Heart failure and diabetes: lessons from outcome studies




Cristiana VITALE,MD, PhD
Department of Medical
Sciences, IRCCS San Raffaele
Pisana, Rome, ITALY

Juan Carlos Kaski,DSc, MD,
DM (Hons), FRCP, FESC, FACC,
FAHA
Cardiovascular and Cell
Sciences Research Institute
St George’s, University of
London, London, UK

Heart failure and diabetes:
lessons from outcome studies

 

by C. Vitale and J. C. Kaski , Italy and United Kingdom

The prevalence of heart failure (HF) and diabetes mellitus (DM) is increasing exponentially worldwide. The coexistence of these diseases, which confers a worse prognosis than HF or DM alone, identifies a large population at very high cardiovascular risk. Intuitively, reducing glucose levels appears a way of improving clinical outcomes in HF patients with DM, as glucose lowering is a therapeutic target in diabetes treatment and many effective glucose-lowering agents are available for the control of hyperglycemia. However, recent studies have shown that some of these pharmacological agents are responsible for negative cardiovascular outcomes. Indeed, the use of “antidiabetic” drugs appears to be associated with an increased rate of HF events, which is higher than that of other undesirable cardiovascular outcomes, such as myocardial infarction. A cardiovascular outcomes dichotomy —characterised by an increased risk of HF, but a neutral effect on other cardiovascular outcomes—has been described with the use of “newer” glucose- lowering agents. The definition of “optimal” glucose control in patients with DM remains controversial, particularly in those with concomitant HF. Current evidence suggests that tight glycemic control, ie, glycated hemoglobin ≤7%, may be associated with worse survival rates and greater HF risk than less tight glucose control strategies, regardless of the agent used. Further research is required to clarify uncertainties regarding the best way to control glucose levels with glucose-lowering agents in patients with DM and HF.

Medicographia. 2016;38:56-64 (see French abstract on page 64)

Heart failure (HF) and diabetes mellitus (DM) are common clinical entities that frequently coexist in an individual patient. The relationship between DM and HF is more than just the sum of each part because both conditions appear to adversely affect the natural course of the other, resulting in a poorer prognosis than that afforded by having either disease alone. In patients presenting with both conditions, however, long-term prognosis and survival are mainly determined by HF rather than DM, making HF a therapeutic priority in these cases. In patients with DM, the prevalence of HF is between 10% and 22%, which is four times higher than that seen in the general population.1 Conversely, HF is an independent risk factor for the development of DM as shown by the fact that during a 3-year follow-up, 29% of HF patients without DM were shown to develop DM compared with 18% of matched control subjects.2 Nearly one quarter of all HF patients have concomitant DM and this number rises up to 40% in patients admitted with acute decompensated HF.3 the Framingham Heart Study demonstrated that a clinical history of DM is independently associated with the risk of developing HF, with a two-fold increase in risk in men and a five-fold increase in risk in women.4 Age, diabetes duration, insulin use, ischemic heart disease, and elevated serum creatinine have all been shown to be independent risk factors for the development of HF in patients with DM.1 A meta-analysis of 21 studies, involving 1 111 569 patients of whom 507 637 had DM, showed that during a follow-up ranging from 1 to 12 years, insulin use, glycemic control (ie, fasting glucose and glycated hemoglobin [HbA1c]), age, and coronary artery disease were variables associated with incident HF in patients with DM, suggesting the potential role of glycemic control and antidiabetic medications in the development of HF.5

Figure 1
Figure 1. Mechanisms contributing to diabetic cardiomyopathy.

A number of different mechanisms—metabolic abnormalities, endothelial dysfunction and atherosclerosis, proinflammatory state, oxidative stress, comorbidities, neurohormonal activation, and altered cardiac metabolism—play a role in the development of diabetic cardiomyopathy, which is associated with increased myocardial stiffness, fibrosis, and cardiomyocyte apoptosis and with decreased myocardial contractility.
Abbreviation: ACE, angiotensin-converting enzyme; AGE, advanced glycation end [product]; ANP, atrial natriuretic peptide; ATP, adenosine triphosphate; BNP, B-type natriuretic peptide; CAD, coronary artery disease; IL, interleukin; NO, nitric oxide; PAD, peripheral artery disease; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; TNF, tumor necrosis factor.

