Article

Sodium–Glucose Cotransporter-2 Inhibitors and Heart Failure Prevention in Type 2 Diabetes

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Average (ratings)
No ratings
Your rating

Abstract

Diabetes and heart failure (HF) are closely linked, with one causing a worse prognosis in the other. The majority of anti-hyperglycaemic agents primarily reduce risk of ischaemic microvascular events without targeting the mechanisms involved for diabetes cardiomyopathy and HF. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a novel class of glucose-lowering agents that have consistently reduced HF hospitalisations, unlike other agents. The authors discuss the current evidence and highlight possible future directions for the role of SGLT2 inhibitors in HF prevention.

Disclosure:JB has received research support from the NIH, Patient-Centered Outcomes Research Institute and the EU. He serves as a consultant for Abbott, Adrenomed, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, CVRx, Innolife, Janssen, LinaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, V-Wave and Vifor. MSK has no has no conflicts of interest to declare.

Received:

Accepted:

Correspondence Details:Javed Butler, Department of Medicine, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, US. E: jbutler4@umc.edu

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

In 2008, the European Medicines Agency and US Food and Drug Administration (FDA) issued industry guidance stating that all future novel glucose-lowering agent trials must undergo routine cardiovascular risk evaluation either before approval or as a post-marketing commitment.1 This mandated that all cardiovascular endpoint committees prospectively adjudicate all major adverse cardiovascular events, including cardiovascular death, non-fatal MI and stroke, occurring across Phase II and III diabetes trials. However, the statement did not specifically mention heart failure (HF) as an endpoint.

HF is the second most common cardiovascular presentation of diabetes after peripheral arterial disease.2 In people with diabetes, mortality from HF constitutes a large proportion of overall mortality. Moreover, approximately 40% of hospitalised HF patients have concomitant diabetes, a trend that is expected to increase even further.3–5 Both diabetes and HF are closely linked, with one causing a worse prognosis in the other. The majority of anti-hyperglycaemic agents primarily reduce the risk of ischaemic microvascular events without targeting the mechanisms involved for diabetes cardiomyopathy and HF.

Some glucose-lowering agents, such as thiazolidinediones and saxigliptin, have been linked to increased risk of incident HF and HF hospitalisations.6,7 Other drugs, such as liraglutide, have shown overall cardiovascular benefit without specifically improving outcomes in established HF patients.8 However, unlike other anti-hyperglycaemics, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a novel class of glucose-lowering agents that have consistently reduced HF hospitalisations.9–15 This class of medication works by selectively inhibiting SGLT2, thus causing decreased renal absorption of glucose. Multiple studies have shown that SGLT2 inhibitors are associated with weight loss and blood pressure reduction in addition to glycaemic control.16 In this article, we discuss the current evidence and highlight the future direction for SGLT2 inhibitors in HF prevention.

Evidence from Randomised Clinical Trial and Observational Data

There are three completed cardiovascular safety trials for SGLT2 inhibitors: EMPAgliflozin cardiovascular outcome event trial in type 2 diabetes – Removing Excess Glucose (EMPA-REG OUTCOME), CANagliflozin cardioVascular Assessment Study (CANVAS) and Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58).9,11,12

In EMPA-REG OUTCOME, 7,020 people with diabetes and established cardiovascular disease were randomised to empagliflozin or placebo.9 The primary endpoint of the trial – major adverse cardiovascular events – was significantly reduced (HR 0.86; 95% CI [0.74–0.99]; p=0.04) in the empagliflozin arm. HF hospitalisation was an undefined secondary outcome. Compared with placebo, empagliflozin significantly reduced the risk of HF hospitalisations (4.1% versus 2.7%; HR 0.65; 95% CI [0.50–0.85]) and composite outcome of HF hospitalisations and cardiovascular death (5.7% versus 8.5%; HR 0.66; 95% CI [0.55–0.79]; p<0.001). Consistent benefit in HF hospitalisation was observed in all subgroups including age, race, estimated glomerular filtration rate (eGFR) and baseline medications for HF. Empagliflozin was also beneficial across a spectrum of HF patients.17 The results of these trials led to empagliflozin being approved by the FDA in 2016 for the prevention of major adverse cardiovascular events in people with diabetes.18 However, no specific recommendation was given for HF prevention, as HF was not one of the primary endpoints.

Baseline Characteristics of the Three Sodium–Glucose Cotransporter-2 Inhibitor Trials

Article image

Hospitalisation for Heart Failure and Cardiovascular Death Stratified by Presence of Heart Failure

Article image

In the CANVAS trial,10,142 people with diabetes and high cardiovascular risk were randomised to canagliflozin or placebo.11 The primary endpoint was major adverse cardiovascular events, which was significantly reduced in the canagliflozin group (HR 0.86; 95% CI [0.75–0.97]; p<0.001 for non-inferiority; p=0.02 for superiority). Canagliflozin was also associated with a significant reduction in the risk of HF hospitalisation (5.5 versus 8.7 per 1,000 patient-years; HR 0.67; 95% CI [0.52–0.87]). Subgroup analyses showed that patients with baseline HF derived a greater benefit in terms of cardiovascular death and HF hospitalisations.

