APRIL 2019 I 1

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Dr Eric KlugCardiologist in Private PracticeSunninghill, Sunward Park and Charlotte Maxeke Johannesburg Hospitals

This report was made possible by an unrestricted educational grant from AstraZeneca. The content of the report is independent of the sponsor.

Diabetes and heart failureIntroduction

Heart failure is one of the most common initial presentations of cardiovascular disease in type 2 diabetes.1 Diabetes is independently associated with the risk of developing heart failure, such that in comparison with individuals without diabetes, the risk is increased more than two-fold in men and more than five-fold in women. The prevalence of heart failure in diabetes is four-fold higher than that in the general population, suggesting that diabetes plays a pathogenic role in the development of the disease and the risk increases with age, duration of diabetes, insulin use, presence of coronary artery disease and elevated serum creatinine.2 Patients with diabetes have a 33% greater risk of hospitalisation for heart failure, and the prognosis is extremely poor. Median survival among patients with diabetes and ischaemic heart failure is approximately four years.3,4

KEY MESSAGES

• Heart failure is a common macrovascular complication of type 2 diabetes and is associated with a poor prognosis

• In patients without diabetes, heart failure increases the risk of incident type 2 diabetes

• Both hyperglycaemia and hyperinsulinaemia are associated with increased risk of heart failure

• Of the antidiabetic medications, only metformin and sodium glucose cotransporter-2 (SGLT2) inhibitors have a mechanism of action that is independent of insulin

• In patients with type 2 diabetes at high risk for, or with established cardiovascular disease, SGLT2 inhibitors have been shown to reduce hospitalisation for heart failure.

“Diabetes is independently associated with the risk of developing heart failure.”

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2 I APRIL 2019

Diabetes and heart failure

Pathophysiology of heart failure in diabetesIn patients with diabetes, for every 1% increase in HbA1c, the risk of heart fail-ure increases by approximately 17-20%.5 However, hyperglycaemia is not the only risk factor for cardiac pathology. Diabetic cardiomyopathy (DCM) was first described nearly 50 years ago based on post-mortem observations of left ventricular (LV) hypertrophy associated with myocardial fibrosis in patients with diabetes and heart failure, but no coro-nary artery disease or other aetiological conditions to account for heart failure. Subsequently, DCM was defined as the existence of LV dysfunction in diabetic patients without coronary artery dis-ease, hypertension or other potential

aetiological conditions. Diabetes has been shown to be associated with an array of pathological mechanisms that lead directly to myocardial fibrosis, myocar-dial steatosis and increased myocardial cell death (necrosis and apoptosis) (Table 1). In turn, this results in LV remodelling and hypertrophy, longitudinal and radial systolic impairment, alteration of con-tractile reserve, diastolic dysfunction and overt heart failure.6

Advanced glycation end-products acti-vate dendritic cells and upregulate hyper-trophy-associated genes in cardiac cells and may be responsible for the hyper-trophic and fibrotic heart failure pheno-type in individuals with diabetes.7

Table 1. Pathological factors associated with DCM6,7

• Impaired calcium homeostasis

• Alteration of substrates utilisation (increase in lipid use, decrease in glucose oxidation)

• Lipotoxicity

• Glucotoxicity with intervention of advanced glycation end-products

• Mitochondrial dysfunction

• Increased oxidative stress and accumulation of reactive oxygen species affect coronary circulation and cause myocardial hypertrophy and fibrosis

• Increased myocardial levels of cardiotoxic inflammatory cytokines (e.g. tumour necrosis factor α, interleukins)

• Renin-angiotensin-aldosterone system (RAAS) activation

• Cardiac dysautonomy

• Impaired phosphatidylinositol 3-kinases due to hyperinsulinaemia precipitate myocardial dysfunction

• Diabetes increases the risk of other risk factors for heart failure, including coronary artery disease, chronic kidney disease and hypertension.

