New AHA/HFSA Statement on Diabetes and Heart Failure

Pauline Anderson

June 14, 2019

The American Heart Association (AHA) and the Heart Failure Society of America (HFSA) have issued a new scientific statement on the management of comorbid type 2 diabetes mellitus (DM) and heart failure (HF).

The statement — which the document notes does not represent an update of the 2017 American College of Cardiology/AHA/HFSA heart failure guideline — summarizes what is known about the epidemiology and pathology of DM and its impact on HF outcomes, reviews management of those with both conditions, and looks at opportunities for future research, the authors say.

Dr Shannon Dunlay

"The primary goal of this statement is to bring practicing clinicians up-to-date on this topic," writing group co-chair Shannon M. Dunlay, MD, associate professor of Health Services Research and Medicine, Advanced Heart Failure Cardiologist, Mayo Clinic, Rochester, Minnesota, told | Medscape Cardiology.

"We have known for some time that diabetes and heart failure are both common, often occur together, and often require medications to treat one or both conditions," she said. But although separate guidelines cover the management of DM and HF, there's insufficient guidance on caring for patients with both conditions.

The statement was published online June 6 in Circulation, and in the Journal of Cardiac Failure.

The number of patients diagnosed with DM and HF is increasing, the authors note. About 30.3 million Americans, or 9.4% of the US population, have DM, and 6.5 million have HF, and an estimated 1.5 to 2 million have both conditions, Dunlay said.

Diabetes is a "powerful" risk factor for heart failure, and some data suggest that having heart failure increases the risk of developing diabetes, said Dunlay. "The metabolic derangements in diabetes can be toxic to the heart and cause heart failure. In addition, both conditions are characterized by inflammation, which can increase the risk of developing the other."

Medications used to treat one condition can also affect the outcomes of the other, said Dunlay. "Over the last few years, for example, data have emerged enlightening us that the medications we use to treat high blood sugar in diabetes can impact the risk of developing heart failure or risk of poor outcomes, including hospitalization for heart failure, in patients with heart failure."

Glycemic Control

Intensive treatment to achieve low HbA1c targets in type 2 DM reduces the long-term risk of microvascular events such as retinopathy, nephropathy, and peripheral neuropathy. Although intensive glycemic control doesn't appear to reduce the risk of all-cause mortality, cardiovascular mortality, or stroke, it may reduce the risk of nonfatal myocardial infarction, said the authors.

Optimal glycemic targets for patients with DM and HF should be individualized to reflect comorbidity burden, including the severity of HF, and to balance the benefits likely to be achieved by lowering HbA1c with the potential risks. The authors noted that potential harms of intensive treatment include hypoglycemia, polypharmacy, treatment burden, and high costs of care.

The benefits of glucose-lowering therapy should be considered within a broader context of the patient's life expectancy, because, as the authors point out, there's nearly a 10-year lag period to demonstrable benefit of more intensive glycemic control.

Given the lack of HF-specific data to guide HbA1c goals in patients with DM and HF, the authors suggest a target range of HbA1c of 7% to 8% for most patients with HF, consistent with DM clinical practice guidelines.

Treatment decisions should also consider potential benefits and harms of individual glucose-lowering medications. The authors reviewed these medications, which include:

Metformin: Metformin, a biguanide, is the preferred initial pharmacotherapy in patients with type 2 DM in the absence of contraindications. Metformin is effective, safe, and generally well tolerated, they write.

Although metformin was previously contraindicated in HF because of concerns over the rare risk of lactic acidosis, multiple observational studies suggest a survival benefit, said the authors.

The authors concluded that it's reasonable to use metformin in patients with DM at risk of HF or with established HF. But metformin should be discontinued in patients presenting with acute conditions associated with lactic acidosis, such as cardiogenic or distributive shock.

Sulfonylurea Drugs: There are limited data on the use of sulfonylurea therapy and the development of HF in patients with DM. Other agents, such as metformin and SGLT-2 inhibitors, are preferable in patients at high risk for HF and those with established HF, they note.

The ongoing CAROLINA trial (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes) will offer updated evidence on the cardiovascular safety of sulfonylurea drugs, including effects on hospitalization for HF, they noted. (CAROLINA results were just presented during the American Diabetes Association meeting and reported by Medscape Medical News; the report can be found here.)

Insulin: The only randomized controlled trial to specifically assess the cardiovascular safety of insulin was the ORIGIN trial (Outcome Reduction With Initial Glargine Intervention). This study randomly assigned 12,537 patients with pre-DM or DM to insulin glargine or standard care and found no difference in any cardiovascular outcomes, including hospitalization for HF.

However, observational studies suggested an increase in HF with insulin therapy. Most, but not all, observational studies and subgroup analyses of clinical trials have demonstrated that insulin use is associated with greater risk of death in patients with DM and HF.

The authors noted that insulin use is associated with weight gain and risk of hypoglycemia and should be used with caution and close monitoring. Other agents, such as metformin and SGLT-2 inhibitors, are preferred if adequate glycemic control can be achieved without insulin, they say.

Thiazolidinedione Drugs:  Randomized controlled trials have shown that thiazolidinedione drugs (TZDs) are associated with increased rates of HF hospitalization in patients without HF at baseline. The association of TZDs with increased HF risk has also been demonstrated in patients with DM and heart failure with reduced ejection fraction (HFrEF),

TZDs are not recommended in patients with established HF, and may increase the risk of HF events in individuals who have DM without HF, said the authors.

GLP-1 Receptor Agonists: Glucagon-like peptide-1 (GLP-1) receptor agonists stimulate glucose-dependent insulin release with a low risk of hypoglycemia. Important secondary effects include a decrease in appetite and food intake (which leads to weight loss) and improved lipid levels, with decreased triglyceride levels and increased high-density lipoprotein levels.

