)^Citation16	HbA1c 5.5%–11.0%; acute coronary event ≤180 days prior to screening	6068	2.1	Lixisenatide versus placebo	Composite: CV death, non-fatal MI, non-fatal stroke, or hospitalization for UA; HR 1.02 (95% CI: 0.89, 1.17); p = 0.81 for superiority; p < 0.001 for non-inferiority
LEADER (2016)^Citation17	HbA1c ≥7.0%; ≥50 years + CVD; ≥60 years + ≥1 CV risk factor	9340	3.8	Liraglutide versus placebo	Composite: CV death, non-fatal MI, or non-fatal stroke; HR 0.87 (95% CI: 0.78, 0.97); p = 0.01 for superiority; p < 0.001 for non-inferiority
SUSTAIN-6 (2016)^Citation18	HbA1c ≥7.0%; ≥50 years + CVD; ≥60 years + ≥1 CV risk factor	3297	2.1	Semaglutide 0.5 mg versus semaglutide 1.0 mg versus placebo	Composite: CV death, non-fatal MI, or non-fatal stroke; HR 0.74 (95% CI: 0.58, 0.95); p = 0.02 for superiority; p < 0.001 for non-inferiority
EXSCEL (2017)^Citation19	HbA1c >6.5%; 40 years + CVD history	14,752	3.2	Subcutaneous injections of extended-release exenatide 2 mg versus placebo (once weekly)	Composite: CV death, non-fatal MI, or non-fatal stroke; HR 0.91 (95% CI: 0.83, 1.00); p = 0.06 for superiority; p < 0.001 for non- inferiority
FREEDOM-CVO (NCT01455896)	HbA1c >6.5%; 40 years + CVD history	4156		ITCA 650 (continuous subcutaneous exenatide 60 mcg/day) versus placebo	Composite: CV death, MI, stroke, or hospitalization for UA (data not published; study met primary and secondary endpoints by demonstrating FDA-required non-inferiority for preapproval CV safety^Citation20)
Insulin
DEVOTE (2017)^Citation21	HbA1c ≥7.0% or <7.0% with basal insulin 20 U/day; ≥50 years + CVD or renal disease; ≥60 years + CV risk factors	7637	~2.0	Insulin degludec versus insulin glargine	Composite: CV death, non-fatal MI, or non-fatal stroke; degludec versus glargine; HR 0.91 (95% CI: 0.78, 1.06); p < 0.001 for non- inferiority in a one-sided test
PPAR-gamma agonists
TOSCA.IT (2017)^Citation22	HbA1c ≥7.0% and ≤9.0%; metformin monotherapy	3028	4.75	Pioglitazone versus sulfonylurea	Composite: death, non-fatal MI, non-fatal stroke or urgent coronary revascularization; HR 0.96 (95% CI: 0.74, 1.26); p = 0.79
SGLT2 inhibitors
EMPA-REG OUTCOME (2015)^Citation23	HbA1c 7.0%–9.0% (if drug naïve) or 7.0%–10.0% (if receiving stable glucose- lowering medication >12 weeks pre-randomization); established CVD	7020	3.1	Empagliflozin 10 mg versus empagliflozin 25 mg versus placebo (analyzed as empagliflozin pooled vs placebo)	Composite: CV death, non-fatal MI, or non-fatal stroke; HR 0.86 (95.02% CI: 0.74, 0.99); p = 0.04 for superiority; p < 0.001 for non-inferiority
CANVAS Program (2017)^Citation24 (CANVAS + CANVAS-R)	HbA1c 7.0%–10.5%; ≥30 years history of CVD, or ≥50 years high risk of CVD	10,142 (CANVAS 4330 + CANVAS-R 5812)	2.4	Canagliflozin 100 mg versus canagliflozin 300 mg versus placebo	Composite: CV death, non-fatal MI, and non-fatal stroke; HR 0.86 (95% CI: 0.75, 0.97); p = 0.02 for superiority; p < 0.001 for non-inferiority
CVD-REAL* (2017)^Citation25	T2DM; new users of SGLT2 inhibitors or other GLD	(Not randomized; observational) 309,056	Retrospective registries study	SGLT2 inhibitors versus other classes of GLD	Hospitalization for heart failure; HR 0.61 (95% CI: 0.51, 0.73); p < 0.001
CVD-REAL Nordic* (2017)^Citation26	T2DM; new users of SGLT2 inhibitors or other GLD	(Not randomized; observational) 91,320	Retrospective registries study	SGLT2 inhibitors versus other classes of GLD	CV death; HR 0.53 (95% CI: 0.40, 0.71); p < 0.0001; Composite: CV death, MI, or stroke; HR 0.78 (95% CI: 0.69, 0.87); p < 0.0001; Hospitalization for heart failure; HR 0.70 (95% CI: 0.61, 0.81); p < 0.0001

