Treatment of Diabetes in People with Heart Failure

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

Jonathan G. Howlett MD, FRCPC, FACC, FSCAI John C. MacFadyen MD, FRCPC

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

Key Messages

  • Heart failure is still under-recognized and misdiagnosed. This has significant clinical implications as the prognosis of untreated or undertreated heart failure is poor, and yet very effective proven therapies are widely available to most physicians.
  • Diabetes can cause heart failure independently of ischemic heart disease by causing a diabetic cardiomyopathy that may manifest in the setting of normal or reduced left ventricular ejection fraction. The incidence of heart failure is 2- to 4-fold higher in people with diabetes compared to those without and, when present, occurs at an earlier age.
  • Even though heart failure in people with diabetes should be treated similarly to heart failure in those without diabetes, they are less likely to receive appropriate therapies. The presence of diabetes should not affect the decision for treatment of heart failure.
  • Comorbidities, such as renal dysfunction and propensity for hyperkalemia, are more prevalent in people with diabetes and may influence heart failure drug doses and monitoring of therapy but not therapeutic targets.

Introduction

Type 2 diabetes often occurs in association with other cardiovascular risk factors, such as hypertension, dyslipidemia, smoking and obesity, which together are strongly associated with atherosclerosis, ischemic heart disease and left ventricular (LV) dysfunction. LV dysfunction can be clinically silent or associated with the typical clinical signs and symptoms of heart failure (e.g. peripheral edema, shortness of breath, fatigue), although the elderly may have atypical symptoms (1). These symptoms need to be differentiated from other conditions that may have similar presentations, such as chronic obstructive pulmonary disease, pneumonia, anemia, varicose veins, depression, etc.

Heart Failure in People with Diabetes

The diagnosis of heart failure is made by association of typical clinical signs and symptoms with objective evidence, such as that obtained from a chest x-ray, an echocardiogram or plasma natriuretic peptide testing (brain natriuretic peptide [BNP] and prohormone of BNP [NT-pro-BNP]) (1). Documentation of systolic and diastolic myocardial function is recommended at the time of diagnosis of heart failure or with any significant change in clinical stability. Heart failure can occur over the entire range of LV ejection fractions (LVEFs), from <10% to >60%. The measurement of plasma BNP and NT-pro-BNP, which are acutely released by ventricular myocytes when the myocardium is stretched due to increased filling pressures, may help make an accurate diagnosis where clinical uncertainty exists (2). However, the practising physician may still under-recognize and misdiagnose heart failure. This has significant clinical implications as the prognosis of untreated or undertreated heart failure is poor, yet very effective proven therapies are widely available to most physicians. Because of this, many studies have explored the clinical utility of screening patients with diabetes for the presence of reduced LV function with BNP/NT-pro-BNP testing. The results to date are mixed, with no clear consensus to institute this strategy. Diabetes is associated with increased prevalence of heart failure, both systolic (commonly defined as LVEF <40%) and diastolic (commonly defined as LVEF >50%, but also referred to as preserved systolic function or preserved EF). However, the overlap between systolic and diastolic heart failure is considerable, and many people have a combination of systolic and diastolic dysfunction, although 1 is often reported to be predominant. Current tests, such as echocardiography, do usually fully characterize all aspects of systolic and diastolic dysfunction in individuals.

It is recognized that diabetes can cause heart failure independently of ischemic heart disease by causing a diabetic cardiomyopathy (3). Epidemiological studies have shown that the incidence of heart failure is 2- to 4-fold higher in people with diabetes compared to those without diabetes (4,5). Additionally, studies have shown the occurrence of asymptomatic abnormalities of ventricular systolic and diastolic function, independently from ischemic heart disease or systemic hypertension. While an increase in glycated hemoglobin (A1C) among individuals with diabetes is a recognized risk factor for heart failure (6–10) , no prospective study to date has demonstrated that improved glycemic control significantly reduces the incidence of heart failure (11). Microalbuminuria is also an independent risk factor for heart failure, especially in people with diabetes. In individuals with and without diabetes, increasing urinary albumin-to-creatinine ratio is associated with a stepwise increase (2- to 4-fold) in the risk of heart failure development (8,12). Angiotensin-converting enzyme (ACE) inhibitors significantly reduce urinary albumin excretion, and, in large clinical trials of subjects with cardiovascular disease or diabetes, they have been shown to lower the risk of new-onset heart failure (13–15).

Treatment of Individuals with Both Diabetes and Heart Failure

In nearly every clinical trial involving patients with heart failure, diabetes is present in over one-third of subjects. In the large landmark clinical trials of heart failure, subgroup analysis of diabetic populations has shown that, despite their increased risk of morbidity and mortality, they derive greater absolute benefit from efficacious therapies as compared to patients without diabetes (15–17). As such, heart failure in people with diabetes should be treated similarly to those without diabetes, although comorbidities, such as renal dysfunction and hyperkalemia, may be more prevalent in people with diabetes ( ccsguidelineprograms.ca ).

