19.8 Diabetes and heart failure

Type 2 diabetes is an important and common co-morbidity in chronic heart failure. It makes the prognosis of heart failure worse and chronic heart failure impacts the choice of treatment for type 2 diabetes.

The prevalence of chronic heart failure among patients with diabetes is about twice as common as in those without diabetes according to a registry from Kaiser Permanente in Oregon, United States (see Chapter 37.14).¹ In the Reykjavik Study, prevalence of heart failure was 6% and 11.8% among those with impaired glucose tolerance and those with type 2 diabetes (T2DM), respectively. These figures were twice as large as among those with normal glucose tolerance.² The opposite (i.e. prevalence of diabetes in patients with heart failure) was 24% in a large Swedish Heart Failure Registry of over 36,000 individuals.³ In more recent large clinical trials in chronic heart failure, the prevalence of T2DM varies between 20% and 40%. The combination of T2DM and heart failure is expected to rise in the future partly due to the increase in prevalence and longevity of patients with T2DM but also due to improved survival after myocardial infarction and a more systematic screening for the combination.

Having T2DM in combination with chronic heart failure increases the risk for mortality and morbidity. T2DM was indeed the most important risk factor for morbidity/mortality next to age and low ejection fraction in a multivariate model in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) programme.⁴ This was consistent across both reduced and preserved left ventricular ejection fraction (Figure 19.8.1).⁵ In the report from the Swedish Heart Failure Registry, patients with the combination of T2DM and chronic heart failure had an increased mortality and shorter survival time, especially if the heart failure was of ischaemic origin.³ Chronic heart failure with preserved systolic as well as reduced systolic function is more frequent among patients with T2DM. In the recent Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor (ARNI) With Angiotensin Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, it was shown that not only was diabetes associated with increased risk but an elevated glycated haemoglobin concentration without a diagnosis of diabetes was also associated with increased risk.⁶

How can diabetes influence worsening heart failure? There is no clear answer to this question but ischaemic heart disease and myocardial hypertrophy caused by hypertension (see Chapter 44.10) have been considered important contributors. Deterioration of both systolic and preserved left ventricular dysfunction may be caused by a deranged myocardial metabolism. Myocardial characteristics thought to be involved are myocardial lipid overload, altered myocardial production of energy-rich phosphates due to a decreased glucose oxidation and a proportionately increased beta-oxidation of free fatty acids, mitochondrial dysfunction, oxidative stress, inflammation, and diffuse fibrosis.⁷ The presence of a special cardiomyopathy caused by diabetes has been discussed but this condition is difficult to tease out with several interacting co-morbidities (e.g. hypertension and coronary artery disease).

Treatment of chronic heart failure in patient with diabetes should follow the same guidelines as for those without diabetes (see Chapters 37.23–37.29).⁸ The experiences are derived from sub-analyses from large clinical trials in patients with T2DM as no study has primarily examined this combination. Accordingly, the use of an angiotensin-converting enzyme inhibitor (or an angiotensin receptor blocker, if there is angiotensin-converting enzyme inhibitor intolerance; see Chapter 37.24) is recommended in all patients with heart failure and reduced ejection fraction (HFREF). A beta-blocker is also recommended even if there are differences in glycaemic control with better control with carvedilol (see Chapter 37.26).⁹ The combination with a mineral receptor antagonist is also recommended. The addition of the sinus node inhibitor ivabradine is indicated if the heart rate is elevated in sinus rhythm (see Chapter 37.27). In patients who remain symptomatic, the angiotensin-converting enzyme inhibitor is recommended to be replaced by sacubitril/valsartan (see Chapter 37.25). Indications for device therapies with resynchronization and/or an implantable defibrillator also remain similar.

In patients with heart failure and preserved ejection fraction (HFPEF), the treatment approach is to control co-morbidities, in particular hypertension and of course T2DM (see Chapter 37.14).

In trials where these agents have been studied, chronic heart failure as an outcome has not been included in any primary outcome in spite of the common outcome of heart failure in T2DM (see Chapter 5.10). This limitation in clinical trials in diabetes has been discussed by McMurray and colleagues.¹⁰ Any effect on heart failure of glucose lowering is therefore based on effects on secondary outcomes or ad hoc analyses. However, it can be concluded that treatment of T2DM in patients with heart failure should be modified by their background condition. The recommendations for glycaemic control are the same. In general, thiazolidinediones should not be used in patients with heart failure as they worsen outcome. The use of metformin as the first agent for glycaemic control is recommended if no severe renal dysfunction is present.⁸

The recent EMPA-REG OUTCOME^® (BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial demonstrated an improved prognosis by the sodium–glucose co-transporter 2 (SGLT2) inhibitor empagliflozin in 7020 patients with T2DM and cardiovascular risk. Heart failure was allowed at inclusion (see Chapter 19.5). About 10% of participants had such a diagnosis at baseline. The primary cardiovascular composite outcome was observed in 12.1% and 10.5% of the placebo and empagliflozin groups, respectively (hazard ratio 0.86; 95% confidence interval (CI) 0.74–0.99; p = 0.04).¹¹ Hospitalization for heart failure occurred in 4.1% and 2.9%, respectively, and was reduced by 35% (p = 0.002). This finding was particularly interesting for those patients with no heart failure at baseline (about 90%) as hospitalizations for heart failure were reduced by 41%. For patients with heart failure at baseline, the risk of hospitalization for heart failure was 3–4 times higher than among those without heart failure.¹²

In the Canagliflozin Cardiovascular Assessment Study (CANVAS) programme, two trials involving 10,142 patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo.¹³ Around 14% of patients had a history of heart failure and there was a 33% reduction in hospitalization for heart failure (hazard ratio 0.67 (95% CI 0.52–0.87)). The effect was particularly pronounced among those with a history of heart failure. However, again the type of heart failure was not collected.