Furthermore, there appears to be a bi-directional relationship between diabe-tes and heart failure, in that heart failure itself precipitates the progression of dia-betes. In a retrospective analysis of data from the prospective Cardiovascular Health Study among elderly subjects (age ≥65 years) with normal fasting glucose at baseline, the presence of heart failure at baseline was associated with increased odds of developing impaired fasting plasma glucose (odds ratio [OR] 2.18) or overt diabetes (OR 4.78) after 3-4 years.

The association between heart failure and worsening diabetes status remained significant after adjustment for age, gen-der and cardiovascular comorbidities.8 The risk of developing diabetes may be directly proportional to the severity of heart failure (measured by loop diuretic dose requirements), and there is limited evidence to suggest that improvements in heart failure treatment (e.g. use of RAAS blockers, ventricular assistance devices) may result in better glycaemic control and improvements in the course of diabetes.9,10

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Diabetes and heart failure

There are several postulated mechanisms to account for the relationship between

heart failure status and worsening diabe-tes (Table 2).

Table 2. Proposed mechanisms to explain how heart failure might contribute to risk of impaired glucose tolerance and diabetes7,8

• Increased blood glucose due to increased levels of cortisol and catecholamines

• Stimulation of gluconeogenesis and glycogenolysis by sympathetic activation

• Increased catecholamines increase insulin resistance, thereby stimulating pancreatic insulin release

• Low-grade chronic inflammation (e.g. tumour necrosis factor α, interleukins)

• Metabolic effects of medication (e.g. diuretics, beta-blockers)

• Hypoperfusion and congestion of liver and pancreas

• Decreased physical activity.

It is clear that the relationship between diabetes and heart failure is complex. Without detailed biomarker informa-tion on both diseases, it is difficult to dis-criminate between the pathologies, and

whether impaired glucose metabolism leads to worsening heart failure or, con-versely, whether worse heart failure status is responsible for greater impairment of glucose metabolism.

Management of hyperglycaemia in patients with diabetes and heart failureOnly a few diabetes treatments have spe-cifically been studied in patients with heart failure. However, tighter glycae-mic control (i.e. lower HbA1c) has not been shown to decrease the risk of either fatal or non-fatal heart failure-related events.11,12 Both glucose and insulin are toxic to the cardiac myocyte and conse-quently the choice of therapy to improve glucose metabolism in patients with dia-betes and heart failure needs to be care-fully considered. At a minimum, therapy should not increase the risk of worsening heart failure.

Potentiation of insulin signalling has been shown to contribute to heart failure in type 2 diabetes regardless of glycae-mic control. Insulin receptors are abun-dant in the heart, vasculature, kidneys and adipose tissue. Stimulation by insu-lin results in activation of intracellular pathways leading to pathological cardiac hypertrophy, remodelling, inflammation and fibrosis; as well as endothelial dys-function in the vasculature and vascular smooth muscle cell hyperplasia. Insulin increases sodium reabsorption in the proximal and distal tubules of the kid-ney, promotes the actions of angioten-sin II, inhibits the effects of endogenous

natriuretic peptides and directly increases the activity of numerous ion transport mechanisms in the renal tubules. Insulin promotes adipogenesis and accumulation and dysfunction of epicardial adipose tis-sue, causing production of inflammatory cytokines which promote cardiac fibrosis and impaired ventricular function.13

The majority of antihyperglycaemic drugs exert their effects by stimulating the release or potentiating the actions of insulin, and treatments that increase insulin signalling increase the risk of heart failure.13-17 Insulin use is indepen-dently associated with an increased risk of heart failure. Sulphonylureas, which are insulin secretagogues, and thiazoli-dinediones, which promote insulin sig-nalling by increasing the sensitivity of tissues to its metabolic actions, have both been shown to increase the risk of heart failure in randomised controlled clinical trials. Incretin-based drugs, the dipepti-dyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) recep-tor agonists, stimulate release of insulin from pancreatic beta-cells by potentiat-ing the actions of GLP-1. Members of both of these classes of drugs have been associated with adverse remodelling and

