Article

Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs

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Abstract

Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

Disclosure:TAZ is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft ZE 1109/1-1 to TAZ). EB has no conflicts of interest to declare.

Received:

Accepted:

Correspondence Details:Eugene Braunwald, TIMI Study Group, 60 Fenwood Road, 7th floor, Boston, MA 02115, USA. E: ebraunwald@partners.org

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.

With progressive ageing and the growing incidence of obesity in the population, the prevalence of type 2 diabetes (T2D) has been rising rapidly and has become a major cause of death and disability worldwide.1 It is well established that atherosclerotic cardiovascular disease (ASCVD) and renal failure are responsible for a large majority of deaths in patients with T2D.2-4 Over the past decade, the management of T2D has been undergoing an important transformation from simply targeting abnormally elevated glucose concentration to preventing complications of ASCVD, including heart failure (HF) and the progression of diabetic renal disease.5,6

Several pathophysiological mechanisms may explain the relationship between T2D and HF: T2D is associated with accelerated atherogenesis, which is responsible for macrovascular coronary atherosclerosis leading to MI and impairment of cardiovascular function. Arterial hypertension, which is common in T2D, and the ensuing left ventricular hypertrophy and increased wall stiffness also contribute to the development of HF. Some observations have suggested that T2D may be associated with a specific form of cardiomyopathy, termed diabetic cardiomyopathy, which can lead first to HF with preserved ejection fraction then progressing to HF with reduced ejection fraction.7,8

T2D can also cause microvascular obstruction, which can play an important role in the development and progression of diabetic nephropathy, which is now the leading cause of end-stage renal disease in Europe and North America.9

Disorders of the coronary microcirculation may also contribute to the development of HF with preserved ejection fraction. In addition, the importance of the cardiorenal axis is well established with disorders of either cardiac or renal function causing malfunction in the other organ, leading to a vicious circle.10–13 In addition, HF intensifies the impairment of glucose control in patients with T2D, with the resultant glucotoxicity setting the stage for a second vicious circle.14,15

In a recent cohort study, the Swedish National Diabetes Register, >270,000 patients with T2D were matched with >1,300,000 non-diabetic controls. It showed that T2D patients in whom all five risk factors (HbA1c, LDL cholesterol, albuminuria, smoking and blood pressure) were within the target ranges exhibited similar risks of MI, stroke and death as people who do not have diabetes, but they remained at increased risk for the development of HF.16 From such studies, it has become apparent that the treatment of T2D must not only include control of glucose metabolism and of the well-established risk factors for atherosclerosis but must also reduce the risk of HF and advanced kidney disease.

Recent Developments in Type 2 Diabetes

Concerns about the cardiovascular safety of the widely-used thiazolidinedione rosiglitazone in the first decade of this century prompted the US Food and Drug Administration in 2008 and the European Medicines Agency in 2009 to issue new requirements for approval of antidiabetic drugs.17–19 Specifically, these agencies required the safety of antidiabetic drugs to be demonstrated in well-powered, non-inferiority trials. The resultant trials have both enhanced understanding of the pathobiology of T2D and confirmed that the reduction of HbA1c does not necessarily translate into a reduction of major adverse cardiovascular events.5,6,20

SGLT2i Treatment Effects

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Differential Treatment Effects of SGLT2i

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Overview of Unfavourable and Favourable<br />
Effects of SGLT2i in Patients with Type 2 Diabetes

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Sodium-Glucose Cotransporter 2 Inhibitors: an Advance in Type 2 Diabetes Treatment

A number of large cardiovascular outcomes trials showed that these agents reduce HbA1c levels and are generally safe.20–23 In contrast, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial of empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), lowered major adverse cardiovascular events (MACE), the composite of cardiovascular (CV) death, MI and stroke, by a modest, albeit statistically significant 14%, a finding that was, of course, welcomed.24 Unexpectedly, this trial also demonstrated a significant 38% reduction (HR 0.62; 95% CI [0.49–0.77]) in CV death and a 32% fall in all-cause death. A significant 35% lowering in hospitalisation for HF was also observed, indicating that the improvement in cardiac pump function was primarily responsible for these reductions of CV and all-cause death.

Subsequently, the results of large trials involving two other SGLT2i drugs in patients with T2D were reported: the CANagliflozin cardioVascular Assessment Study (CANVAS) Program with canagliflozin; and the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI) 58 trial, which studied dapagliflozin.25,26 A recent meta-analysis of the three published CV outcomes trials included a total of 34,322 patients with T2D, with 20,650 patients having established ASCVD, and 13,672 patients with multiple risk factors but no clinically apparent ASCVD.27 Overall, SGLT2i reduced the risk of hospitalization for HF and the progression of renal disease in these patients by 31% and 45%, respectively (Figure 1). However, the benefit in reducing atherosclerotic MACE was modest and confined to those with known ASCVD (Figure 2).

