Impact of SGLT2i on cardiovascular outcomes and heart failure in patients with type 2 diabetes

Juan José Rodríguez; Luis Ortega-Paz; Salvatore Brugaletta; Manel Sabaté; Juan José Rodríguez; Luis Ortega-Paz; Salvatore Brugaletta; Manel Sabaté

doi:10.3934/medsci.2018.1.67

AIMS Medical Science

2018, Volume 5, Issue 1: 67-79. doi: 10.3934/medsci.2018.1.67

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Review

Impact of SGLT2i on cardiovascular outcomes and heart failure in patients with type 2 diabetes

Department of cardiology, cardiovascular institute, hospital clinic, Biomedical Investigation Institute, IDIBAPS, Barcelona, Spain

Received: 11 November 2017 Accepted: 02 January 2018 Published: 17 January 2018

The concurrent management of type 2 diabetes mellitus and heart failure presents several challenges and unmet clinical needs. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new generation of oral hypoglycemic agents, they inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels and contributing to a modest reduction in HbA1C. In two pivotal randomized clinical trial, SGLT2i have showed a clinically important reduction in cardiovascular mortality and hospitalization due to heart failure. However, also important adverse effects such as increased risk of bone fractures and lower limb amputations were found. Currently, physiological mechanisms leading to cardiovascular benefits with SGLT2i are not completely understood, but it seems accepted that some of these benefits are related to non-glycemic effects. In this review, we analyze the available clinical evidence focusing in cardiovascular outcomes and heart failure, physiological mechanism of action, and comment on future directions of research.
- sodium-glucose cotransporter 2 inhibitors,
- dapagliflozin,
- canagliflozin,
- empagliflozin,
- diabetes mellitus,
- cardiovascular outcome trials,
- heart failure
Citation: Juan José Rodríguez, Luis Ortega-Paz, Salvatore Brugaletta, Manel Sabaté. Impact of SGLT2i on cardiovascular outcomes and heart failure in patients with type 2 diabetes[J]. AIMS Medical Science, 2018, 5(1): 67-79. doi: 10.3934/medsci.2018.1.67

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Abstract

The concurrent management of type 2 diabetes mellitus and heart failure presents several challenges and unmet clinical needs. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new generation of oral hypoglycemic agents, they inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels and contributing to a modest reduction in HbA1C. In two pivotal randomized clinical trial, SGLT2i have showed a clinically important reduction in cardiovascular mortality and hospitalization due to heart failure. However, also important adverse effects such as increased risk of bone fractures and lower limb amputations were found. Currently, physiological mechanisms leading to cardiovascular benefits with SGLT2i are not completely understood, but it seems accepted that some of these benefits are related to non-glycemic effects. In this review, we analyze the available clinical evidence focusing in cardiovascular outcomes and heart failure, physiological mechanism of action, and comment on future directions of research.

