Diabetes and heart failure have both gone from being global epidemics to pandemics over the past ten years. Singapore has a higher prevalence of diabetes mellitus than the world’s average and has the second highest proportion of diabetic patients amongst the developed nations. The country has also declared war against diabetes mellitus in 2016 and its citizens have shown increased awareness in the disease since then.
On the other hand, heart failure remains lesser known here but the spotlight was thrown at it when it was reported in studies conducted in Singapore, that Southeast Asian patients present with acute heart failure at a much younger age compared to the Americans and have more severe clinical features.
The prevalence of symptomatic heart failure is also higher in Southeast Asia than in other parts of the world. Even between the different ethnicities, Malay and Indian patients have much higher hospitalisation rates compared to the Chinese and mortality is three and a half times higher in Malays, compared to Chinese and Indians.
These two diseases are interlinked. Studies have shown that up to 35% of heart failure patients are diabetic and diabetic patients have up to a four times higher risk of developing heart failure.
It is a predictor of mortality and morbidity in heart failure and heart failure patients with poor glycaemic control have been shown to have higher mortality as well. While strict glycaemic control has not been shown to directly improve outcomes in these patients, good glucose control is critical to preventing progression of heart disease.
This does not only apply in patients with heart failure with reduced ejection fraction, but also in heart failure with preserved ejection fraction as well.
This is especially important to us because diabetes has been found to be three times more common in Southeast Asian heart failure patients, and associated with worse outcomes compared to their Caucasian counterparts.
Primary care physicians play a fundamental role in the management of diabetes mellitus and are essential in this uphill battle.
The diabetic heart undergoes many structural and metabolic changes. Triglyceride deposition in the heart and insulin resistance are some of the mechanisms that contribute to myocardial hypertrophy. The renin angiotensin aldosterone and sympathetic systems are both activated which lead to increased collagen deposition and fibrosis via the transforming growth factor B1 pathway and dysregulation of the extracellular matrix.
With the excess glucose and free fatty acids in the blood stream, there is increased deposition of lipid in the myocardium and this alters the supply and demand relationship in the cardiomyocytes. As a result of the latter, there is excessive reactive oxygen species production which is implicated in endothelial dysfunction and atherosclerosis.
Diabetic cardiomyopathy is defined as ventricular dysfunction in the absence of coronary atherosclerosis and hypertension in diabetic patients.
It spans the whole spectrum from diastolic dysfunction to heart failure with reduced ejection fraction. It starts as left ventricular hypertrophy and impaired diastolic function, in view of the mechanisms discussed above. This condition also includes microvascular dysfunction which impairs myocardial perfusion and can also lead to fatal outcomes. Eventually, there may be reduction of systolic function and an enlarged left ventricle.
In the history of these two diseases, there have been two drugs that have toxicities that made them relatively or absolutely contraindicated in patients with heart failure.
The first to come to mind would be thiazolidinediones – the glitazones cause fluid retention and can precipitate heart failure via renal sodium retention. Therefore, they are contraindicated in patients with heart failure.
The negative experience with rosiglitazone has resulted in the Food and Drug Administration (FDA) asking for cardiovascular outcome trials for all new type 2 diabetes therapies.
Metformin had a FDA boxed warning concerning the risks of developing lactic acidosis in patients with heart failure after a study published in 1998 demonstrated increased risk. However, they have removed this warning in 2006 as metformin has been shown to be safe in large populations of heart failure patients.
It remains the first line for diabetic patients whose estimated glomerular filtration rate (eGFR) is more than or equals to 30ml per minute per 1.73m2.
Fortunately, SGLT2 inhibitors, the new kid on the block, has shown great promise in heart failure management. Other than increasing renal glucose excretion, it also promotes natriuresis, osmotic diuresis and plasma volume contraction. More positive effects of the drug include weight loss and blood pressure reduction.
In the EMPA-REG trial involving
empaglifozin, patients with type 2 diabetes had a lower rate of the primary composite cardiovascular outcome and of death from any cause. Empaglifozin also reduced heart failure hospitalisation and cardiovascular death, in patients with and without heart failure at baseline.
In the DECLARE TIMI 58 trial,
dapaglifozin did not result in a difference in the rate of major adverse cardiovascular events than placebo but it did lead to a lower rate of cardiovascular death or hospitalisation for heart failure.
The third SGLT2 inhibitor,
canaglifozin, has also shown a lower risk of cardiovascular events than placebo in the CANVAS Programme but it is associated with a higher risk of amputation at the level of the toe or metatarsal. All three drugs have also shown to offer renal protection.
The basis of good diabetes control would always be diet and lifestyle modification, and compliance to medication.
However, the birth of SGLT2 inhibitors brings great promise as a new class of drugs that can benefit patients with diabetes in many aspects.
There are multiple ongoing trials to test the efficacy of this class of drugs in heart failure with preserved ejection fraction and also in non-diabetic patients.
Heart failure and diabetes are both chronic diseases with multiple complications and would need effective shared care between primary care physicians and cardiologists to improve outcomes.
Assistant Professor Laura Chan is a Consultant with the Department of Cardiology
at the National Heart Centre Singapore (NHCS). Her main interests are in
inheritable cardiomyopathy and cardiovascular magnetic resonance. Additionally,
Assistant Professor Laura Chan subspecialises in heart failure.
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