Sodium-Glucose Cotransporter 2 Inhibitor Mechanisms of Action

Although the precise molecular mechanisms mediating the reduction in adverse cardiovascular and renal outcomes of SGLT2i have not been fully defined (Figure 3), their principal beneficial action appears to result from blockade of the reabsorption of glucose and sodium from the glomerular filtrate by the proximal tubule, leading to their excretion into the urine. This action reduces extracellular fluid volume, which in turn increases hematocrit and lowers cardiac preload, afterload, arterial stiffness, blood pressure and left ventricular mass.28 There is a reduction in epicardial adipose tissue and with it, a number of noxious stimuli.29,30

It has also been suggested that SGLT2i drugs improve myocardial performance by increasing the metabolism of beta-hydroxybutyrate, a preferential fuel.31,32 They may also inhibit the Na+/H+ exchanger, resulting in a lowering of cytosolic Na+ and Ca2+ which may be cardioprotective.33 It has also been suggested that SGLT2i may inhibit cardiac fibrosis.34

SGLT2i drugs cause vasoconstriction of the afferent glomerular arterioles and dilatation of the efferent arterioles. These changes in the nephrons’ microcirculation lower the intraglomerular pressure, thereby reducing albuminuria and glomerular fibrosis and delaying the decline in renal function.28,35 However, in two of the three large trials in the SGLT2i meta-analysis, patients with estimated glomerular filtration rates (eGFR) lower than 30 ml/min/1.73m2 body surface area (BSA) were excluded and, in the third, patients with a creatinine clearance <60 ml/min/1.73m2 BSA were excluded. Given the frequency of reductions of eGFR below these values in people with T2D, it is important to determine the efficacy and safety of these drugs in such patients.

Adverse Effects

SGLT2i drugs are generally well tolerated and safe. However, their glucosuric effect increases the risk of genital infections. An increased risk of fractures and lower limb amputations (predominantly of the toes and metatarsal bones) have been reported with canagliflozin, but not with empagliflozin or dapagliflozin.25 A near doubling of an uncommon complication, diabetic ketoacidosis, has also been observed.27 Initial concerns about an increased risk of bladder cancer have not been borne out.26,27

The salutary effects of SGLT2i on HF in patients with T2D have raised the intriguing question of whether these agents can also be effective in the treatment and/or the prevention of HF in patients with HF without T2D; this question is being addressed by ongoing trials. The form of HF affected in the SGLT2i trials – with reduced and/or preserved ejection fraction – was not defined in the above-mentioned trials and this issue is receiving attention.

Glucagon-like Peptide 1 Receptor Agonists

In addition to the SGLT2i, three glucagon-like peptide 1 receptor agonists (GLP1-RA) have been shown to be of clinical benefit in T2D cardiovascular outcomes trials. This class of drugs has been used for a number of years to reduce HbA1c.

Liraglutide, semaglutide and albiglutide have been demonstrated to reduce the risk of MACE significantly, with liraglutide also lowering the incidence of CV death.36–38 In addition, a recent press release has stated that the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial (NCT01394952) studying the CV safety of dulaglutide in a predominantly primary prevention cohort reduced the risk of MACE significantly.39 A press release about the trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6; NCT02692716) reported that oral semaglutide had been proven to be safe and reduced the risk of CV death significantly but it did not meet statistical significance for MACE.40 No significant reduction in hospitalisation for HF or a slowing in the decline of eGFR have been reported for any GLP1-RA to date, although numerical reductions in HF have been seen for both liraglutide and albiglutide.36,38

The most recent guidelines for the treatment of T2D released by the American Diabetes Association and the European Association for the Study of Diabetes begin with a recommendation for lifestyle changes for all patients.41 Metformin remains the primary pharmaceutical agent for reducing HbA1c. This drug is efficacious, well tolerated and inexpensive. If HbA1c remains above target levels despite the above-cited therapy, either an SGLT2i or one of the aforementioned GLP1-RAs with proven benefit should be added.

Based on the finding in the meta-analysis summarised above, which was published after the release of the most recent practice guidelines, the authors of this review recommend the administration of an SGLT2i first, especially in patients with T2D and ASCVD, HF, chronic kidney disease and/or kidney disease and/or multiple risk factors.27 When SGLT2i drugs are not tolerated, contraindicated or do not bring the HbA1c to target levels, the addition or substitution of a GLP1-RA with proven CV benefit should be considered.