Altered glucose metabolism and established DM are known to contribute to structural and functional abnormalities of the heart, which may culminate in different degrees of cardiac dysfunction and ultimately lead to HF, not necessarily as a result of coronary artery disease, but also via other pathogenic mechanisms. Obesity, metabolic syndrome, dyslipidemia, hypertension, and renal impairment are all often associated with the occurrence of DM.6 Altered cardiac glucose metabolism can affect cardiac contractility, leading to left ventricular dysfunction, even in the absence of coronary artery disease or structural heart disease. Hyperglycemia and insulin resistance are known to contribute directly to cardiac dysfunction through mechanisms related to impaired microvascular endothelial function, abnormalities of cardiac metabolism (ie, shifting myocardial utilization of glucose toward fatty acid oxidation), increased myocardial fibrosis, deposition of advanced glycation end products, oxidative stress, proinflammatory state, lipid accumulation, and increased local activation of the reninangiotensin- aldosterone system, as well as increased sympathetic nervous system activity (Figure 1).7,8

The presence of DM in patients with HF is also widely recognized as an independent risk factor for hospitalization as well as poor clinical outcomes due to cardiovascular events and all-cause mortality. the suggestion that DM may be a predictor of poor clinical outcomes in patients with HF emerged from subgroup data analysis of the SOLVD (Studies Of Left Ventricular Dysfunction) trial, which showed that all-cause and cardiovascular mortality were higher in DM than in nondiabetic patients.9

Both population studies and clinical trials have demonstrated that the presence of DM in HF patients markedly increases the risk of recurrent HF hospitalizations, hospital stay duration, and mortality compared with HF patients without DM.10-12

In the CHARM (Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity) study, DM emerged as the most deleterious prognostic factor and was associated with an approximate 2-fold increase in either death or the composite outcome of cardiovascular death and hospitalization for HF in insulin users, and a 50% increase in risk in noninsulin-dependent patients.13

However, the interaction between DM and impaired clinical outcomes seems weaker in patients hospitalized for HF compared with outpatients, suggesting that the severity of HF and/or decompensation drive clinical outcomes to a larger degree than other risk factors.3,13 In population-based studies, such as the Framingham Heart Study, mortality in diabetic patients is 34% one year after the diagnosis of HF.14

The excess mortality rate related to DM is applicable to both HF with or without preserved left ventricular ejection fraction (LVEF) and to ischemic or nonischemic HF.

Intuitively, managing hyperglycemia effectively appears to be a suitable way of improving clinical outcome in HF patients. Glucose lowering is one of the strategic targets of diabetes treatment. However, drastic reductions in plasma glucose may result in the development of HF even in the absence of structural heart disease. Indeed, the results of recent studies have raised uncertainty as towhether some glucose-lowering agents may actually be causing harm in HF patients with DM.

Heart failure treatment in patients with diabetes

Although no randomized clinical trials have been performed to date to specifically study the effects of pharmacological intervention in patients with HF and DM, current international guidelines for the treatment of HF15 and for DM16 give special recommendations for the use of cardiovascular therapies in patients with coexistent HF and DM. these recommendations are based on subgroup analyses of existing randomized clinical trials, in which approximately 30% of patients usually have DM. 

β-Blockers and angiotensin-converting enzyme (ACE) inhibitors (or angiotensin II receptor antagonists [ARBs] in patients intolerant to ACE inhibitors) have been shown to be beneficial in patients with DM, and their use is associated with reduced mortality and hospitalization in these individuals. ACE inhibitors and ARBs have either a neutral or beneficial effect on glycemia,15,16 but β1-selective β-blockers may negatively affect glycemic control, thus increasing the risk of future DM and also potentially blunting the physiologic adrenergic response to hypoglycemia. this may explain why despite the unquestionable, large body of evidence in favor of the use of β-blockers in HF patients with DM, these patients are currently less likely to be discharged from hospital on a β-blocker than nondiabetic patients with HF. Slow-release metoprolol succinate, bisoprolol, and carvedilol appear to be the most appropriate choices for management of patients with DM and HF.16

