Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes

Cannon, Christopher P.; Pratley, Richard E.; Dagogo‐Jack, Samuel; Mancuso, James P.; Huyck, Susan; Masiukiewicz, Urszula; Charbonnel, B.; Frederich, Robert; Gallo, Silvina; Cosentino, Francesco; Shih, Weichung J.; Gantz, Ira; Terra, Steven G.; Cherney, David Z.I.; McGuire, Darren K.

doi:10.1056/nejmoa2004967

Cited by 1,135 publications

(1,147 citation statements)

References 14 publications

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“…This meta‐analysis included event‐driven, randomized, placebo‐controlled SGLT2 inhibitor cardiovascular or kidney outcome trials that reported at least one cardiovascular, kidney or mortality outcome by baseline metformin use. Treatment effects by baseline metformin use were obtained from published reports 10–13 . For eligible trials of SGLT2 inhibitors that recruited participants with and without T2DM, we included data only from participants with T2DM.…”

Section: Methodsmentioning

confidence: 99%

Sodium‐glucose co‐transporter‐2 inhibitors with and without metformin: A meta‐analysis of cardiovascular, kidney and mortality outcomes

Neuen

Arnott

Perkovic

et al. 2020

Diabetes Obesity Metabolism

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Aim To assess whether the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use. Material and methods We conducted a meta‐analysis of event‐driven, randomized, placebo‐controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects, reported as hazards ratios (HRs) and 95% confidence intervals (CIs), were pooled using random‐effects meta‐analysis. The main outcomes in this analysis were (i) major adverse cardiovascular events (MACE) and (ii) hospitalization for heart failure (HHF) or cardiovascular death. Results We included six trials of four SGLT2 inhibitors that enrolled a total of 51 743 participants. Baseline metformin use varied from 21% in DAPA‐HF to 82% in DECLARE‐TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87–1.00 and HR 0.82, 95% CI 0.71–0.86, respectively; P‐heterogeneity = 0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors, irrespective of metformin use (HR 0.79, 95% CI 0.73–0.86 and HR 0.74, 95% CI 0.63–0.87, respectively; P‐heterogeneity = 0.48), as well as for major kidney outcomes and all‐cause mortality (all P‐heterogeneity > 0.40). Conclusion Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin.

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Section: Methodsmentioning

confidence: 99%

Sodium‐glucose co‐transporter‐2 inhibitors with and without metformin: A meta‐analysis of cardiovascular, kidney and mortality outcomes

Neuen

Arnott

Perkovic

et al. 2020

Diabetes Obesity Metabolism

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“…Canagliflozin Dapagliflozin Ertugliflozin EMPA-REG Outcome 10,14,31 EMPEROR -REDUCED 16 CANVAS Program 11 CREDENCE 17,32 DECLARE-TIMI 58 12,33 DAPA-HF 15 DAPA-CKD 18 VERTIS-CV 13 Primary Outcome Note: Unless stated otherwise, summaries are reported as N (%) or mean ± SD. Albuminuria is graded according to KDIGO as mild (UACR <30 mg/g), moderate (UACR: 30-300 mg/g) and severe (UACR >300 mg/g).…”

Section: Empagliflozinmentioning

confidence: 99%

“…The CVOTs reported to date include empagliflozin's EMPA-REG Outcome, 10 canagliflozin's integrated CANVAS Program 11 (comprised of two trials: CANVAS and CANVAS-R), dapagliflozin's DECLARE-TIMI-58 12 and ertugliflozin's VERTIS-CV. 13 The EMPA-REG OUT-COME trial, 10,14 demonstrated superiority of empagliflozin for the three-point major cardiovascular event (MACE-3: a composite of cardiovascular death, nonfatal myocardial infarction [MI] or nonfatal stroke), with significantly lower rates of cardiovascular death, hospitalization for heart failure (HHF), all cause death and kidney outcomes.…”

mentioning

confidence: 99%

The cardiovascular outcomes, heart failure and kidney disease trials tell that the time to use Sodium Glucose Cotransporter 2 inhibitors is now