Notes: Bold text indicates superiority in reducing risk of major adverse CV events (MACE) demonstrated versus placebo. SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; ELIXA, Evaluation of LIXisenatide in Acute Coronary Syndrome; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; FREEDOM CVO, A Study to Evaluate Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With ITCA 650; DEVOTE, A Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events; TOSCA.IT, Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents. Intervention Trial; EMPA-REG OUTCOME, Empagliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients; CANVAS Program, CANVAS, Canagliflozin Cardiovascular Assessment Study, + CANVAS-R, A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus; CVD-REAL, Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (listed by alphabetical order of drug class and then by chronological order of primary publication).

* CVD-REAL is included for completeness, as the data support the CV benefits of SGLT2 inhibitors in T2DM, as demonstrated in EMPA-REG OUTCOME and the CANVAS Program.

Abbreviations: CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; GLD, glucose-lowering drug; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; HR, hazard ratio; MI, myocardial infarction; PPAR, peroxisome proliferator-activated receptor; SGLT2, sodium glucose cotransporter 2; T2DM, type 2 diabetes mellitus; UA, unstable angina.

Table 2 Ongoing drug-specific CV outcome trials in patients with T2DM

Trial acronym (ClinicalTrials.gov identifier)a	Patient population	Estimated enrollment, Nb	Intervention	Primary outcome	Estimated end date
DPP-4 inhibitors
CARMELINA (NCT01897532)	HbA1c 6.5%–10%; ≥18 years; high CV risk defined by micro- or macroalbuminuria and previous macrovascular disease and/or impaired renal function with predefined UACR	7053	Linagliptin versus placebo	Composite: CV death, non-fatal MI, non-fatal stroke, or hospitalization for UA	December 2017
CAROLINA (NCT01243424)^Citation27	HbA1c 6.5%–8.5% (SU naïve) or 6.5%–7.5% (previous SU exposure); 40–85 years; CV risk	6072	Linagliptin versus glimepiride	Composite: CV death, non-fatal MI, non-fatal stroke, or hospitalization for UA	March 2019
GLP-1 receptor agonists
REWIND (NCT01394952)	HbA1c ≤9.5%; 50 years + CVD; 55 years + subclinical CVD; ≥60 years + CV risk factors	9622	Dulaglutide versus placebo	Composite: CV death, non-fatal MI, or non- fatal stroke	July 2018
HARMONY Outcomes (NCT02465515)	HbA1c >7.0%; 40 years + CVD	9400	Albiglutide versus placebo	Composite: CV death, MI, or stroke	May 2019
SGLT2 inhibitors
DECLARE-TIMI 58 (NCT01730534)	HbA1c criteria not stated; ≥40 years; known CVD or high CV risk	17,276	Dapagliflozin 10 mg versus placebo	Composite: CV death, MI, or stroke Composite: CV death or hospitalization for heart failure	April 2019
CREDENCE (NCT02065791)^Citation28	HbA1c 6.5%–12.0%; ≥30 years; eGFR ≥30–<90 mL/min/1.73 m^2; stable dose ACE inhibitor or ARB; UACR >300–≤5000 mg/g	4200	Canagliflozin 100 mg versus placebo	Composite: end- stage kidney disease, doubling of serum creatinine, renal or CV death	June 2019
VERTIS CV trial (NCT01986881)	HbA1c 7.0%–10.5%; ≥40 years; history or evidence of atherosclerotic vascular disease	8000	Ertugliflozin 5 mg versus ertugliflozin 15 mg versus placebo	Composite: CV death, non-fatal MI, or non- fatal stroke	October 2019