Recent data suggest that treatment with low-dose mineralocorticoid receptor antagonist can reduce the risk of hospitalization and premature death in patients with persistent HF symptoms (ie, New york Heart Association [NyHA] class II-IV) and a LVEF ≤35%, even if they are receiving treatment with ACE inhibitors (or ARBs) and β-blockers. Careful surveillance of renal function is mandatory in these cases due to the increased risk of nephropathy with the use of these agents in patients with DM.16 Ivabradine should also be added to conventional therapy in patients in sinus rhythm with a heart rate ≥70/75 bpm, with persistent HF symptoms (NyHA class II-IV).15

The newer LCZ696 (angiotensin-neprilysin inhibitor) agent has recently been shown to reduce both cardiovascular death and hospitalization for HF in patients with HF.17 LCZ696, mineralocorticoid receptor antagonists, and ivabradine have been all shown to be similarly effective in patients with or without DM and should be used whenever possible in HF patients in the presence or absence of DM. Current recommendations are that pharmacotherapy for HF should be similar in patients with or without DM.15,16

Glucose-lowering treatment in patients with diabetes and heart failure

Assessment of cardiovascular safety was not compulsory before 2008. However, following the controversy about the potentially harmful cardiovascular effects of thiazolidinediones, regulatory agencies such as the European Medicines Agency and the US Food and Drug Administration imposed the assessment of cardiovascular safety for all antidiabetic drugs.18,19 Importantly, the efficacy of these agents has usually been assessed from a glucose-lowering perspective, ie, glycemic control expressed as HbA1c. the cardiovascular safety of antidiabetic drugs was based on the assumption that treatments that effectively lower HbA1c have better cardiovascular outcomes. However, the inadequacy of this assumption has now become evident after large sample-size and longer follow-up studies failed to show a reduction in cardiovascular mortality and/or morbidity (including HF) in patients with DM receiving intensive glucose-lowering therapy. Indeed, a meta-analysis restricted to high quality studies (Jadad score >3) of 13 studies in 34 533 patients showed that intensive glucose-lowering therapy was not associated with a significant reduction in cardiovascular risk.20 In fact, quite the opposite was true: intensive glucose-lowering therapy resulted in a 47% increase in HF risk (P<0.001).

In studies assessing the effect of more intensive glucose-lowering therapy, the presence of HF was often considered to be an exclusion criterion and the first study performed in patients with both DM and advanced HF (mean LVEF = 25%}7%) reported an inverse relationship between HbA1c levels and HF mortality, as the 2-year all-cause mortality rate for patients with HbA1c levels <7% was 35% compared with 20% for those with HbA1c >7% (P<0.01).21 these data have been further confirmed by a retrospective study in a large national cohort of 5815 veterans with DM and established HF, where a U-shaped association between HbA1c and mortality was observed, with increased risk of death at both higher and lower HbA1c levels in comparison with modest glucose control (7.1% < HbA1c <7.8%).22

These results have highlighted the problem of increased HF risk in patients with DM receiving glucose-lowering therapy, which now needs to be addressed systematically. At present, regulatory agencies just require a demonstration of cardiovascular safety with respect to the end points of death, myocardial infarction (MI), and stroke, while HF outcomes such as incident HF and recurrent hospitalization for HF are not required primary prespecified cardiovascular end points. This is despite the fact that the assessment of HF outcomes related to the use of glucose-lowering therapy is of particular importance because HF is a common finding of major prognostic relevance in patients with DM. Emerging data, in particular regarding thiazolidinediones and incretin-based therapies, have shown that the rate of HF outcomes can exceed that of acute MI. A dichotomous trend—characterized by an increase in the occurrence of HF outcomes, but a neutral effect on or sometimes even decrease in primary composite cardiovascular outcomes—has been observed.

