Advertisement

Obesity as a modifier of the cardiovascular effectiveness of sodium-glucose cotransporter-2 inhibitors in type 2 diabetes

  • Karine Suissa
    Correspondence
    Corresponding author at: Division of Pharmacoepidemiology and Pharmacoeconomics, Mass General Brigham, 1620 Tremont St, Boston, MA 02120, United States.
    Affiliations
    Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
    Search for articles by this author
  • Sebastian Schneeweiss
    Affiliations
    Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
    Search for articles by this author
  • Antonios Douros
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada

    Department of Medicine, McGill University, Montreal, Canada

    Institute of Clinical Pharmacology and Toxicology, Charité – Universitätsmedizin Berlin, Berlin, Germany
    Search for articles by this author
  • Hui Yin
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
    Search for articles by this author
  • Elisabetta Patorno
    Affiliations
    Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
    Search for articles by this author
  • Laurent Azoulay
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada

    Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
    Search for articles by this author
Published:September 24, 2022DOI:https://doi.org/10.1016/j.diabres.2022.110094

      Abstract

      Aims

      To assess the association between the use of sodium-glucose cotransporter-2 (SGLT2i) and cardiovascular outcomes and death as a function of obesity among patients with type 2 diabetes.

      Methods

      This new-user, active-comparator cohort study used U.K.’s Clinical Practice Research Datalink linked to Hospital Episodes Statistics repository and Office for National Statistics. The cohort included 34,128 new-users of SGLT2i matched 1:1 to 34,128 new-users of dipeptidyl peptidase-4 inhibitors (DPP-4i) on body mass index and propensity score. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), overall and in body mass index (BMI) categories (≤24.9 kg/m2, 25.0–29.9 kg/m2, 30.0–39.9 kg/m2, ≥40 kg/m2). Secondary outcomes included all-cause mortality and hospitalization for heart failure.

      Results

      SGLT2i were associated with a decreased risk of MACE (HR: 0.78, 95 %CI: 0.69–0.88) compared to DPP-4i. This decreased risk was most pronounced among obese and severely obese patients (HR: 0.77, 95 %CI: 0.66–0.91; HR: 0.67, 95% CI: 0.49–0.91, respectively) but not among overweight patients (HR: 0.94, 95 %CI: 0.73–1.22). Similar patterns were observed for cardiovascular mortality, all-cause mortality, and heart failure.

      Conclusion

      Compared with DPP-4i, the cardioprotective effect associated with SGLT2i is stronger among patients with higher BMI.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • Fitchett D.
        • Bluhmki E.
        • Hantel S.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128https://doi.org/10.1056/NEJMoa1504720
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • de Zeeuw D.
        • Fulcher G.
        • Erondu N.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657https://doi.org/10.1056/NEJMoa1611925
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • Mosenzon O.
        • Kato E.T.
        • Cahn A.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357https://doi.org/10.1056/NEJMoa1812389
        • Cheymol G.
        Effects of obesity on pharmacokinetics implications for drug therapy.
        Clin Pharmacokinet. 2000; 39: 215-231https://doi.org/10.2165/00003088-200039030-00004
        • Hanley M.J.
        • Abernethy D.R.
        • Greenblatt D.J.
        Effect of obesity on the pharmacokinetics of drugs in humans.
        Clin Pharmacokinet. 2010; 49: 71-87https://doi.org/10.2165/11318100-000000000-00000
      1. Liebig S, Martin HJ, Mark M, E; M. Comparison in tissue distribution and selectivity among the 3 sodium-glucose co-transporter inhibitors empagliflozin, dapagliflozin and canagliflozin. In. European Association for the Study of Diabetes: Virtual Meeting. Munich, Germany; 2016.

        • Herrett E.
        • Thomas S.L.
        • Schoonen W.M.
        • Smeeth L.
        • Hall A.J.
        Validation and validity of diagnoses in the general practice research database: a systematic review.
        Br J Clin Pharmacol. 2010; 69: 4-14https://doi.org/10.1111/j.1365-2125.2009.03537.x
        • Yandrapalli S.
        • Jolly G.
        • Horblitt A.
        • Sanaani A.
        • Aronow W.S.
        Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus.
        Postgrad Med. 2017; 129: 811-821https://doi.org/10.1080/00325481.2017.1358064
        • Fernandez C.J.
        • Radhakrishnan C.
        Efficacy and cardiovascular safety of insulins.
        Curr Drug Saf. 2021; 16: 217-232https://doi.org/10.2174/1574886315999201105153458
      2. WHO. Obesity: Preventing and managing the global epidemic. Geneva, Switzerland; WHO; 2000.

      3. Inzucchi SE, Wanner C, Hehnke U, et al. Retinopathy Outcomes With Empagliflozin Versus Placebo in the EMPA-REG OUTCOME Trial. Diabetes Care 2019;42:e53-e55. doi: 10.2337/dc18-1355.