GLP-1 receptor agonists may reduce the risk of major adverse cardiovascular events and mortality in DM patients. In large clinical trials, they had no impact on the risk of HF hospitalization, which suggests they're safe but not beneficial in preventing HF in patients at risk for HF, they write.

In patients with established HFrEF and recent decompensation, GLP-1 receptor agonists should be used with caution, given no evidence of benefit and a trend toward worse outcomes in two small randomized controlled trials, said the authors.

Dipeptidyl Peptidase-4 Inhibitors: Dipeptidyl peptidase-4 (DPP-4) is an enzyme involved in the rapid degradation of GLP-1, so the effects of the incretin system could be enhanced by DPP-4 inhibition. Alogliptin, linagliptin, saxagliptin, and sitagliptin are FDA-approved oral treatments in type 2 DM.

There's no evidence that DPP-4 inhibitors provide cardiovascular benefit. In patients with DM at high cardiovascular risk, some DPP-4 inhibitors could increase the risk of hospitalization for HF, said the authors.

The effects in patients with established HF have not been well studied, with some potentially concerning signals in mechanistic trials.

"On the basis of these data, the risk-benefit balance for most DPP-4 inhibitors does not justify their use in patients with established HF or those at high risk for HF," the authors write.

SGLT-2 Inhibitors: SGLT-2 inhibitors lower glucose through increased urinary excretion. In addition, they increase fractional excretion of sodium and have modest diuretic and natriuretic effects. Canagliflozin, dapagliflozin, and empagliflozin are FDA approved for the treatment of type 2 DM.

"SGLT-2 inhibitors may be a good choice for patients with diabetes who are at high risk for heart failure or already have heart failure, as they may decrease risk of cardiovascular events and heart failure hospitalization," said Dunlay.

"Recent trials have consistently demonstrated this. There are also ongoing trials testing whether SGLT-2 inhibitors are useful as a treatment for heart failure, even in patients without diabetes," she added.

Dunlay said that she's "very excited" to learn more about how SGLT-2 inhibitors work and how they can be best used in heart failure management — in both reduced and preserved EF.

But the authors cautioned that cardiovascular benefits of SGLT-2 inhibitors should be balanced with their potential risks, including genital candidiasis and other, rare potential complications such as euglycemic diabetic ketoacidosis, lower-limb amputation, and fractures.

The authors also summarized existing data comparing the effectiveness of HF therapies in patients with and without DM. These include:

ACE inhibitors: A meta-analysis of 6 angiotensin-converting enzyme (ACE) inhibitor trials demonstrated reductions in morbidity and mortality in patients with HF with or without DM. The pooled analysis of 2398 patients found a relative risk for death of 0.84 (95% confidence interval [CI], 0.70 - 1.00) in patients with DM vs 0.85 (95% CI, 0.78 - 0.92) in those without DM.

Similar results were seen in pivotal HF trials of angiotensin receptor blockers (ARBs). Research has also uncovered treatment benefits for the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril-valsartan in patients with and without DM, the authors note.

Mineralocorticoid receptor antagonists (MRAs) have been shown to have consistent benefits in HFrEF patients with and without DM.

β-Blockers: Most meta-analyses of β-blocker trials by DM status have demonstrated a consistent benefit in individuals with DM and HFrEF, although one suggested a comparatively greater benefit in individuals without DM, the authors note.

Overall, the three FDA-indicated β-blockers for use in HFrEF (carvedilol, metoprolol succinate, and bisoprolol) have been shown to substantially reduce morbidity and mortality in individuals with DM, they write.

Ivabradine: In the ivabradine versus placebo in chronic systolic heart failure trial (SHIFT), ivabradine significantly reduced the primary endpoint of cardiovascular death or HF hospitalization in patients with and without DM (interaction P = .57). There was also a significant reduction in HF hospitalization in both groups. 

Implantable Therapy: In general, pivotal trials of both implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) found consistent benefits in patients with and without DM.

Some of the newest data show that left ventricular assist device (LVAD) therapy can improve glycemic control in patients with diabetes, said Dunlay. "This is important because LVAD is essentially improving the heart failure, and that can improve the diabetes control."

Patients With CKD

The authors concluded that metformin is a reasonable first-line therapy in patients with HF and chronic kidney disease (CKD), as long as the estimated glomerular filtration rate (eGFR) exceeds 30 mL/min/1.73 m2.

Insulin is safe to use in patients with CKD and HF, although lower doses are required with impaired renal function. Clinicians may consider other hypoglycemic agents, although dose adjustment might be needed in those with CKD, and the risk of adverse effects can be enhanced as renal function declines, said the authors.

Use of SGLT-2 inhibitors in patients with CKD seems promising given their HF benefit and potential for renal protection. But the authors stressed that results of ongoing clinical trials are needed to ensure they're safe to use at lower eGFR levels.  

The authors highlighted the need for collaborative management of DM and HF. "It's easy to focus on the main condition you're treating, such as heart failure, but it's important to think about how the patient's other conditions, including diabetes, may be impacted by the medications you're using," said Dunlay.

She stressed that team-based care is essential. "Communication and coordination of care are so important for patients with complex medication regimens and complex medical conditions such as diabetes and heart failure."

Lifestyle management is another important element of managing these patients, said Dunlay. "Exercise is safe and beneficial for patients with heart failure and diabetes."

The American Heart Association and the Heart Failure Society of America make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.

Circulation. Published online June 6, 2019. Abstract

Journal of Cardiac Failure. Published online June 6, 2019. Abstract

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