Advertisement

Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors

  • Soo Lim
    Affiliations
    Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea
    Search for articles by this author
  • Robert H. Eckel
    Correspondence
    Corresponding author. Division of Endocrinology, Diabetes and Metabolism and Division or Cardiology, Department of Medicine, University of Colorado, Anschutz Medical Campus, 12801 East 17th Ave., RC1 South, Room 7107, Aurora, CO 80045, USA.
    Affiliations
    Division of Endocrinology, Metabolism and Diabetes, and Division of Cardiology, Department of Medicine, University of Colorado, Aurora, CO, USA
    Search for articles by this author
  • Kwang Kon Koh
    Correspondence
    Corresponding author. Cardiometabolic Syndrome Unit, Department of Cardiovascular Medicine, Gachon University, Gil Medical Center, 774 Beongil 21, Namdongdaero, Namdong-Gu, Incheon, 21565, South Korea.
    Affiliations
    Department of Cardiovascular Medicine, Heart Center, Gachon University Gil Medical Center, Incheon, South Korea

    Gachon Cardiovascular Research Institute, Incheon, South Korea
    Search for articles by this author

      Highlights

      • Most clinical trials with DPP4 inhibitors have shown no inferiority compared with placebo treatments in terms of CV safety.
      • CV outcome trials with GLP1 receptor agonists showed inconsistent results.
      • Two large-scale CV outcome trials with SGLT2 inhibitors showed very significant results.
      • Controlling cardiometabolic risk factors by SGLT2 inhibitors are suggested to be the main mechanisms.

      Abstract

      The final goal in the management of patients with type 2 diabetes (T2D) is reduction in cardiovascular (CV) complications and total mortality. Various factors including hyperglycemia contribute to these complications and mortality directly and indirectly. In recent years, large-scale CV outcome trials with new antidiabetic medications, such as dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and sodium glucose cotransporter-2 (SGLT2) inhibitors, have been completed. Most clinical trials with DPP4 inhibitors have shown no inferiority compared with placebo treatments in terms of CV safety. However, they did not show benefits in terms of adverse CV events or mortality. CV outcome trials with GLP1 receptor agonists showed inconsistent results: lixisenatide did not show benefits in preventing major adverse CV events. In contrast, liraglutide and semaglutide (longer acting GLP1 receptor agonists) proved to be superior in terms of alleviating CV morbidity and mortality. Two large-scale CV outcome trials with SGLT2 inhibitors showed significant results: empagliflozin proved to be superior in preventing CV and all-cause mortality, and canagliflozin proved to be superior in preventing CV mortality but not all-cause mortality. So far, controlling cardiometabolic risk factors such as hemodynamic changes and weight loss by SGLT2 inhibitors are suggested to be the main mechanisms for these results. However, the risk–benefit profile for these new drugs will need further elucidation, and more studies are warranted to reveal the possible mechanisms. It will also be important to confirm these results from other ongoing trials with SGLT2 inhibitors.