In the recent DECLARE-TIMI 58 trial, which evaluated 17,160 patients, dapagliflozin also significantly reduced the risk of HF hospitalisation (6.2 versus 8.5 per 1,000 patient years; HR 0.73; 95% CI [0.61–0.88]).12 Approximately 4% of patients had HF with reduced ejection fraction (HFrEF) at baseline. Dapagliflozin was shown to reduce the composite endpoint of cardiovascular death/HF hospitalisation more in patients with HFrEF (HR 0.62; 95% CI [0.45–0.86]) compared to those without HFrEF (HR 0.88; 95% CI [0.76–1.02]; p-interaction 0.046). The borderline non-significant results in the non-HFrEF patients were mainly driven by cardiovascular death as in the subgroup analysis; dapagliflozin decreased HF hospitalisation both in patients with HFrEF (HR 0.64; 95% CI [0.43–0.95]) and without HFrEF (HR 0.76; 95% CI [0.62–0.92]). However, the statistically significant reduction in cardiovascular death was observed only in the HFrEF group (HR 0.55; 95% CI [0.34–0.90]).

The DECLARE-TIMI 58 trial was unique compared with the previous two trials because it enrolled more patients without known atherosclerotic cardiovascular disease (n=10,186) and was the first trial to include HF hospitalisation as the co-primary endpoint. The baseline HF rate in all three trials was <15%. Table 1 shows baseline characteristics of the three SGLT2 inhibitor trials, and Table 2 shows detailed HF outcomes.

These clinical trial data are further supported by the real-world evidence from observational studies.13–15 The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors study (CVD-REAL), comprising more than 300,000 newly diagnosed diabetes patients, compared those who were initiated on SGLT2 inhibitors with those receiving any other glucose-lowering therapy. SGLT2 inhibitors led to an almost 40% relative reduction in HF hospitalisation compared with other therapies.13 A consistent benefit was seen in mortality and HF hospitalisation across the spectrum of patients, including those with or without HF at baseline. Moreover, a network meta-analysis suggested that SGLT2 inhibitors have 99.6% probability of being the most effective anti-hyperglycaemic agent for reducing the risk of HF hospitalisation.19 Table 3 shows the main HF outcomes from the real-world observational data of SGLT2 inhibitors.

Mechanism for Benefit

The cardioprotective effects offered by SGLT2 inhibitors cannot be solely attributed to glycaemic control. Several mechanisms for the beneficial effect of SGLT2 inhibitors in regards to HF have been proposed and are highlighted in Figure 1.

First, SGLT2 inhibitors have a direct effect on cardiac metabolism by increasing hepatic neogenesis of ketone bodies, which serve as the alternate fuel for a hypertrophied and failing heart.20 Second, SGLT2 inhibitors are believed to inhibit myocardial and renal sodium–hydrogen exchanger 3, leading to modification of intracellular calcium and thus prevention of HF-associated remodelling.21 Third, improvement in renal function and interstitial volume regulation by SGLT2 inhibitors may also contribute to improvement in HF risk.22 Finally, SGLT2 inhibitors cause osmotic diuresis through glycosuria and natriuresis, which may help in optimising loading conditions of the myocardium. SGLT2 inhibitors have also been shown to significantly reduce blood pressure and biomarkers of arterial stiffness, which can lead to better oxygen consumption of the heart.20–22 These mechanisms – aside from glycaemic control – also suggest a role for the use of SGLT2 inhibitors solely for HF prevention, regardless of diabetes status.

Effect on Subgroups

In the early SGLT2 inhibitor trials, the benefit for major adverse cardiovascular events seemed to be higher in patients with established atherosclerotic cardiovascular disease, although formal heterogeneity was not shown. This led to the American and European guidelines recommending the use of SGLT2 inhibitors in people with diabetes and atherosclerotic cardiovascular disease.23,24 However, a recent meta-analysis including data from EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58 showed that SGLT2 inhibitors reduce HF hospitalisations regardless of the presence of HF or atherosclerotic cardiovascular disease at baseline.25 There was an approximately 30% relative risk reduction for HF hospitalisation in both the subgroups. Interestingly, the benefit for major adverse cardiovascular events was only limited to patients with baseline atherosclerotic cardiovascular disease. Thus, data suggest that SGLT2 inhibitors are especially beneficial for HF over a broad spectrum of patients with diabetes. Studies have also demonstrated that the beneficial effect of SGLT2 inhibitors on HF hospitalisation is similar in males and females.26

Observational Data for Mortality and Hospitalisation for Heart Failure

Article image

Reno-protective Effects of SGLT2 Inhibitors

A possible explanation for SGLT2 inhibitors reducing HF hospitalisations, regardless of the presence of HF or atherosclerotic cardiovascular disease at baseline, is the reno-protective effects of SGLT2 inhibitors coupled with natriuresis. There are four studies that have assessed the effect of SGLT2 inhibitors on renal outcomes: the Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE), EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58. EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58 were primarily designed as cardiovascular outcome trials with a range of pre-specified exploratory and post hoc renal outcomes.