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4 I APRIL 2019

Diabetes and heart failure

“Only two classes of antidiabetic medication, metformin and the SGLT2 inhibitors, reduce glycaemia by mechanisms that are independent of insulin.”

worsening instability of heart failure in patients with type 2 diabetes.13-17

Only two classes of antidiabetic medi-cation, metformin and the sodium glucose cotransporter type 2 (SGLT2) inhibitors, reduce glycaemia by mechanisms that are independent of insulin. Metformin is rec-ommended as first-line pharmacotherapy for patients with type 2 diabetes and is also first-line treatment of choice in those with heart failure.15,18 It is safe and effective in heart failure with preserved or reduced ejection fraction. Retrospective analy-sis of data in a large population-based cohort study showed that, in comparison to monotherapy with a sulphonylurea, metformin alone, or in combination with a sulphonylurea, was associated with sig-nificantly fewer deaths at one year and over long-term follow-up.19 Metformin is contraindicated in patients with severe hepatic or renal impairment.15

Large randomised clinical studies have shown a consistent association between SGLT2 inhibitors and reduced hospitali-sation for heart failure in diabetic patients with prior cardiovascular events or at high cardiovascular risk.20-22

In the prospective, randomised EMPA-REG OUTCOME (Empagliflozin, Cardio- vascular outcomes, and mortality in Type 2 Diabetes) trial, treatment with empagli-flozin was associated with a statistically significant 14% reduction in the primary outcome, a composite of death from car-diovascular causes, nonfatal myocardial infarction (MI) (excluding silent MI) or nonfatal stroke.20 Rates of MI and stroke did not differ between groups, but in com-parison with placebo, death from cardio-vascular causes, hospitalisation for heart failure and all-cause mortality were reduced by 38%, 35% and 32%, respectively, in the empagliflozin group.

Similar results were observed in the Canagliflozin Cardiovascular Assessment (CANVAS) programme, in which the primary outcome, comprising a compos-ite of death from cardiovascular causes, nonfatal MI or nonfatal stroke, was sig-nificantly reduced by 14% in patients randomised to treatment with canagliflo-zin.21 Hospitalisation for heart failure was reduced by 33%. In both EMPA-REG OUTCOME and CANVAS, patients had a history of atherosclerotic cardiovascular disease or were at high cardiovascular risk at baseline; hospitalisation for heart failure was a predefined exploratory endpoint.21,23

DECLARE-TIMI 58 was a randomised, double-blind, multinational, placebo-controlled phase 3 study in which 17  160 patients with type 2 diabetes and established atherosclerotic cardiovascular disease (sec-ondary prevention: n=6  974) or multiple cardiovascular risk factors (primary pre-vention: n=10  186) were randomised to dapagliflozin 10mg daily or placebo in addi-tion to treatment as usual.22 The principle primary outcome was to demonstrate the safety of dapagliflozin with respect to major adverse cardiovascular events (MACE: CV death, MI or ischaemic stroke). The rate of MACE was similar in the placebo and dapa-gliflozin groups, with dapagliflozin meeting the prespecified criteria for noninferiority (P<0.001). Another prespecified primary endpoint was the incidence of cardiovascu-lar death or hospitalisation for heart failure. This was significantly lower in the dapagli-flozin group (hazard ratio [HR] 0.83; 95% CI 0.73-0.95), primarily consequent to a lower rate of hospitalisation for heart fail-ure (HR 0.73; 95% CI 0.61-0.88), which remained consistent regardless of the pres-ence or absence of heart failure at baseline.