      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 Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Nissen S.E.
        • Wolski K.
        Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
        N. Engl. J. Med. 2007; 356: 2457-2471
        • Duckworth W.
        • Abraira C.
        • Moritz T.
        • et al.
        Glucose control and vascular complications in veterans with type 2 diabetes.
        N. Engl. J. Med. 2009; 360: 129-139
        • Gerstein H.C.
        • Miller M.E.
        • Genuth S.
        • et al.
        Long-term effects of intensive glucose lowering on cardiovascular outcomes.
        N. Engl. J. Med. 2011; 364: 818-828
        • Patel A.
        • MacMahon S.
        • Chalmers J.
        • et al.
        Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
        N. Engl. J. Med. 2008; 358: 2560-2572
        • Green J.B.
        • Bethel M.A.
        • Armstrong P.W.
        • et al.
        Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
        N. Engl. J. Med. 2015; 373: 232-242
        • White W.B.
        • Cannon C.P.
        • Heller S.R.
        • et al.
        Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
        N. Engl. J. Med. 2013; 369: 1327-1335
        • Scirica B.M.
        • Bhatt D.L.
        • Braunwald E.
        • et al.
        Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
        N. Engl. J. Med. 2013; 369: 1317-1326
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N. Engl. J. Med. 2015; 373: 2247-2257
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N. Engl. J. Med. 2016; 375: 1834-1844
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N. Engl. J. Med. 2016; 375: 311-322
        • Holman R.R.
        • Bethel M.A.
        • Mentz R.J.
        • et al.
        Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
        N. Engl. J. Med. 2017 Dec 21; 377: 2502
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N. Engl. J. Med. 2015; 373: 2117-2128
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N. Engl. J. Med. 2017; 377: 644-657
        • Fadini G.P.
        • Avogaro A.
        SGTL2 inhibitors and amputations in the US FDA adverse event reporting system.
        Lancet Diabetes Endocrinol. 2017 Sep; 5: 680-681
        • Koh K.K.
        Letter by Koh regarding Article, “Randomized trials to evaluate cardiovascular safety of antihyperglycemic medications: a worthwhile Effort?”.
        Circulation. 2016; 134: e650-e651
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N. Engl. J. Med. 2016; 375: 323-334
        • Kosiborod M.
        • Cavender M.A.
        • Fu A.Z.
        • et al.
        Lower risk of heart failure and death in patients initiated on sodium-glucose Cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose Cotransporter-2 inhibitors).
        Circulation. 2017; 136: 249-259
        • Gerich J.E.
        Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications.
        Diabet. Med. 2010; 27: 136-142
        • DeFronzo R.A.
        • Davidson J.A.
        • Del Prato S.
        The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia.
        Diabetes Obes. Metabol. 2012; 14: 5-14
        • Hippisley-Cox J.
        • Coupland C.
        Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care.
        BMJ. 2016; 354 (i3477)
        • Palmer S.C.
        • Mavridis D.
        • Nicolucci A.
        • et al.
        Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis.
        J. Am. Med. Assoc. 2016; 316: 313-324
        • Han J.H.
        • Oh T.J.
        • Lee G.
        • et al.
        The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE -/- mice fed a western diet.
        Diabetologia. 2017; 60: 364-376
        • Lim S.
        • Lee G.Y.
        • Park H.S.
        • et al.
        Attenuation of carotid neointimal formation after direct delivery of a recombinant adenovirus expressing glucagon-like peptide-1 in diabetic rats.
        Cardiovasc. Res. 2017; 113: 183-194
        • Chilton R.
        • Tikkanen I.
        • Cannon C.P.
        • et al.
        Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.
        Diabetes Obes. Metabol. 2015; 17: 1180-1193
        • Cherney D.Z.
        • Perkins B.A.
        • Soleymanlou N.
        • et al.
        Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.
        Circulation. 2014; 129: 587-597
        • Kobori H.
        • Nangaku M.
        • Navar L.G.
        • et al.
        The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.
        Pharmacol. Rev. 2007; 59: 251-287
        • Schoolwerth A.C.
        • Sica D.A.
        • Ballermann B.J.
        • et al.
        Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the council on the kidney in cardiovascular disease and the council for high blood pressure research of the american heart association.
        Circulation. 2001; 104: 1985-1991
        • Ferrannini E.
        • Solini A.
        SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects.
        Nat. Rev. Endocrinol. 2012; 8: 495-502
        • Bolinder J.
        • Ljunggren O.
        • Kullberg J.
        • et al.
        Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.
        J. Clin. Endocrinol. Metab. 2012; 97: 1020-1031
        • Yamamoto C.
        • Miyoshi H.
        • Ono K.
        • et al.
        Ipragliflozin effectively reduced visceral fat in Japanese patients with type 2 diabetes under adequate diet therapy.
        Endocr. J. 2016; 63: 589-596
        • Tang L.
        • Wu Y.
        • Tian M.
        • et al.
        Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes.
        Am. J. Physiol. Endocrinol. Metab. 2017; 313: E563-E576
        • Ito D.
        • Shimizu S.
        • Inoue K.
        • et al.
        Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial.
        Diabetes Care. 2017; 40: 1364-1372
        • Ferrannini E.
        • Muscelli E.
        • Frascerra S.
        • et al.
        Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.
        J. Clin. Invest. 2014; 124: 499-508
        • Peters A.L.
        • Buschur E.O.
        • Buse J.B.
        • et al.
        Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition.
        Diabetes Care. 2015; 38: 1687-1693
        • Newman J.C.
        • Verdin E.
        Ketone bodies as signaling metabolites.
        Trends Endocrinol. Metabol.: TEM. 2014; 25: 42-52
        • Plaisance E.P.
        • Lukasova M.
        • Offermanns S.
        • et al.
        Niacin stimulates adiponectin secretion through the GPR109A receptor.
        Am. J. Physiol. Endocrinol. Metab. 2009; 296: E549-E558
        • Youm Y.H.
        • Nguyen K.Y.
        • Grant R.W.
        • et al.
        The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.
        Nat. Med. 2015; 21: 263-269
        • Shimazu T.
        • Hirschey M.D.
        • Newman J.
        • et al.
        Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor.
        Science. 2013; 339: 211-214
        • Al Jobori H.
        • Daniele G.
        • Adams J.
        • et al.
        Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients.
        Diabetes Obes. Metabol. 2017; 19: 809-813
        • Ferrannini E.
        • Mark M.
        • Mayoux E.
        CV protection in the EMPA-REG OUTCOME trial: a “Thrifty substrate”.
        Hypothesis. Diabetes Care. 2016; 39: 1108-1114
        • Mudaliar S.
        • Alloju S.
        • Henry R.R.
        Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A unifying hypothesis.
        Diabetes Care. 2016; 39: 1115-1122
        • Min S.H.
        • Oh T.J.
        • Baek S.I.
        • et al.
        Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes.
        Diabetes Metab. 2018; 44: 73-76
        • Bonner C.
        • Kerr-Conte J.
        • Gmyr V.
        • et al.
        Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion.
        Nat. Med. 2015; 21: 512-517
        • Salem V.
        • Izzi-Engbeaya C.
        • Coello C.
        • et al.
        Glucagon increases energy expenditure independently of brown adipose tissue activation in humans.
        Diabetes Obes. Metabol. 2016; 18: 72-81
        • Bailey C.J.
        • Gross J.L.
        • Pieters A.
        • et al.
        Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.
        Lancet. 2010; 375: 2223-2233
        • Nauck M.A.
        • Del Prato S.
        • Meier J.J.
        • et al.
        Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.
        Diabetes Care. 2011; 34: 2015-2022
        • Rosenstock J.
        • Aggarwal N.
        • Polidori D.
        • et al.
        Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes.
        Diabetes Care. 2012; 35: 1232-1238
        • Pieber T.R.
        • Famulla S.
        • Eilbracht J.
        • et al.
        Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1).
        Diabetes Obes. Metabol. 2015; 17: 928-935
        • Briand F.
        • Mayoux E.
        • Brousseau E.
        • et al.
        Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism.
        Diabetes. 2016; 65: 2032-2038
        • Hayashi T.
        • Fukui T.
        • Nakanishi N.
        • et al.
        Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin.
        Cardiovasc. Diabetol. 2017; 16: 8
        • Bando Y.
        • Tohyama H.
        • Aoki K.
        • et al.
        Ipragliflozin lowers small, dense low-density lipoprotein cholesterol levels in Japanese patients with type 2 diabetes mellitus.
        J.Clin. Transl. Endocrinol. 2016; 6: 1-7
        • Ferrannini E.
        • Ramos S.J.
        • Salsali A.
        • et al.
        Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.
        Diabetes Care. 2010; 33: 2217-2224
        • Weber M.A.
        • Mansfield T.A.
        • Alessi F.
        • et al.
        Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade.
