New guidelines recommend cardioprotective antihyperglycemic drugs for patients with diabetes in combination with cardiovascular disease


Recent studies that confirm the cardiovascular benefit of some antihyperglycemic agents are shaping the newest therapeutic recommendations for patients with diabetes and comorbid atherosclerotic cardiovascular disease (ASCVD).

Treatment for these patients – as all with diabetes – should start with lifestyle modifications and metformin. But in its new position statement, the American Diabetes Association now recommends that clinicians consider adding agents proved to reduce major cardiovascular events and cardiovascular death – such as the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin or the glucagon-like peptide 1 (GLP-1) agonist liraglutide – to the regimens of patients with diabetes and ASCVD ( Diabetes Care 2018;41(Suppl. 1):S86-S104. doi: 10.2337/dc18-S009 ).

The medications are indicated if, after being treated with lifestyle and metformin therapy, the patient isn’t meeting hemoglobin A1c goals, said Rita R. Kalyani, MD, who led the ADA’s 12-member writing committee. But clinicians may also consider adding these agents for cardiovascular benefit alone, even when glucose control is adequate on a regimen of lifestyle modification and metformin, with dose adjustments as appropriate, she said in an interview.

“A1c remains the main target of sequencing antihyperglycemic therapies, if it’s not reached after 3 months,” said Dr. Kalyani of Johns Hopkins University, Baltimore. “But, it could also be that the provider, after consulting with the patient, feels it’s appropriate to add one of these agents solely for cardioprotective benefit in patients with ASCVD.”

The recommendation to incorporate agents with cardiovascular benefit is related directly to data from two trials, LEADER and EMPA-REG , which support this recommendation. All of these cardiovascular outcome trials included a majority of patients who were already on metformin. “We developed these evidence-based recommendations based on these trials and to appropriately reflect the populations studied,” said Dr. Kalyani.

The ADA’s “Standards of Medical Care in Diabetes 2018” is the first position statement from any professional society to provide specific recommendations for the incorporation of these newer antihyperglycemic agents for their cardioprotective benefit, as well as their ability to lower blood glucose effectively. But the document provides much more than an algorithm for treating patients with concomitant ASCVD, Dr. Kalyani said. It is a comprehensive clinical guide covering recommendations for diagnosis, medical evaluation, comorbidities, lifestyle change, cardiovascular risk management, and treating diabetes in children and teens, pregnant women, and patients with hypertension.

The 2018 update contains a number of new recommendations; more will be added as new data emerge, since the ADA intends it to be a continuously refreshed “living document.” This makes it especially clinically useful, Paul S. Jellinger , MD, said in an interview. A member of the writing committee of the American Association of Clinical Endocrinologists’ diabetes management guidelines , Dr. Jellinger feels ADA’s previous versions have not been as targeted as this new one and, he hopes, its subsequent iterations.

“This is a nice enhancement of previously published guidelines for diabetes therapy,” said Dr. Jellinger, professor of clinical medicine at the University of Miami. “For the first time, ADA is providing some guidance in terms of which agents to use. It’s definitely more prescriptive than it was in the past, when, unlike the AACE Diabetes Guidelines, it was a palette of choice for clinicians, but with very little guidance about which agent to pick. The guidance for patients with cardiovascular disease in particular is big news because these antihyperglycemic agents showed such a significant cardiovascular benefit in the trials.”

While the document gives a detailed algorithm of advancing therapy in patients with ASCVD, it doesn’t specify a preference for a specific drug class after metformin therapy in patients without ASCVD. Instead, it provides a detailed table listing the drug-specific effects and patient factors to consider when selecting from different classes of antihyperglycemic agents ( SGLT2 inhibitors, GLP-1 agonists, DPP-4 inhibitors, thiazolidinones, sulfonylureas, and insulins). The table notes the drugs’ general efficacy in diabetes, and their impact on hypoglycemia, weight gain, and cardiovascular and renal health. The table also includes the Food and Drug Administration black box warnings that are on some of these medications.

Another helpful feature is a cost comparison of antidiabetic agents, Dr. Kalyani noted. “Last year we added comprehensive cost tables for all the different insulins and noninsulins, and this year we added a second data set of cost information, to assist the provider when prescribing these agents.”

The pricing information is a very important addition to this guideline, and one that clinicians will appreciate, said Richard Hellman, MD, clinical professor of medicine at the University of Missouri–Kansas City.

“In this document, ADA is urging providers of care to ask about whether the cost of their diabetes care is more than they can deal with. They present tables which compare the costs of the current blood glucose lowering agents used in the U.S., and it is plain to see that many patients, without insurance coverage, will find some of the medications unaffordable,” said Dr. Hellman, a past president of AACE. “They also provide data that show half of all patients with diabetes have financial problems,” and he suspects that medication costs are an important component of their financial insecurity.

The document also notes data from the 2017 National Health and Nutrition Examination Survey , which found that 10% of people with diabetes have severe food insecurity and 20% have mild food insecurity ( Diabetes Educ. 2017;43:260-71. doi: 10.1177/0145721717699890 ).

“Another thing the document points out is that two-thirds of the patients who don’t take all their medications due to cost don’t tell their doctor,” Dr. Hellman said. “The ADA is making the point that providers have a responsibility to ask if a patient is not taking certain medications because of the cost. We have so many better tools to manage this disease, but so many of these tools are unaffordable.”

While the treatment algorithm for patients with ASCVD will likely be embraced, another new recommendation may stir the pot a bit, Dr. Hellman noted. The section on cardiovascular disease and risk management goes out on its own, sticking to a definition of hypertension as 140/90 mm Hg or higher – a striking diversion from the new 130/80 mm Hg limit set this fall by both the American Heart Association and the American College of Cardiology.

“This difference in recommendations is very important and will be controversial,” Dr. Hellman said, adding that he agrees with this clinical point.

Again, this recommendation is grounded in clinical trials, which suggest that people with diabetes don’t benefit from overly strict blood pressure control. The new AHA/ACC recommendations largely drew on data from the SPRINT trial, which was conducted in an entirely nondiabetic population. “These gave a clear signal that a lower BP target is beneficial to that group,” Dr. Hellman said.

But large well-designed randomized controlled trials of intensive blood pressure lowering in people with diabetes, such as ACCORD-BP , did not demonstrate that intensive blood-pressure lowering targeting a systolic less than120 mm Hg had a significant benefit on the composite primary cardiovascular endpoint. And while the ADVANCE BP trial found that the composite endpoint was improved with intensive blood pressure lowering, the blood pressure level achieved in the intervention group was 136/73 mm Hg.

“This recommendation is based on current evidence for people with diabetes,” Dr. Kalyani said. “We maintain our definition of hypertension as 140/90 mm Hg or higher on the results of large clinical trials specifically in people with diabetes but emphasize that intensification of antihypertensive therapy to target lower blood pressures (less than 130/80 mm Hg) may be beneficial for high-risk patients with diabetes such as those with cardiovascular disease. We are constantly assessing the evidence and will continue to review the results of new studies for potential incorporation into recommendations in the future.”

Dr. Kalyani and Dr. Hellman had no financial disclosures. Dr. Jellinger has been a speaker for several pharmaceutical companies.

SOURCE: Kalyani R et al. Diabetes Care 2018;41(Suppl. 1):S86-S104 doi: 10.2337/dc18-S009


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