The mechanisms by which SGLT2 inhibitors may reduce incident heart fail-ure are uncertain. A recent in vitro study showed that exposing cardiomyocytes to high glucose concentrations increases SGLT1 and SGLT2 expression more than seven-fold and expression of GLUT1, which encodes the glucose-regulated glu-cose transporter 1, almost three-fold.24 Upregulation of SGLT is associated with an increase in sodium influx into cardio-myocytes that increases cytosolic calcium loading via the sodium-calcium exchanger. In patients with diabetes, intracellular calcium overload impairs cell relaxation, causes electrical instability increasing the propensity to tachycardia, and activates a calcium-sensitive hypertrophic signalling pathway. When exposed to high glucose, the cells exhibited markedly impaired con-tractility with reduced cell shortening and relaxation, reduced re-lengthening veloc-ity and marked hypertrophic changes with increased cell size. Exposure to high glu-cose also increased expression of NPPB, which encodes the brain-type natriuretic peptide (BNP). When the cardiomyocytes were exposed to empagliflozin, despite no change in cell viability or glycolytic capac-ity, these high glucose-induced abnormali-ties were attenuated and the expression of the NPPB, SGLT1, SGLT2 and GLUT1

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Diabetes and heart failure

“Current evidence for benefit of SGLT2 inhibitor therapy is limited to patients at high risk for or with established cardiovascular disease.”

genes were restored to normal levels. These effects were associated with improvements in contractility and relaxation, and in the calcium-handling properties of the cardio- myocytes. This suggests that the clini-cal benefits of SGLT2 inhibitors in heart failure may arise consequent to downreg-ulation of SGLT1, SGLT2 and GLUT1 gene expression, which is associated with improved functionality of cardiomyo-cytes. Early (but not late) application of empagliflozin also neutralised an increase

in production of caspase 3 protein that occurred in response to high glucose levels. Increased caspase 3 protein may predispose cardiomyocytes to an early apoptotic stage.

It is important to note that current evidence for benefit of SGLT2 inhibi-tor therapy is limited to patients at high risk for or with established cardiovascu-lar disease. Their effect in heart failure is unknown, but studies to investigate these agents’ utility in these patients are ongo-ing (Table 3).

Table 3. Large randomised controlled clinical trials of SGLT2 inhibitors in patients with heart failure25-27

Trial Patient population Intervention Primary outcome

EMPEROR-Reduced 2 850 patients with HFrEFEmpagliflozin vs placebo

Cardiovascular death or hospitalisation for heart failure

EMPEROR-Preserved 4 126 patients with HFpEF

DAPA-HF 4 500 patients with HFrEF Dapagliflozin vs placebo

Soloist-WHF4 000 patients with diabetes plus HFrEF or worsening HF

Sotagliflozin vs placebo

HFrEF: Heart failure with reduced ejection fraction; HFpEF: Heart failure with preserved ejection fraction; WHF: Worsening heart failure

Heart failure treatments in people with diabetesIn general, patients with diabetes and heart failure should be treated in the same way as those without diabetes. General

principles and recommendations relating to heart failure-specific treatments in peo-ple with diabetes are listed in Table 4.

Table 4. Treatment of heart failure in diabetes2

• There are no randomised controlled clinical studies to test the effect of cardiovascular interventions (drugs and/or devices) in patients with heart failure and diabetes

• All interventions effective at improving prognosis in patients with heart failure are equally beneficial in patients with and without diabetes

• There is no reason to suggest preferential use of one beta-blocker over another on the basis of possible negative effects on glucose control

• Diabetics are less likely to be discharged from hospital on a beta-blocker than non-diabetic patients with heart failure

• When using a mineralocorticoid receptor antagonist, close surveillance of electrolyte and renal function is recommended in order to exclude hyperkalemia

• Sacubitril/valsartan combination therapy is similarly effective in heart failure patients with and without diabetes

• Metformin is recommended if eGFR >30ml/min/1.73m2

• If eGFR is <60ml/min/1.73m2, care should be taken when prescribing a RAAS blocker or sacubitril/valsartan

• Thiazolidinediones and saxagliptin should be avoided.

