Metabolic syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a post hoc analyses of the EMPA-REG OUTCOME trial

Abstract

Background: Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial.

Methods: A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10 mg or 25 mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models.

Results: MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR = 1.73 (95% CI 1.01-2.98), heart failure hospitalization: HR = 2.64 (95% CI 1.22, 5.72), and new or worsening nephropathy: HR = 3.11 (95% CI 2.17-4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS.

Conclusions: A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS. Trial registration Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.

Keywords: Cardiovascular disease; Empagliflozin; Metabolic syndrome; Treatment effect; Type 2 diabetes mellitus.

Conflict of interest statement

J.P.F. has received travelling fees from Behringer Ingelheim. S.V. is President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization; holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; S.V. has also received grants and personal fees for speaker honoraria and advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Merck. He has received grants and personal fees for advisory board participation from Amgen, grants from Bristol-Myers Squibb, personal fees for speaker honoraria and advisory board participation from Eli Lilly, Novo Nordisk and Sanofi, and personal fees for speaker honoraria from EOCI Pharmacomm Ltd, Novartis, Sun Pharmaceuticals and Toronto Knowledge Translation Working Group. D.H.F. has received honoraria from Amgen, AstraZeneca, BI, Eli Lilly and Company, Merck & Co., and Sanofi. C.W. has received honoraria for consultancy and lecturing from AstraZeneca, Bayer, BI, GlaxoSmithKline, Eli Lilly and Company, Merck Sharp & Dome, Mundipharma, Sanofi Genzyme, and Takeda. B.Z. has received research grants awarded to his institution from BI, AstraZeneca and Novo Nordisk, and honoraria from Janssen, Sanofi, Eli Lilly and Company, BI, Novo Nordisk and Merck Sharp & Dome. S.E.I. has consulted and/or served on Clinical Trial Steering/Executive/Publications Committees for Boehringer Ingelheim (BI), AstraZeneca, Novo Nordisk, Sanofi/Lexicon Pharmaceuticals, Merck and Abbott. A.P.O, I.Z. and J.T.G. are employees of Boehringer Ingelheim. S.L. has received honoraria for consultancy from BI and F. Hoffmann La Roche.

Figures

Fig. 1

Incidence rates of outcomes in the placebo group in those with versus those without metabolic syndrome at baseline. *Excluding fatal stroke. CV cardiovascular, HHF hospitalization for HF, PY patient years

Fig. 2

Association of metabolic syndrome at baseline and outcomes in the placebo group (patients without metabolic syndrome is reference group). *Excluding fatal stroke. Cox models include terms for baseline age, sex, HbA1c, eGFR, geographical region, treatment, MetS at baseline and treatment*MetS at baseline interaction. CV cardiovascular, HHF hospitalization for heart failure, MetS metabolic syndrome

Fig. 3

Consistent treatment effect of empagliflozin vs. placebo in those with and without metabolic syndrome at baseline. *Excluding fatal stroke. Cox models include terms for baseline age, sex, HbA1c, eGFR, geographical region, treatment, MetS at baseline and treatment*MetS at baseline interaction. p-values for treatment-by-subgroup interaction were obtained from tests of homogeneity of treatment group differences among subgroups with no adjustment for multiple testing. CV cardiovascular, HHF hospitalization for heart failure, MetS metabolic syndrome, py patient-years

Fig. 4

Change from baseline in metabolic outcomes in those with (left panel) vs without (right panel) metabolic syndrome at baseline: a HbA1c, b SBP, c weight, d triglycerides, e HDL, f log(UACR), g waist circumference. Results from MMRM models as described in "Materials and methods" section. HbA1c glycated hemoglobin, HDL-C high-density lipoprotein, SBP systolic blood pressure, UACR urine albumin creatinine ratio

Fig. 4

Change from baseline in metabolic outcomes in those with (left panel) vs without (right panel) metabolic syndrome at baseline: a HbA1c, b SBP, c weight, d triglycerides, e HDL, f log(UACR), g waist circumference. Results from MMRM models as described in "Materials and methods" section. HbA1c glycated hemoglobin, HDL-C high-density lipoprotein, SBP systolic blood pressure, UACR urine albumin creatinine ratio