With recent clinical trials on new anti-diabetic drugs providing insight into the cardioprotective benefits of these agents, I would like to further explore the diabetes and heart failure link. The Framingham Heart Study found that male patients with diabetes had a twofold increased risk of developing heart failure, while their female counterparts had a fivefold risk¹. This added risk was present even after adjusting for conventional risk factors such as age, hypertension, hypercholesterolemia and coronary artery disease². Patients with diabetes and heart failure had poorer outcomes as well. A meta-analysis by Targher et al found that diabetes was associated with a higher risk of hospitalization, as well as all-cause death and cardiovascular death³. The increase in cardiovascular morbidity and mortality was seen in heart failure with reduced ejection fraction as well as in those with preserved ejection fraction⁴.

Abnormal cardiac structure and function in people with diabetes without other cardiac risk factors has been termed diabetic cardiomyopathy. The development of heart failure in this population occurs not only due to coronary artery disease, but also involves metabolic abnormalities induced by hyperglycemia and hyperinsulinemia. These conditions lead to cardiac insulin resistance and metabolic disorders that augment mitochondrial dysfunction, oxidative stress, inflammation and activation of the renin-angiotensinogen-aldosterone system⁵. These metabolic disorders also induce stiffness, hypertrophy and fibrosis of the cardiac muscles which then results in diastolic and systolic dysfunction and, eventually, heart failure. Diastolic dysfunction often precedes systolic dysfunction and has been identified in up to 63% of asymptomatic, normotensive patients with well-controlled diabetes⁶.

Traditional Treatment and New Options

The treatment for heart failure in individuals with diabetes does not differ from the general population and includes the use of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, mineralocorticoid receptor antagonists and diuretics. Other agents in the heart failure pipeline are ivabradine and angiotensin receptor-neprilysin inhibitor which are used in patients with chronic heart failure with reduced ejection fraction and a New York Heart Classification of II or III. Medications used in the treatment of diabetes in the presence of heart failure need careful consideration as certain drugs may precipitate or increase the risk of heart failure. The use of thiazolidinediones has fallen out of favor due to reports of edema and increased incidence of cardiovascular death². DPP4 inhibitors generally have neutral cardiovascular outcomes, however, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 trial reported increased incidence of hospitalization for heart failure. This elevated risk was highest among patients with raised levels of natriuretic peptides, previous heart failure, or chronic kidney disease⁷.

Emerging Information on SGLT2 Inhibitors

Historically the use of metformin has been avoided in patients with heart failure due to potential occurrence of lactic acidosis. Large observational studies did not find this association and, in fact, saw a reduction in mortality compared to controls⁸. SGLT2 inhibitors seem to have a potential role in the treatment of heart failure with trials for the drug reporting a reduction in heart failure hospitalization. In the study Effects of Empaglifozin on Cardiac Structure in patients with Type 2 Diabetes (EMPA-HEART), which was conducted over a period of six months, researchers found a reduction in left ventricular mass⁹. This trial gave us the first mechanistic explanation for how these drugs improve heart failure and cardiovascular outcomes. Dedicated trials on the use of SGLT2 inhibitors for the treatment of heart failure are underway and will provide us with further understanding, especially in patients with heart failure with preserved ejection fraction.

There is still room for improvement in the management of heart failure in patient with diabetes as evidenced by the increased risk and mortality experienced in this population. Diabetes and heart failure are complex and chronic diseases that require integrated management involving multidisciplinary teams working together with the patient. Personalized care that includes the consideration of multiple comorbidities is vital to improving patient outcomes.

Note: In June 2019, the American Heart Association (AHA) and the Heart Failure Society of America (HFSA) issued a scientific statement on the management of Type 2 diabetes and heart failure. Read their abstract here.

References:

1. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035–2038.
2. Ofstad AP, Atar D, Gullestad L, Langslet G, Johansen OE. The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions. Heart Fail Rev. 2018;23(3):303–323.
3. Dauriz M, Mantovani A, Bonapace S, Verlato G, Zoppini G, Bonora E, Targher G. Prognostic impact of diabetes on long-term survival outcomes in patients with heart failure: a meta-analysis. Diabetes Care. 2017;40:1597–1605.
4. MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29(11):1377–1385.
5. Kenny HC & Abel ED. Heart Failure in Type 2 Diabetes Mellitus. Circulation Research. 2019. 124(1): 121–141.
6. Exiara T, Konstantis A, Papazoglou L, Kouroupi M, Kalpaka A, Mporgi L, et al. Left ventricular diastolic dysfunction in diabetes mellitus Type 2. J Hypertens 2010;28:e294.
7. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.
8. Eurich DT, Weir DL, Majumdar SR, et al.Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6:395-402.
9. Brauser D. EMPA-HEART: Empagliflozin May Reduce LV Mass in Patients With CVD, Diabetes.
   Medscape. https://www.medscape.com/viewarticle/904819#vp_1. November 13, 2018. Accessed July 15^th 2019.

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