The CREDENCE trial, published in 2019, was the first study to specifically determine the effect of SGLT2 inhibitors on renal outcomes in patients with already-established diabetic kidney disease.27 The primary composite outcome of the CREDENCE trial was doubling of serum creatinine, end-stage renal disease or mortality due to cardiovascular or renal cause. The relative risk of the primary outcome was 30% lower in the SGLT2 inhibitor group compared with the placebo group (event rates of 43.2 and 61.2 per 1,000 patient-years, respectively; RR 0.70; 95% CI [0.59–0.82]; p=0.00001). On pooling results from all the four studies, SGLT2 inhibitors were shown to decrease the risk of dialysis, transplantation or mortality due to renal disease by approximately one-third.28 SGLT2 inhibitors were also shown to decrease the risk of acute kidney injury by 25%. Results from each of the individual studies on various renal endpoints are shown in Table 4. Moreover, significant evidence of benefit was apparent for all eGFR subgroups,, including for patients with a baseline eGFR <45 ml/min/1.73 m2.28 An eGFR rate of ≥30 ml/min/1.73 m2 was an inclusion criterion for all four studies apart from DECLARE-TIMI 58, in which a creatinine clearance of ≥60 ml/min was used. Similar to the HF effect, the reno-protective effect was robust in both patients with and without atherosclerotic cardiovascular disease. It is known that patients with lower eGFR are at higher risk for HF hospitalisation, and thus SGLT2 inhibitors conferring reno-protection and natriuresis could be the main contributing mechanism for HF prevention.29,30

Possible Mechanisms for Heart Failure Prevention Through Sodium–Glucose Cotransporter-2 Inhibitors

Article image

Current Position and Future Direction

In the current guidelines published by the American Diabetes Association and European Association for the Study of Diabetes, metformin remains the first-line treatment for people with diabetes, with SGLT2 inhibitors as the second-line therapy.31 Given the absence of any mortality or cardiovascular benefit with metformin, future studies should investigate the role of SGLT2 inhibitors as a first-line therapy.32 Moreover, the role of SGLT2 inhibitors in stage D HF patients remains unknown. Considering that stage D HF patients often do not tolerate HF therapy, SGLT2 inhibitors might be an attractive alternative.33

Although SGLT2 inhibitors have shown substantial improvement in HF outcomes, data collected need to be further expanded to include ejection fraction and New York Heart Association (NYHA) class, allowing for more specific subgroup analyses. Moreover, endpoints apart from HF hospitalisation should be considered, such as emergency department visits and urgent office visits. A recent systematic review has highlighted significant gaps regarding HF data capture in novel glucose-lowering therapy trials.34 Apart from EMPA-REG OUTCOME, none of the SGLT2 inhibitor trials provided details of how HF was defined at baseline. EMPA-REG OUTCOME defined HF using a query for cardiac failure through the Medical Dictionary for Regulatory Activities. None of the trials reported brain natriuretic peptide data, ejection fraction or degree of optimisation in patients who had baseline HF. Moreover, no trial commented on outcome data once the patient had incident HF.

Effects of SGLT2 Inhibitors on Renal Outcomes

Article image

There are three on-going trials that will further evaluate the role of SGLT2 inhibitors for HF treatment, irrespective of diabetes status – EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced; NCT03057977), EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved; NCT03057951) and the 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]; NCT03036124).

EMPEROR-Reduced and EMPEROR-Preserved will randomise patients to empagliflozin or placebo with cardiovascular death and HF-related hospitalisation as the primary endpoint. Similarly, DAPA-HF will randomise patients to dapagliflozin or placebo with cardiovascular death and HF-related hospitalisation as the primary endpoint. Inclusion criteria include established HFrEF (NYHA class II–IV) and ejection fraction ≤40%. There is also an on-going trial evaluating ertugliflozin in diabetes patients with vascular disease: Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease ([VERTIS CV]; NCT01986881). VERTIS CV is expected to enrol 8,000 patients with a primary outcome of time to first occurrence of major adverse cardiovascular event (cardiovascular death, non-fatal MI or stroke). Secondary endpoints include HF-related hospitalisation.