Johansen

Argyropoulos

2020

Clinical Cardiology

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Sodium glucose contrasporter 2 inhibitors (SGLT2i) were initially introduced as a novel class of modestly effective antiglycemics. Over the last 5 years, multiple members of this class have been examined for their cardiovascular safety, effects on heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD) in diverse populations with or without diabetes type 2. The plethora of studies and outcomes examined make it difficult for the practitioner to track the entirety of the evidence. SGLT2i improve cardiorenal outcomes and have a beneficial risk benefit ratio across populations with cardiovascular disease, HFrEF and kidney disease. In this quantitative review, we synthesize the data from the large outcomes trials about the benefits and risks of SGLT2i. SGLT2i reduce all cause, cardiovascular mortality, heart failure hospitalizations, need for dialysis and acute kidney injury as a class effect across a broad range of populations with diabetes Type 2 at risk for cardiovascular disease, patients with HFrEF or CKD with or without diabetes. While certain adverse events for example, diabetic ketoacidosis and genital mycotic infections are reproducibly increased by SGLT2i, the absolute increase in the risk of these complications is smaller than the absolute risk reductions conferred by SGLT2i. Other complications such as amputations, fractures and urinary tract infections are increased to a lesser degree, or not at all (e.g., hypoglycemia). Overall, SGLT2is appear to have a favorable safety profile and thus should be used by cardiologists, nephrologists, endocrinologists, primary care physicians when managing the cardiorenal risk of their patients.

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“…Finally, thirteen studies published up to November 20, 2020, were selected for our meta-analysis according to the inclusion criteria. [12,[28][29][30][31][32][33][34][35][36][37][38][39] Out of thirteen studies, six studies were RCTs that compared SGLT-2 inhibitors (Canagli ozin, [12,29] Dapagli ozin, [31] Empagli ozin, [30] Ertugli ozin [28], and Sotagli ozin [32]) with placebo; seven studies compared GLP-1 RAs (Albiglutide, [34] Dulaglutide weekly, [33] Exenatide weekly, [35] Liraglutide, [37] Lixisenatide, [39] Semaglutide subcutaneously weekly, [38] and Semaglutide oral [36]) with placebo. The pooled population consisted of 20,106 patients in SGLT-2 inhibitor studies (10,716 in the group treated with SGLT-2 inhibitors and 9,390 in the control group) and 12,843 patients in GLP-1 RA studies (6,364 in the group treated with GLP-1 RAs and 6,479 in the control group).…”

Section: Literature Search and Included Studiesmentioning

confidence: 99%

“…For renal outcomes, all studies included ESRD; ve studies included renal death; [28-30, 33, 35] two studies included renal or cardiovascular death; [12,31] one study de ned reduced kidney function as a decrease in eGFR ≥ 30%, [33] three as a decrease in eGFR ≥ 40%, [29,31,35] one as a decrease in eGFR ≥ 50%, [11] and four as a doubling of creatinine. [12,28,30,37] Study characteristics and quality assessment The de nitions of terms, including a composite of renal outcomes and characteristics of the included studies, are listed in Table 1. Table 2 highlights the demographics of included studies.…”

Section: Literature Search and Included Studiesmentioning

confidence: 99%

Cardiovascular and Renal Outcomes with SGLT-2 Inhibitors versus GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Systematic Review and Network Meta-analysis

Yamada

Wakabayashi²,

Bhalla³

et al. 2020

Preprint

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Background Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. Methods We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. Results Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95 %CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]). Conclusions In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

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Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes

Cited by 1,135 publications

References 14 publications

Sodium‐glucose co‐transporter‐2 inhibitors with and without metformin: A meta‐analysis of cardiovascular, kidney and mortality outcomes

Sodium‐glucose co‐transporter‐2 inhibitors with and without metformin: A meta‐analysis of cardiovascular, kidney and mortality outcomes

The cardiovascular outcomes, heart failure and kidney disease trials tell that the time to use Sodium Glucose Cotransporter 2 inhibitors is now

Cardiovascular and Renal Outcomes with SGLT-2 Inhibitors versus GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Systematic Review and Network Meta-analysis

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