In particular, patients with diabetes are at increased risk for development of hyperkalemia and worsening renal dysfunction in the setting of renin-angiotensin-aldosterone (RAAS) blocking agents (18–23). Clinicians should be aware of this potential complication, especially in view of current guidelines advocating the expanded use of combined RAAS blockade in patients with mild-to-moderate heart failure and low EF.

Three beta blockers have been shown to reduce morbidity and mortality for patients with heart failure and diabetes: carvedilol, bisoprolol and metoprolol. Data to date suggest overall glycemic control for these patients improves as their heart failure syndrome improves on therapy (24–26). Carvedilol, in comparison to other beta blockers, has been shown to be associated with improved glycemic control. In addition, some data suggest the improvement in LVEF is also greater with carvedilol (17,27). For this reason, some clinicians prefer carvedilol as the beta blocker of choice in such patients. While there is a theoretical concern for the occurrence of severe hypoglycemia without awareness associated with the use of nonselective beta blockers, this has not been reported in clinical trials.

Numerous registries and reports indicate that persons with diabetes are less likely than those without diabetes to receive efficacious and evidence-based therapies for systolic heart failure. Perhaps this is due, in part, to the increased incidence of side effects and/or intolerance to RAAS blockade and the increased prevalence of renal disease in patients with diabetes. However, even when controlled for these conditions, the differences persist. This is particularly concerning considering the increased absolute benefit the agents confer to patients with heart failure and diabetes in comparison to unselected heart failure populations. As such, prescribers must be diligent in providing these therapies.

Metformin

Metformin is an effective oral antihyperglycemic agent, but, based on isolated case reports and a biochemical rationale for a risk of lactic acidosis, it is approved for use under a warning in the setting of several conditions, including heart failure. Meta-analyses have evaluated the occurrence of lactic acidosis with the use of metformin (over 70 000 patient-years) or other antihyperglycemic agents (over 55 000 patient-years) and they have consistently shown no increase in lactic acidosis in the metformin group (28,29). In fact, cardiovascular outcomes in heart failure patients taking metformin were better than in those taking other antihyperglycemic agents (30). The current evidence suggests that patients with heart failure fare at least as well, if not better, with metformin than with other antihyperglycemic agents if they have only mild-to-moderate renal dysfunction (estimated glomerular filtration rate >30 mL/min) (30). As such, metformin should still be considered as first-line therapy in heart failure patients with mild-to-moderate renal dysfunction.

A detailed discussion of the rationale and evidence for the treatment approach to heart failure patients is available in the Canadian Cardiovascular Society consensus recommendations ( ccsguidelineprograms.ca) (31).

Recommendations

  1. 1.Individuals with diabetes and heart failure should receive the same heart failure therapies as those identified in the evidence-based Canadian Cardiovascular Society heart failure recommendations (ccsguidelineprograms.ca) [Grade D, Consensus].
  2. 2.In people with diabetes and heart failure and an estimated glomerular filtration rate <60 mL/min, or if combined renin-angiotensin-aldosterone blockade is employed:
    • Starting doses of angiotensin-converting enzyme inhibitors or angiotensin receptor II antagonists (angiotensin receptor blockers) should be halved [Grade D, Consensus].
    • Serum electrolytes and creatinine, blood pressure and body weight, as well as heart failure symptoms and signs, should be monitored within 7–10 days of any initiation or titration of therapy [Grade D, Consensus].
    • Dose-up titration should be more gradual (with monitoring of blood pressure, serum potassium and creatinine) [Grade D, Consensus].
    • The target drug doses should be the same as those identified in the evidence-based Canadian Cardiovascular Society recommendations on heart failure (see here), if well tolerated [Grade D, Consensus].
  3. 3.Beta blockers should be prescribed when indicated for systolic heart failure, as they provide similar benefits in people with diabetes compared with people without diabetes [Grade B, Level 2 (17,27)].