        • Kim N.H.
        • Choi J.
        • Kim N.H.
        • Choi K.M.
        • Baik S.H.
        • Lee J.
        • et al.
        Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: a population-based study.
        Diabetes Metab. 2018; 44: 361-367https://doi.org/10.1016/j.diabet.2018.03.004
        • Nikolic M.
        • Zivkovic V.
        • Jovic J.J.
        • Sretenovic J.
        • Davidovic G.
        • Simovic S.
        • et al.
        SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms.
        Heart Fail Rev. 2022; 27: 935-949https://doi.org/10.1007/s10741-021-10079-9
        • Ohkuma T.
        • Van Gaal L.
        • Shaw W.
        • Mahaffey K.W.
        • Zeeuw D.
        • Matthews D.R.
        • et al.
        Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program.
        Diabetes Obes Metab. 2020; 22: 530-539https://doi.org/10.1111/dom.13920
        • Cheymol G.
        Clinical pharmacokinetics of drugs in obesity.
        An update Clin Pharmacokinet. 1993; 25: 103-114https://doi.org/10.2165/00003088-199325020-00003
        • Bruno C.D.
        • Harmatz J.S.
        • Duan S.X.
        • Zhang Q.
        • Chow C.R.
        • Greenblatt D.J.
        Effect of lipophilicity on drug distribution and elimination: Influence of obesity.
        Br J Clin Pharmacol. 2021; 87: 3197-3205https://doi.org/10.1111/bcp.14735
        • Sell H.
        • Blüher M.
        • Klöting N.
        • Schlich R.
        • Willems M.
        • Ruppe F.
        • et al.
        Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro.
        Diabetes Care. 2013; 36: 4083-4090https://doi.org/10.2337/dc13-0496
        • Aso Y.
        • Ozeki N.
        • Terasawa T.
        • Naruse R.
        • Hara K.
        • Suetsugu M.
        • et al.
        Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea.
        Transl Res. 2012; 159: 25-31https://doi.org/10.1016/j.trsl.2011.09.005
        • Muscelli E.
        • Mari A.
        • Casolaro A.
        • Camastra S.
        • Seghieri G.
        • Gastaldelli A.
        • et al.
        Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients.
        Diabetes. 2008; 57: 1340-1348https://doi.org/10.2337/db07-1315
        • Schienkiewitz A.
        • Schulze M.B.
        • Hoffmann K.
        • Kroke A.
        • Boeing H.
        Body mass index history and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-potsdam study.
        Am J Clin Nutr. 2006; 84: 427-433https://doi.org/10.1093/ajcn/84.1.427
        • Edwards C.H.
        • Aas E.
        • Kinge J.M.
        Body mass index and lifetime healthcare utilization.
        BMC Health Serv Res. 2019; 19: 696https://doi.org/10.1186/s12913-019-4577-0
        • Zaccardi F.
        • Webb D.R.
        • Htike Z.Z.
        • Youssef D.
        • Khunti K.
        • Davies M.J.
        Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis.
        Diabetes Obes Metab. 2016; 18: 783-794https://doi.org/10.1111/dom.12670
        • Pereira M.J.
        • Eriksson J.W.
        Emerging role of sglt-2 inhibitors for the treatment of obesity.
        Drugs. 2019; 79: 219-230https://doi.org/10.1007/s40265-019-1057-0
        • Schork A.
        • Saynisch J.
        • Vosseler A.
        • Jaghutriz B.A.
        • Heyne N.
        • Peter A.
        • et al.
        Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy.
        Cardiovasc Diabetol. 2019; 18https://doi.org/10.1186/s12933-019-0852-y
        • Lee P.C.
        • Ganguly S.
        • Goh S.-Y.
        Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms.
        Obes Rev. 2018; 19: 1630-1641https://doi.org/10.1111/obr.12755
        • Guh D.P.
        • Zhang W.
        • Bansback N.
        • Amarsi Z.
        • Birmingham C.L.
        • Anis A.H.
        The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.
        BMC Public Health. 2009; 9https://doi.org/10.1186/1471-2458-9-88
        • Apovian C.M.
        • Okemah J.
        • O’Neil P.M.
        Body weight considerations in the management of type 2 diabetes.
        Adv Ther. 2019; 36: 44-58https://doi.org/10.1007/s12325-018-0824-8
        • Arana A.
        • Margulis A.V.
        • Varas‐Lorenzo C.
        • Bui C.L.
        • Gilsenan A.
        • McQuay L.J.
        • et al.
        Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.
        Pharmacoepidemiol Drug Saf. 2021; 30: 237-247https://doi.org/10.1002/pds.5150
        • Green J.B.
        • Bethel M.A.
        • Armstrong P.W.
        • Buse J.B.
        • Engel S.S.
        • Garg J.
        • et al.
        Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2015; 373: 232-242https://doi.org/10.1056/NEJMoa1501352
        • Rosenstock J.
        • Perkovic V.
        • Johansen O.E.
        • Cooper M.E.
        • Kahn S.E.
        • Marx N.
        • et al.
        Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.
        JAMA. 2019; 321: 69https://doi.org/10.1001/jama.2018.18269
        • Scirica B.M.
        • Bhatt D.L.
        • Braunwald E.
        • Steg P.G.
        • Davidson J.
        • Hirshberg B.
        • et al.
        Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
        N Engl J Med. 2013; 369: 1317-1326https://doi.org/10.1056/NEJMoa1307684
        • White W.B.
        • Cannon C.P.
        • Heller S.R.
        • Nissen S.E.
        • Bergenstal R.M.
        • Bakris G.L.
        • et al.
        Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
        N Engl J Med. 2013; 369: 1327-1335https://doi.org/10.1056/NEJMoa1305889