        Blood Pres. 2016; 25: 93-103
        • Lu C.H.
        • Min K.W.
        • Chuang L.M.
        • et al.
        Efficacy, safety, and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin: results of a phase 3 randomized, placebo-controlled, double-blind, multicenter trial.
        J. Diabetes Investig. 2016; 7: 366-373
        • Lin B.
        • Koibuchi N.
        • Hasegawa Y.
        • et al.
        Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice.
        Cardiovasc. Diabetol. 2014; 13: 148
        • Bautista R.
        • Manning R.
        • Martinez F.
        • et al.
        Angiotensin II-dependent increased expression of Na+-glucose cotransporter in hypertension.
        Am. J. Physiol. Ren. Physiol. 2004; 286: F127-F133
        • Skrtic M.
        • Yang G.K.
        • Perkins B.A.
        • et al.
        Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration.
        Diabetologia. 2014; 57: 2599-2602
        • Vallon V.
        • Gerasimova M.
        • Rose M.A.
        • et al.
        SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice.
        Am. J. Physiol. Ren. Physiol. 2014; 306: F194-F204
        • Ojima A.
        • Matsui T.
        • Nishino Y.
        • et al.
        Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor Axis.
        Horm. Metab. Res. 2015; 47: 686-692
        • Vallon V.
        • Miracle C.
        • Thomson S.
        Adenosine and kidney function: potential implications in patients with heart failure.
        Eur. J. Heart Fail. 2008; 10: 176-187
        • Skrtic M.
        • Cherney D.Z.
        Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy.
        Curr. Opin. Nephrol. Hypertens. 2015; 24: 96-103
        • List J.F.
        • Woo V.
        • Morales E.
        • et al.
        Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.
        Diabetes Care. 2009; 32: 650-657
        • Iliesiu A.
        • Campeanu A.
        • Dusceac D.
        Serum uric acid and cardiovascular disease.
        Maedica (Buchar). 2010; 5: 186-192
        • Watanabe S.
        • Kang D.H.
        • Feng L.
        • et al.
        Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity.
        Hypertension. 2002; 40: 355-360
        • Corry D.B.
        • Eslami P.
        • Yamamoto K.
        • et al.
        Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.
        J. Hypertens. 2008; 26: 269-275
        • Li P.
        • Zhang L.
        • Zhang M.
        • et al.
        Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: a mechanism for uric acid-induced endothelial dysfunction.
        Int. J. Mol. Med. 2016; 37: 989-997
        • Jung C.H.
        • Jang J.E.
        • Park J.Y.
        A novel therapeutic agent for type 2 diabetes mellitus: SGLT2 inhibitor.
        Diabetes Metab. J. 2014; 38: 261-273
        • Chino Y.
        • Samukawa Y.
        • Sakai S.
        • et al.
        SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria.
        Biopharm Drug Dispos. 2014; 35: 391-404
        • Caulfield M.J.
        • Munroe P.B.
        • O'Neill D.
        • et al.
        SLC2A9 is a high-capacity urate transporter in humans.
        PLoS Med. 2008; 5: e197
        • Terasaki M.
        • Hiromura M.
        • Mori Y.
        • et al.
        Amelioration of hyperglycemia with a sodium-glucose cotransporter 2 inhibitor prevents macrophage-driven atherosclerosis through macrophage foam cell formation suppression in type 1 and type 2 diabetic mice.
        PLoS One. 2015; 10 (e0143396)
        • Barnett A.H.
        • Mithal A.
        • Manassie J.
        • et al.
        Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2014; 2: 369-384
        • Yale J.F.
        • Bakris G.
        • Cariou B.
        • et al.
        Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease.
        Diabetes Obes. Metabol. 2014; 16: 1016-1027
        • Wanner C.
        • Lachin J.M.
        • Inzucchi S.E.
        • et al.
        Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.
        Circulation. 2018; 137: 119-129
        • Dekkers C.C.J.
        • Wheeler D.C.
        • Sjostrom C.D.
        • et al.
        Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b-4 chronic kidney disease.
        Nephrol. Dial. Transplant. 2018 Jan 23; https://doi.org/10.1093/ndt/gfx350
        • American Diabetes A
        8. Pharmacologic approaches to glycemic treatment.
        Diabetes Care. 2017; 40: S64-S74
        • Garber A.J.
        • Abrahamson M.J.
        • Barzilay J.I.
        • et al.
        Consensus statement by the american association of clinical Endocrinologists and american College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2017 executive summary.
        Endocr. Pract. 2017; 23: 207-238
        • Canadian Diabetes Association Clinical Practice Guidelines Expert C
        Pharmacologic management of type 2 diabetes: 2016 interim update.
        Can. J. Diabetes. 2016; 40: 484-486