In the Dapagliflozin Effect on Cardiovascular Events–TIMI-58 (DECLARE) study in 17,160 patients with T2DM without heart failure, treatment with dapagliflozin did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs 5.8%; hazard ratio 0.83; 95% CI 0.73–0.95; p = 0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio 0.73; 95% CI 0.61–0.88).¹⁴

A problem for giving recommendations regarding the use of SGLT2 treatments in T2DM and heart failure is that there were no assessments of the type of background heart failure. Thus we do not know if the beneficial effect is confined to HFREF, HFPEF, or both. In addition, we do not know the mechanisms for the effects but probably the fluid volume loss due to osmotic diuresis through glucose release together with sodium loss is a possibility together with reduced arterial stiffness¹⁵ (Figure 19.8.2). Mechanistic studies will hopefully elucidate more knowledge in the future. At present, there are five outcome trials in heart failure ongoing both in HFrEF and HFpEF where SGLT2 inhibitors are being studied. We will then know how to recommend these agents in patients with both diabetes and heart failure.

Another study with the glucagon-like peptide 1 (GLP-1) analogue liraglutide showed a significant 13% reduction in an extended composite outcome which included hospitalization for heart failure¹⁶ The effect on heart failure alone was also a non-significant 13% lowering of the risk. This finding suggests that liraglutide is safe to use in heart failure.

Another class of agents for glycaemic control, the dipeptidyl peptidase 4 (DPP-4) inhibitors, has reported effects on heart failure. Saxagliptin was used in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, a study including 16,492 patients with T2DM at high risk of cardiovascular events. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or ischaemic stroke. A primary endpoint event occurred in 7.3% in the saxagliptin group and 7.2% in the placebo group (hazard ratio 1.00).¹⁷ More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs 2.8%; hazard ratio 1.27; 95% CI 1.07–1.51; p = 0.007). This unexpected finding caused concerns about DPP-4 agents in heart failure. In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial where alogliptin was compared to placebo in 5380 patients after an acute coronary syndrome, there was a neutral effect on the primary outcome. Hospitalization for heart failure occurred in 3.1% and 2.9% in the alogliptin and placebo groups, respectively.¹⁸ Further, in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), sitagliptin was compared to placebo in 14,671 patients at risk for cardiovascular events. There was no effect on the primary composite cardiovascular outcome. Hospitalization for heart failure was observed in 3.1% in both groups.¹⁹ A meta-analysis of these three trials for the risk of hospitalization for heart failure included 1169 events. The hazard ratio was 1.14 (95% CI 0.97–1.37; p = 0.1). The conclusion by the authors was that there is no risk for heart failure or cardiovascular outcomes by the use of DPP-4-agents.²⁰ However, the Food and Drug Administration has taken a slightly different position recommending that ‘Health care professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control and that these drugs should be used with caution in patients at risk to develop heart failure’.²¹

There have been attempts to prevent the development of T2DM by using neurohormonal antagonists used in the treatment of heart failure. In the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, the angiotensin receptor blocker valsartan was compared to placebo in 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors. There was a 14% reduction in the incidence of T2DM in the valsartan group but this did not translate into a reduction of cardiovascular outcomes.²²

The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial randomized 5269 participants without cardiovascular disease, but with impaired fasting glucose levels or impaired glucose tolerance, to receive the angiotensin-converting enzyme inhibitor ramipril or placebo. There was no reduction in the incidence of T2DM or death by ramipril.²³

In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM- HF) trial, 3778 patients with known diabetes or an HbA1c of at least 6.5% and HFrEF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. During the first year of follow-up, HbA1c concentrations decreased by 0.16% (standard deviation 1.40) in the enalapril group and 0.26% (standard deviation 1.25) in the sacubitril/valsartan group (between-group reduction 0.13%; 95% CI 0.05–0.22; p = 0,0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0.14%; 95% CI 0.06–0.23; p = 0.0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan.²⁴ These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF better than enalapril. Accordingly, the mode of renin–angiotensin–aldosterone system inhibition seems of importance.

In patients with heart failure, the concomitant presence of T2DM increases the risk of having a cardiovascular event including death. In T2DM or impaired glucose tolerance, the development of heart failure will also increase the risk for a subsequent event. Treatment of heart failure should not be modified by concomitant T2DM. However, the treatment of T2DM should be modified by concomitant heart failure. Some agents should be avoided (glitazones), while other agents may be prioritized (e.g. SGLT-2 inhibitors).