References

[1]	Using D, Criteria C (2010) Prevalence of Diabetes and High Risk for Population in 1988–2006. Diabetes Care 33: 562–568. doi: 10.2337/dc09-1524
[2]	Cas AD, Khan SS, Butler J, et al. (2015) Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Hear Fail 3: 136–145. doi: 10.1016/j.jchf.2014.08.004
[3]	Varas-Lorenzo C, Margulis AV, Pladevall M, et al. (2014) The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: Systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord 14: 129. doi: 10.1186/1471-2261-14-129
[4]	Wilding JP, Rajeev SP, DeFronzo RA (2016) Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm. Diabetes Care 39(Supplement 2): S154–S164.
[5]	Zinman B, Wanner C, Lachin JM, et al. ( 2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117–2128.
[6]	Neal B, Perkovic V, Mahaffey KW, et al. (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377: 644–657. doi: 10.1056/NEJMoa1611925
[7]	Scheen AJ (2016) DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: From rationale to clinical aspects. Expert Opin Drug Metab Toxicol 12: 1. doi: 10.1517/17425255.2016.1116520
[8]	Heerspink HJL, Perkins BA, Fitchett DH, et al. (2016) Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation 134: 752–772. doi: 10.1161/CIRCULATIONAHA.116.021887
[9]	Kim ES, Deeks ED (2015) Empagliflozin/Linagliptin: A review in type 2 diabetes. Drugs 75: 1547–1557. doi: 10.1007/s40265-015-0457-z
[10]	Rosenwasser RF, Sultan S, Sutton D, et al. (2013) SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes, Metab Syndr Obes: Targets Ther 6: 453–467.
[11]	Peters AL, Buschur EO, Buse JB, et al. (2015) Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 38: 1687–1693. doi: 10.2337/dc15-0843
[12]	Bailey CJ (2013) Interpreting adverse signals in diabetes drug development programs. Diabetes Care 36: 2098–2106. doi: 10.2337/dc13-0182
[13]	Fitchett D, Zinman B, Wanner C, et al. (2016) Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG outcome® trial. Eur Heart J 37: 1526–1534. doi: 10.1093/eurheartj/ehv728
[14]	Chang LC, Mahmood R, Qureshi S,et al. (2017) Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications. PLoS One 12: e0178104. doi: 10.1371/journal.pone.0178104
[15]	Fitchett D, Butler J, Borne P Van De, et al. (2017) Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG outcome® trial. Eur Heart J.
[16]	Home PD, Pocock SJ, Beck-Nielsen H, et al. (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet 373: 2125–2135. doi: 10.1016/S0140-6736(09)60953-3
[17]	Scirica BM, Bhatt DL, Braunwald E, et al. (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369: 1317–1326. doi: 10.1056/NEJMoa1307684
[18]	Pfeffer MA, Claggett B, Diaz R, et al. (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373: 2247–2257. doi: 10.1056/NEJMoa1509225
[19]	Marso SP, Bain SC, Consoli A, et al. (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375: 1834–1844. doi: 10.1056/NEJMoa1607141
[20]	Marso SP, Daniels GH, Brown-Frandsen K, et al. (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375: 311–322. doi: 10.1056/NEJMoa1603827
[21]	Holman RR, Bethel MA, Mentz RJ, et al. (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 377: 1228. doi: 10.1056/NEJMoa1612917
[22]	Lytvyn Y, Bjornstad P, Udell JA,et al. (2017) Sodium glucose cotransporter-2 inhibition in heart failure. Circulation 136: 1643. doi: 10.1161/CIRCULATIONAHA.117.030012
[23]	Verma S, McMurray JJV, Cherney DZI. (2017) The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition. JAMA Cardiol.
[24]	Packer M, Anker SD, Butler J, et al. (2017) Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure. JAMA Cardiol 143: 29–35.
[25]	Wu JHY, Foote C, Blomster J, et al. (2016) Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: A systematic review and meta-analysis. Lancet Diabetes Endocrinol 4: 411–419. doi: 10.1016/S2213-8587(16)00052-8
[26]	Inoue BH, Dos SL, Pessoa TD, et al. (2012) Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol: Regul, Integr Comp Physiol 302: R166–R174. doi: 10.1152/ajpregu.00127.2011
[27]	Pessoa TD, Campos LCG, Carraro-Lacroix L, et al. (2014) Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na⁺/H⁺ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol 25: 2028–2039. doi: 10.1681/ASN.2013060588
[28]	ClinicalTrials.gov [Internet]. Identifier NCT03030235, Dapagliflozin in type 2 diabetes or pre-diabetes, and preserved ejection fraction heart failure (PRESERVED-HF), 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT03030235?term=NCT03030235&rank=1.
[29]	ClinicalTrials.gov [Internet]. Identifier NCT03190694, Effects of dapagliflozin in non-diabetic patients with proteinuria (DIAMOND), 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT03190694?term=NCT03190694&rank=1.
[30]	Tahara A, Takasu T, Yokono M, et al. (2016) Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. J Pharmacol Sci 130: 159–169. doi: 10.1016/j.jphs.2016.02.003
[31]	ClinicalTrials.gov [Internet]. Identifier NCT01730534, Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58), 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534?term=NCT01730534&rank=1.
[32]	ClinicalTrials.gov [Internet]. Identifier NCT03057977, Empagliflozin outcome trial in patients with chronic heart failure with reduced ejection fraction (EMPEROR-Reduced), 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT03057977?term=NCT03057977&rank=1.
[33]	ClinicalTrials.gov [Internet]. Identifier NCT03057951, Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction (EMPEROR-Preserved), 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT03057951?term=NCT03057951&rank=1.
[34]	ClinicalTrials.gov [Internet]. Identifier NCT03036124, 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), 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT03036124?term=NCT03036124&rank=1.

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