If these trials show improvement in HF outcomes with SGLT2 inhibitors, it would represent a paradigm shift in management of HF. While we await results from these trials, it is important to acknowledge that we already have strong evidence that SGLT2 inhibitors provide benefit for primary HF prevention in people with diabetes. Given the robust data and dire public health consequences of concomitant diabetes and HF, clinicians should consider initiating SGLT2 inhibitors for HF prevention at least in diabetes patients, regardless of their HbA1c and atherosclerotic disease status.

References

  1. US Food and Drug Administration. Diabetes mellitus –evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes (accessed 25 September 2019)
  2. Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018;379:633–44.
    Crossref | PubMed
  3. Sharma A, Green JB, Dunning A, et al. Causes of death in a contemporary cohort of patients with type 2 diabetes and atherosclerotic cardiovascular disease: insights from the TECOS trial. Diabetes Care 2017;40:1763–70.
    Crossref | PubMed
  4. Sharma A, Zhao X, Hammill BG, et al. Trends in noncardiovascular comorbidities among patients hospitalized for heart failure. Circ Heart Fail 2018;11:e004646.
    Crossref | PubMed
  5. Dei Cas A, Khan SS, Butler J, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail 2015;3:136–45.
    Crossref | PubMed
  6. Komajda M, McMurray JJV, Beck-Nielsen H, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J 2010;31:824–31.
    Crossref | PubMed
  7. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26.
    Crossref | PubMed
  8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22.
    Crossref | PubMed
  9. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.
    Crossref | PubMed
  10. Fitchett D, Zinman B, Wanner C, et al. 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 2016;37:1526–34.
    Crossref | PubMed
  11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57.
    Crossref | PubMed
  12. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57.
    Crossref | PubMed
  13. Cavender MA, Norhammar A, Birkeland KI, et al. SGLT-2 inhibitors and cardiovascular risk: an analysis of CVD-REAL. J Am Coll Cardiol 2018;71:2497–506.
    Crossref | PubMed
  14. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 Study. J Am Coll Cardiol. 2018;71:2628–39.
    Crossref | PubMed
  15. Patorno E, Goldfine AB, Schneeweiss S, et al. Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin anti diabetic drugs: population based cohort study. BMJ 2018;360:k119.
    Crossref | PubMed
  16. Khan MS, Usman MS, Siddiqi TJ, et al. Effect of canagliflozin use on body weight and blood pressure at one-year follow-up: a systematic review and meta-analysis. Eur J Prev Cardiol 2019;26:1680–2.
    Crossref | PubMed
  17. Fitchett D, Butler J, van de Borne P, et al. 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 2018;39:363–70.
    Crossref | PubMed
  18. US Food and Drug Administration. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. Available at: https:// www.fda.gov/news-events/press-announcements/fda-approves-jardiance-reduce-cardiovascular-death-adults-type-2-diabetes (accessed 25 September 2019).
  19. Kramer CK, Ye C, Campbell S, Retnakaran R. Comparison of new glucose-lowering drugs on risk of heart failure in type 2 diabetes: A network meta-analysis. JACC Heart Fail 2018;6:823–30.
    Crossref | PubMed
  20. Mizuno Y, Harada E, Nakagawa H, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism 2017;77:65–72.
    Crossref | PubMed
  21. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Med 2017;130 (suppl 6):S30–S39.
    Crossref | PubMed
  22. Marti CN, Gheorghiade M, Kalogeropoulos AP, et al. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 2012;60:1455–69.
    Crossref | PubMed
  23. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37:2315–81.
    Crossref | PubMed
  24. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care 2018;41(suppl 1):S73–85.
    Crossref | PubMed
  25. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9.
    Crossref | PubMed
  26. Yamani N, Usman MS, Akhtar T, et al. Sodium–glucose co-transporter 2 inhibitors for the prevention of heart failure in type 2 diabetes: A systematic review and meta-analysis. Eur J Prev Cardiol 2019:2047487319841936.
    Crossref | PubMed
  27. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Eng J Med 2019; 380;2295–306.
    Crossref | PubMed
  28. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019; epub ahead of press.
    Crossref | PubMed
  29. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587–97.
    Crossref | PubMed
  30. Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752–72.
    Crossref | PubMed
  31. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. Diabetologia 2018;61:2461–98.
    Crossref | PubMed
  32. Khan MS, Butler J. Heart failure prevention with sodium–glucose cotransporter 2 inhibitors. J Diabetes 2019;11:601–4.
    Crossref | PubMed
  33. Sharma A, Cooper LB, Fiuzat M, et al. Antihyperglycemic therapies to treat patients with heart failure and diabetes mellitus. JACC Heart Fail 2018;6:813–22.
    Crossref | PubMed
  34. Greene SJ, Vaduganathan M, Khan MS, et al. Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. J Am Coll Cardiol 2018;71:1379–90.
    Crossref | PubMed