Thiazolidinediones have been reported to increase fluid retention and cardiac decompensation and should not be used in patients with HF.42 Caution should also be applied when using certain DPP-4 inhibitors.20

Conclusion

After many neutral findings in CV outcomes trials in patients with T2D, the results of the trials with SGLT2i have shown that drugs in this class cause robust reductions in HF and delay the development of renal failure. Selected GLP-1-RA agents also appear beneficial in reducing atherosclerotic cardiac events in these patients. These two classes of agents are meeting important needs in the management of the growing number of people with T2D.

References

  1. Gregg EW, Li Y, Wang J, Burrows NR, et al. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med 2014;370:1514–23.
    Crossref | PubMed
  2. Ahmad FS, Ning H, Rich JD, et al. Hypertension, obesity, diabetes, and heart failure-free survival: the Cardiovascular Disease Lifetime Risk Pooling Project. JACC Heart Fail 2016;4:911–9.
    Crossref | PubMed
  3. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics – 2018 update: a report from the American Heart Association. Circulation 2018;137:e67–e492.
    Crossref | PubMed
  4. American Diabetes Association. 10. Microvascular complications and foot care: Standards of Medical Care in Diabetes – 2018. Diabetes Care 2018;41(Suppl 1):S105–S18.
    Crossref | PubMed
  5. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59.
    Crossref | PubMed
  6. Advance Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72.
    Crossref | PubMed
  7. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115:3213–23.
    Crossref | PubMed
  8. Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside. Heart Fail Clin 2012;8:619–31.
    Crossref | PubMed
  9. Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis 2018;71:884–95.
    Crossref | PubMed
  10. Sattar N, McGuire DK. Pathways to cardiorenal complications in type 2 diabetes mellitus: a need to rethink. Circulation 2018;138:7–9.
    Crossref | PubMed
  11. Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010;121:2592–600.
    Crossref | PubMed
  12. Hatamizadeh P, Fonarow GC, Budoff MJ, et al. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013;9:99–111.
    Crossref | PubMed
  13. Braam B, Joles JA, Danishwar AH, Gaillard CA. Cardiorenal syndrome –current understanding and future perspectives. Nat Rev Nephrol 2014;10:48–55.
    Crossref | PubMed
  14. Mamas MA, Deaton C, Rutter MK, et al. Impaired glucose tolerance and insulin resistance in heart failure: underrecognized and undertreated? J Card Fail 2010;16:761–8.
    Crossref | PubMed
  15. Maack C, Lehrke M, Backs J, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J 2018;39:4243–54.
    Crossref | PubMed
  16. Rawshani A, Rawshani A, Franzen 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
  17. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71.
    Crossref | PubMed
  18. US Food and Drug Administration. Guidance for industry: diabetes mellitus evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat... (accessed 7 January 2019).
  19. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2018. Available at: https://www.ema.europa.eu/documents/scientific-guideline/draft-guideline... (accessed 16 January 2019).
  20. 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
  21. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42.
    Crossref | PubMed
  22. Rosenstock J, Perkovic V, Johansen OE, 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; epub ahead of press. JAMA 2018.
    Crossref | PubMed
  23. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35.
    Crossref | PubMed
  24. 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
  25. 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
  26. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018; epub ahead of press.
    Crossref | PubMed
  27. 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
  28. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes. J Am Coll Cardiol 2018;72:1845–55.
    Crossref | PubMed
  29. Sato T, Aizawa Y, Yuasa S, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 2018;17:6.
    Crossref | PubMed
  30. Packer M. Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity. Circulation 2018;137:1614–31.
    Crossref | PubMed
  31. Ferrannini G, Hach T, Crowe S, et al. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015;38:1730–5.
    Crossref | PubMed
  32. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190–5.
    Crossref | PubMed
  33. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 2018;61:722–6.
    Crossref | PubMed
  34. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018;61:2108–17.
    Crossref | PubMed
  35. 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
  36. 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
  37. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44.
    Crossref | PubMed
  38. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519–29.
    Crossref | PubMed
  39. Eli Lilly. Trulicity® (dulaglutide) demonstrates superiority in reduction of cardiovascular events for broad range of people with type 2 diabetes. Press release. 11 May 2018. Available at: https://investor.lilly.com/news-releases/news-release-details/trulicityr... (accessed 15 January 2019).
  40. Novo Nordisk. Oral semaglutide demonstrates favourable cardiovascular safety profile and significant reduction in cardiovascular death and all-cause mortality in people with type 2 diabetes in the PIONEER 6 trial. Press release. 23 November 2018. Available at: https://www.novonordisk.com/content/Denmark/HQ/www-novonordisk-com/en_gb...(accessed 15 January 2019).
  41. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669–701.
    Crossref | PubMed
  42. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004;27:256–63.
    Crossref | PubMed