Notes: REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes (https://clinicaltrials.gov/ct2/show/NCT01394952); HARMONY Outcomes, Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus (https://clinicaltrials.gov/ct2/show/record/NCT02465515); CAROLINA, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (https://clinicaltrials.gov/ct2/show/NCT01243424); CARMELINA, Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (https://clinicaltrials.gov/ct2/show/NCT01897532); CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (https://clinicaltrials.gov/ct2/show/NCT02065791); DECLARE-TIMI 58, Dapagliflozin Effects on Cardiovascular Events – Thrombolysis in Myocardial Infarction (https://clinicaltrials.gov/ct2/show/NCT01730534); VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (https://clinicaltrials.gov/ct2/show/NCT01986881) (listed by alphabetical order of drug class and then by chronological order of estimated study end date).

a Citation listed if study details were published.

b Data per ClinicalTrials.gov.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; MI, myocardial infarction; SGLT2, sodium glucose cotransporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; UA, unstable angina; UACR, urine albumin to creatinine ratio.

Table 3 Summary of results from CV outcome trials of glucose-lowering drugs in patients with T2DM showing reduction in risk of CV events versus placebo

Trial name	Drug	Effect on risk of CV outcome		CV indications per US prescribing information
EMPA-REG OUTCOME^Citation23	Empagliflozin	MACE	↓	To reduce the risk of CV death in adult patients with T2DM and established CV disease
		All-cause mortalitya	↓
		CV mortality	↓
		Non-fatal MI	NSD
		Non-fatal stroke	NSD
		Hospitalization for heart failurea	↓
LEADER^Citation17	Liraglutide	MACE	↓	To reduce the risk of MACE (CV death, non-fatal MI, or non-fatal stroke) in adults with T2DM and established CV diseasec
		All-cause mortalitya	↓
		CV mortality	↓
		Non-fatal MI	NSD
		Non-fatal stroke	NSD
		Hospitalization for heart failurea	NSD
SUSTAIN-6^Citation18	Semaglutide	MACE	↓	Not FDA approved to date; FDA regulatory submission in progress
		All-cause mortalitya	NSD
		CV mortality	NSD
		Non-fatal MI	NSD
		Non-fatal stroke	↓
		Hospitalization for heart failurea	NSD
CANVAS Program^Citation24	Canagliflozin	MACE	↓	No FDA-approved CV indications to date; supplemental New Drug Application submitted to FDA for new indication to reduce risk of MACE, October 2017
		All-cause mortalitya	b
		CV mortality	b
		Non-fatal MI	b
		Non-fatal stroke	b
		Hospitalization for heart failurea	b

Notes: EMPA-REG OUTCOME, Empagliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; CANVAS Program, CANVAS, Canagliflozin Cardiovascular Assessment Study, + CANVAS-R, A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (listed in chronological order of primary publication).

a Not part of MACE outcome.

b Hypothesis testing was discontinued, as superiority versus placebo was not shown for all-cause mortality (which was the first secondary outcome in the testing sequence).²⁴

c The FDA decision was based on results from the LEADER trial, which demonstrated that liraglutide reduced the risk of MACE by 13% versus placebo (p = 0.01 for superiority),²⁹ with an absolute risk reduction of 1.9%; this was driven by a significant reduction in CV death (absolute risk reduction of 1.3%), with numerical (but not statistically significant) favorable differences in non-fatal MI and non-fatal stroke.³⁰

Abbreviations: ↓, statistically significant decrease; CV, cardiovascular; FDA, US Food and Drug Administration; MACE, major adverse cardiovascular event; MI, myocardial infarction; NSD, no statistically significant difference; T2DM, type 2 diabetes mellitus.