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DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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Diabetes and heart failure

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ConclusionsHeart failure and diabetes are intimately related, each conferring a poorer progno-sis on the other. However, in patients with type 2 diabetes, careful consideration of the agent to achieve glycaemic control can help prevent incident heart failure.14

SGLT2 inhibitors are the first class of antidiabetic agents to show a con-sistent reduction in the incidence of

hospitalisation for heart failure in patients with type 2 diabetes. Where they are toler-ated and affordable, they may be consid-ered second-line therapy in addition to lifestyle modification and metformin in patients with heart failure, atherosclerotic cardiovascular disease and renal disease as well as for primary prevention of mac-rovascular complications.18

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2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 2015; 3: 105-113.

2. Rosano GMC, Vitale C, Seferovic P. Heart failure in patients with diabetes mellitus. Cardiac Failure Review 2017; 3(1): 52-55.

3. Cavender MA, Steg G, Smith SC, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death. Outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Circulation 2015; 132: 923-931.

4. Cubbon RM, Adams B, Rajwani A, et al. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diabetes Vasc Dis Res 2013; 10(4): 330-336.

5. Filho AP, Kottgen A, Bertoni AG, et al. HbA1c as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Diabetologia 2008; 51(12): 2197-2204.

6. Ernande L, Derumeaux G. Diabetic cardiomyopathy: myth or reality? Arch Cardiovasc Dis 2012; 105: 218-225.

7. Tousoulis D, Oikonomou E, Siasos G, Stefanadis C. Diabetes mellitus and heart failure. Eur Cardiol Rev 2014; 9(1): 37-42.

8. Guglin M, Lynch K, Krischer J. Heart failure as a risk factor for diabetes mellitus. Cardiology 2014; 129: 84-92.

9. Andersson C, Norgaard ML, Hansen PR, et al. Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study. Eur J Heart Fail 2010; 12: 1333-1338.

10. Uriel N, Naka Y, Colombo PC, et al. Improved diabetic control in advanced heart failure patients treated with left ventricular assist devices. Eur J Heart Fail 2011; 13: 195-199.

11. Castagno D, Baird-Gunning J, Jhund PS, et al. Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J 2011; 162: 938-948.e2

12. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52: 2288-2298.

13. Packer M. Potentiation of insulin signalling contributes to heart failure in type 2 diabetes. A hypothesis supported by both mechanistic studies and clinical trials. JACC Basic Transl Sci 2018; 3(3): 415-419.

14. Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care 2018; 41: 11-13.

15. Ponikowski P, Voors AA, Anker SD, et al. The task force

for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; 37(27): 2129-2200. 

16. 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(14): 1317-1326.

17. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-322.

18. Davies MJ, DÁlessio DA, Fradkin J, et al. Management of hyperglycaemia 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(12): 2669-2701.

19. Evans JM, Doney AS, Al Zadjali MA, et al. Effect of metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am J Cardiol 2010; 106(7): 1006-1010.

20. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128.

21. Neal B, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-657.

22. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380(4): 347-357.

23. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME). Cardiovasc Diabetol 2014; 13: 102. Published online. http://www.cardiab.com/content/13/1/102

24. Ng K-M, Lau Y-M, Dhandhania V, et al. Empagliflozin ameliorates high glucose induced-cardiac dysfunction in human iPSC-derived cardiomyocytes. Scientific Reports 2018; 8: 14872. Published online. DOI: 10.1038/s41598-018-33293-2

25. Silva Custodio J, Rodrigues Duraes A, Abreu M, et al. SGLT2 inhibition and heart failure – current concepts. Heart Fail Rev 2018. Published online. DOI: 10.1007/s10741-018-9703-2.

26. Lytvyn Y, Bjornstad P, Udell JA, et al. Sodium glucose cotransporter-2 inhibition in heart failure. Potential mechanisms, clinical applications, and summary of clinical trials. Circulation 2017; 136: 1643-1658.

27. US National Library of Medicine. ClinicalTrials.gov. Effect of sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure (SOLOIST-WHF Trial).

This article is based on a pre-sentation by Dr Eric Klug at the Connecting the Experts in CVRM meeting held in Cape Town on 9-10 February 2019. The meeting and the writing of this report were sponsored by AstraZeneca. The article was written for deNovo Medica by Dr David Webb and reviewed by Dr Klug.