Thiazolidinediones were the first class of new glucose-lowering therapy associated with an increased occurrence of cardiovascular events, which led to a radical change in the approval process for antidiabetic drugs by the regulatory agencies. the use of thiazolidinediones in large randomized clinical trials23,24 and in several meta-analyses (Table I, page 60) has been associated with a significant increase in the risk of HF.25-28

In both the PROACtIVE (PROspective pioglitAzone Clinical trial In macroVascular Events)23 and the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes)24 trials, age, increased body mass index, renal dysfunction, and high systolic blood pressure were identified as independent predictors of HF. this suggests that elderly patients with obesity, increased body mass index, renal dysfunction, or hypertension should be closely monitored for signs and symptoms suggestive of HF when treated with thiazolidinediones. When all available data is considered, rosiglitazone is associated with a 20% greater risk in the occurrence of HF compared with pioglitazone. In a metaanalysis of 56 trials including 35 531 patients, rosiglitazone use was associated with an increased risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=0.04), but not with increased cardiovascular mortality.29

In an American observational, retrospective study of 227 571 Medicare beneficiaries aged 65 years or older, use of rosiglitazone was associated with an increased risk of stroke, HF, and all-cause mortality and increased the risk of the composite outcome of acute MI, stroke, HF, or all-cause mortality over a follow-up of 3 years.30

It is known that thiazolidinediones affect the distal nephron, causing sodium and water retention, but the exact mechanism underlying the development of HF is not well known.

Rosiglitazone has been withdrawn from the market in Europe, and its use has been restricted in the US, while pioglitazone is still available in both Europe and the US. On the basis of available data, current European guidelines on HF and DM as well as the US Food and Drug Administration recommend avoiding the use of thiazolidinediones in patients with coexisting DM and HF, at least in those with HF of NyHA class III or IV.15,16

Table I
Table I. Randomized clinical trials and meta-analyses with thiazolidinediones vs placebo/active drugs reporting heart failure outcomes.

Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; GLT, glucose-lowering therapy; HF, heart failure; HR, hazard ratio; MVD, macrovascular disease; MI, myocardial infarction; ObStud, observational study; OR, odds ratio; RCT, randomized clinical trial; RR, relative risk; TZD, thiazolidinedione.

Incretin-based therapies include treatment with glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase- 4 (DPP-4) inhibitors. While no adequate data on cardiovascular and HF outcomes related to the use of GLP-1 receptor agonists are currently available in patients with DM and HF, data from large randomized clinical trials31-34 and meta-analyses35-38 do exist for the DPP-4 inhibitors (Table II).

DPP-4 inhibitors have a neutral effect on cardiovascular outcomes, but increase the risk of incident HF and/or the risk of hospitalization for HF. Interestingly, a history of HF at baseline did not predict higher rates of cardiovascular disease outcomes or increased HF admission with DPP-4 inhibitors compared with placebo in either of the trials, although patients with a history of HF or higher pro–N-terminal brain natriuretic peptide levels at baseline in the SAVOR-tIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus–thrombolysis In Myocardial Infarction) study had a higher overall rate of HF admissions.31

Table II
Table II. Randomized clinical trials and meta-analyses with dipeptidyl peptidase-4 inhibitors vs placebo/active drugs reporting heart
failure outcomes.

Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; DPP-4I, dipeptidyl peptidase-4 inhibitor; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; RCT, randomized clinical trial; RR, relative risk.

Table III
Table III. Cardiovascular and metabolic effects of metformin.

Abbreviations: HDL, high-density lipoprotein; IMT, intima-media thickness; LDL,
low-density lipoprotein.
Modified from reference 45: Hundal and Inzucchi. Drugs. 2003;63:1879-1894.
© 2003, Adis Data Information BV.

In addition, the VIVIDD (Vildagliptin In VentrIcular Dysfunction Diabetes) trial, which specifically recruited patients with DM and NyHA class I-III HF receiving HF guideline–recommended therapy, showed no difference between vildagliptin and placebo in the primary end point (LVEF assessed at12 months) and, interestingly, no excess of HF hospitalizations.34

Several mechanisms have been postulated to explain the negative impact of DPP-4 inhibitors on HF outcomes, including the occurrence of hypoglycemia, stimulation of the sympathetic and renin-angiotensin-aldosterone systems, and excessive glucose lowering (which seems to be the most important explanation).