References

  1. 1 J.-P. Albertini R. Cohen P. Valensi B-type natriuretic peptide, a marker of asymptomatic left ventricular dysfunction in type 2 diabetic patients Diabetes Metab 34 2008 355 362
  2. 2 M. O'Donoghue P. Kenney E. Oestreicher Usefulness of aminoterminal pro-brain natriuretic peptide testing for the diagnostic and prognostic evaluation of dyspneic patients with diabetes mellitus seen in the emergency department (from the PRIDE Study) Am J Cardiol 100 2007 1336 1340
  3. 3 R. Valle E. Bagolin C. Canali The BNP assay does not identify mild left ventricular diastolic dysfunction in asymptomatic diabetic patients Eur J Echocardiogr 7 2006 40 44
  4. 4 M. Shimabukuro N. Higa Y. Oshiro Diagnostic utility of brain-natriuretic peptide for left ventricular diastolic dysfunction in asymptomatic type 2 diabetic patients Diabetes Obes Metab 9 2007 323 329
  5. 5 M. Galderisi Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography J Am Coll Cardiol 48 2006 1548 1551
  6. 6 K. Karavanaki G. Kazianis I. Konstantopoulos Early signs of left ventricular dysfunction in adolescents with Type 1 diabetes mellitus: the importance of impaired circadian modulation of blood pressure and heart rate J Endocrinol Invest 31 2008 289 296
  7. 7 A.M. Grandi E. Piantanida I. Franzetti Effect of glycemic control on left ventricular diastolic function in type 1 diabetes mellitus Am J Cardiol 97 2006 71 76
  8. 8 A.C.T. Ng V. Delgado M. Bertini Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus Am J Cardiol 104 2009 1398 1401
  9. 9 T.K. Mishra P.K. Rath N.K. Mohanty S.K. Mishra Left ventricular systolic and diastolic dysfunction and their relationship with microvascular complications in normotensive, asymptomatic patients with type 2 diabetes mellitus Indian Heart J 60 2008 548 553
  10. 10 S.M.S. Ashraf F. Basir Association of hypertension and diastolic dysfunction with type-2 diabetes mellitus Pakistan J Med Sci 23 2007 344 348
  11. 11 R. Stahrenberg F. Edelmann M. Mende Association of glucose metabolism with diastolic function along the diabetic continuum Diabetologia 53 2010 1331 1340
  12. 12 W. Dinh R. Futh M. Lankisch Cardiovascular autonomic neuropathy contributes to left ventricular diastolic dysfunction in subjects with Type 2 diabetes and impaired glucose tolerance undergoing coronary angiography Diabet Med 28 2011 311 318
  13. 13 A.M. From C.G. Scott H.H. Chen Changes in diastolic dysfunction in diabetes mellitus over time Am J Cardiol 103 2009 1463 1466
  14. 14 D. Aguilar A. Deswal K. Ramasubbu Comparison of patients with heart failure and preserved left ventricular ejection fraction among those with versus without diabetes mellitus Am J Cardiol 105 2010 373 377
  15. 15 J.K. Ghali J. Boehmer A.M. Feldman Influence of diabetes on cardiac resynchronization therapy with or without defibrillator in patients with advanced heart failure J Card Fail 13 2007 769 773
  16. 16 C. Fantoni F. Regoli A. Ghanem Long-term outcome in diabetic heart failure patients treated with cardiac resynchronization therapy Eur J Heart Fail 10 2008 298 307
  17. 17 S.J. Haas T. Vos R.E. Gilbert Are beta-blockers as efficacious in patients with diabetes mellitus as in patients without diabetes mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials Am Heart J 146 2003 848 853
  18. 18 R.J. Lopes A.P. Lourenco J. Mascarenhas Safety of spironolactone use in ambulatory heart failure patients Clin Cardiol 31 2008 509 513
  19. 19 A.S. Desai K. Swedberg J.J.V. McMurray Incidence and predictors of hyperkalemia in patients with heart failure. An analysis of the CHARM program J Am Coll Cardiol 50 2007 1959 1966
  20. 20 S.A. Sadjadi J.I. McMillan N. Jaipaul A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers Ther Clin Risk Manage 5 2009 547 552
  21. 21 C.O. Phillips A. Kashani D.K. Ko Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials Arch Intern Med 167 2007 1930 1936
  22. 22 M.A. Raebel D.L. McClure K.A. Chan Laboratory evaluation of potassium and creatinine among ambulatory patients prescribed spironolactone: are we monitoring for hyperkalemia? Ann Pharmacother 41 2007 193 200
  23. 23 M.A. Raebel C. Ross S. Xu Diabetes and drug-associated hyperkalemia: Effect of potassium monitoring J Gen Intern Med 25 2010 326 333
  24. 24 D. Feuvray A. Darmellah Diabetes-related metabolic perturbations in cardiac myocyte Diabetes Metab 34 suppl 1 2008 3 9
  25. 25 W. Wenmeng T. Qizhu Early administration of trimetazidine may prevent or ameliorate diabetic cardiomyopathy Med Hypotheses 76 2011 181 183
  26. 26 R. Belardinelli G. Cianci M. Gigli Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy J Cardiovasc Pharmacol 51 2008 611 615
  27. 27 D.S. Bell M.A. Lukas F.K. Holdbrook The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis Curr Med Res Opin 22 2006 287 296
  28. 28 S. Salpeter E. Greyber G. Pasternak E. Salpeter Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database Syst Rev 4 2010 CD 002967
  29. 29 S.R. Salpeter E. Greyber G.A. Pasternak E.E. Salpeter Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Arch Intern Med 163 2003 2594 2602
  30. 30 C. Andersson J.B. Olesen P.R. Hansen Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: retrospective nationwide cohort study Diabetologia 53 2010 2546 2553
  31. 31 J.M.O. Arnold J.G. Howlett P. Dorian Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or acute decompensation, and use of biomarkers Can J Cardiol 23 2007 21 45
 
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