Table 4 EMPA-REG OUTCOME: primary and selected secondary CV outcomes²³

Outcome	Empagliflozin pooled (N = 4687) n (%)	Placebo (N = 2333) n (%)	Hazard ratio (95% CI)	p-valuea
Median treatment and observation time, years (interquartile range)
Treatment	2.6 (2.0–3.4)	2.6 (1.8–3.4)
Observation	3.2 (2.2–3.6)	3.1 (2.2–3.5)
Primary outcome
Death from CV causes, non-fatal MI, or non-fatal stroke	490 (10.5)	282 (12.1)	0.86 (0.74, 0.99)b	Non-inferiority <0.001 Superiority 0.04
Key secondary outcomes
Death from CV causes, non-fatal MI, non-fatal stroke, or hospitalization for UA	599 (12.8)	333 (14.3)	0.89 (0.78, 1.01)	Non-inferiority <0.001 Superiority 0.08
Death from any cause	269 (5.7)	194 (8.3)	0.68 (0.57, 0.82)	<0.001
Death from CV causes	172 (3.7)	137 (5.9)	0.62 (0.49, 0.77)	<0.001
Fatal or non-fatal MI excluding silent MI	223 (4.8)	126 (5.4)	0.87 (0.70, 1.09)	0.23
Non-fatal MI excluding silent MI	213 (4.5)	121 (5.2)	0.87 (0.70, 1.09)	0.22
Hospitalization for UA	133 (2.8)	66 (2.8)	0.99 (0.74, 1.34)	0.97
Fatal or non-fatal stroke	164 (3.5)	69 (3.0)	1.18 (0.89, 1.56)	0.26
Non-fatal stroke	150 (3.2)	60 (2.6)	1.24 (0.92, 1.67)	0.16
Hospitalization for heart failure	126 (2.7)	95 (4.1)	0.65 (0.50, 0.85)	0.002

Notes:

a One-sided p-values are shown for tests of non-inferiority; two-sided p-values are shown for tests of superiority.

b 95.02% CI.

Abbreviations: CI, confidence interval; CV, cardiovascular; EMPA-REG OUTCOME, Empagliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients; MI, myocardial infarction; UA, unstable angina.

Table 5 Clinical trials of sodium glucose cotransporter 2 inhibitors that are underway to investigate heart failure or atherosclerosis

Agent and indication	Trial name and detailsa
Canagliflozin + heart failure	Treatment of Diabetes in Patients With Systolic Heart Failure https://clinicaltrials.gov/ct2/show/NCT02920918
Dapagliflozin + heart failure	Dapagliflozin in Type 2 Diabetes or Pre-diabetes, and PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF) https://clinicaltrials.gov/ct2/show/NCT03030235
	Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (Dapa-HF) https://clinicaltrials.gov/ct2/show/NCT03036124
	Dapagliflozin Effect on Symptoms and Biomarkers in Diabetes Patients With Heart Failure (DEFINE-HF) https://clinicaltrials.gov/ct2/show/NCT02653482
	Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes (REFORM) https://clinicaltrials.gov/ct2/show/NCT02397421
Empagliflozin + heart failure	EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) https://clinicaltrials.gov/ct2/show/NCT03057977
	EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) https://clinicaltrials.gov/ct2/show/NCT03057951
Dapagliflozin + atherosclerosis	Effect of Dapagliflozin on Vascular Functions in Patients With Type 2 Diabetes Compared to Gliclazide https://clinicaltrials.gov/ct2/show/NCT02610088
Empagliflozin + atherosclerosis	Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial^Citation103 Unique Trial Number (Japan): UMIN000024502

Notes:

a Clinical trial registry website (US National Institutes of Health); citation listed if study details have been published.

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