To date, the only drug with beneficial effects on cardiovascular outcomes in patients with both DM and HF is metformin, which—in the past—was paradoxically contraindicated in patients with HF due to the potential risk of lactic acidosis. Clinical experience, post market surveillance, and observational work have shown that the risk is very low and similar to that of other antidiabetic drugs. Pooled data from 347 comparative trials and cohort studies have shown no cases of fatal or nonfatal lactic acidosis in 70 490 patient using metformin.39 More recently, a meta-analysis by Sheen et al confirmed the clinical safety and effectiveness of metformin even in patients with HF.40

International clinical guidelines recommend the use of metformin as first-line therapy in patients with both DM and HF. there is, however, a clear warning regarding its use in patients with severe renal failure, acute decompensated HF, or hepatic impairment.15,16 the well-known beneficial metabolic and cardiovascular effects of metformin (Table III)41 are consistently and unequivocally related to lower mortality rates with metformin compared with other glucose-lowering treatments (1-2 year mortality, 22% vs 34%; >4-year mortality, 38% vs 59%), lower rates of hospitalizations (all-cause hospitalization, 35% vs 64%; HF hospital admission, 34% vs 51%), and fewer adverse events.42

Whether the use of insulin and sulfonylureas in patients with HF and DM is associated with an increased risk of HF is still controversial.16 A retrospective analysis of the Saskatchewan Health Database showed, in 1883 patients with DM and incident HF, that the use of sulfonylureas was associated with increased mortality (52% vs 33%) and hospitalizations (85% vs 77%) compared with the use of metformin.43 Furthermore, in 5631 patients with DM newly treated with a single oral agent and followed for 4.7}2.2 years, treatment with high dose sulfonylurea was associated with a higher incidence of HF compared with treatment with high-dose metformin and lower daily doses (ie, lower than the median daily dose) of sulfonylurea.44 these results were confirmed in a study conducted in Denmark, in 10 920 patients hospitalized for HF for the first time and on treatment with metformin, sulfonylureas, and/ or insulin, which showed that sulfonylureas or insulin were associated with a higher risk of mortality than metformin.45

Box 1
Box 1. Variables to consider in the interpretation of results of
glucose-lowering agents in diabetes mellitus with heart failure.

Abbreviations: DM, diabetes mellitus; HF, heart failure; RCT, randomized clinical trial.

Juhaeri et al showed in 65 619 insulin-treated patients with DM that over a follow-up of 6 years the rate of HF is higher than that of stroke or MI (approximately double and triple, respectively).46 However, the risk of hypoglycemia and weight gain associated with sulfonylureas, as well as the risk of weight gain, sodium retention, and elevated blood pressure associated with insulin, have to be considered and monitored carefully in patients with coexistent DM and HF. In a recent metaanalysis of 14 trials enrolling 95 502 patients, all glucose lowering therapies or modulation strategies increased the risk of HF compared with placebo or standard care (relative risk [RR], 1.14; 95% CI, 1.01-1.30; P=0.041), with the highest risk observed in those using thiazolidinediones, followed by those treated with DPP-4 inhibitors, and with neutral effects in patients receiving insulin.47 “Old” antidiabetic drugs seem safer than the “newer” agents in patients with concomitant DM and HF. Indeed, the latest agents have been shown, in randomized clinical trials, to increase the risk of HF, but to have a neutral effect on other cardiovascular outcomes. The reason for these results is not known and several confounding variables may have had an impact on these findings (Box 1).

Conclusion

In patients with coexisting DM and HF or with an increased risk of HF, a therapeutic strategy based on moderate glycemic control should be implemented, with the glucose-lowering agent metformin having a preferential role. the use of newer glucose-lowering therapies such as thiazolidinediones and incretin-based therapies should be avoided or used with strict cardiovascular monitoring in patients with HF or at increased risk of HF. the choice of antidiabetic treatment in patients with DM and concomitant HF remains controversial, as the optimal level of glycemic control has yet to be established in these patients and more research is needed to determine this.

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Keywords: cardiovascular; diabetes mellitus; glycated hemoglobin; heart failure; outcomes