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Improving Cardiovascular and Renal Outcomes in T2D Patients: GLP-1 Agonists, SGLT2 Inhibitors

Heart failure and renal disease are early complications in type 2 diabetes that pose a significant economic burden and can be fatal for patients. Recent trials of GLP-1 receptor agonists and SGLT2 inhibitors have shown these drug classes could reduce or prevent cardiovascular and renal disease, improving outcomes despite their high cost.

Heart failure and renal disease are two of the most common complications a provider will encounter when managing a patient type 2 diabetes, and the relationship between these diseases is complex. 

Heart failure is four times more prevalent in patients with diabetes than the general population and it is estimated that chronic heart failure and acute heart failure occur in 25% and 40% of diabetes patients, respectively. According to the Centers for Disease Control and Prevention (CDC), the prevalence of chronic kidney disease is 36.5% among patients with diabetes. Diabetes and high blood pressure are also leading causes of chronic kidney disease.

“We counsel the patients about these increased risks,” Robert Busch, MD, an endocrinologist from Albany, NY, told First Report Managed Care in an interview. Interventions for patients with type 2 diabetes include conversations about smoking cessation treatment with statins to lower cardiovascular risk and use of angiotensin-converting enzyme (ACE) inhibitors and angiotensinreceptor blockers (ARBs) to prevent or reduce the progression of kidney disease.

However, these complications can arise early in a patient’s treatment, which is why these interventions need to begin as soon as possible, explained Naeem Khan, MD, vice president of US CVMD Medical Affairs at AstraZeneca. “It’s important that we engage these patients early in the process and continue to assess available treatment options to determine which treatment plan and options are best tailored to help them achieve their health goals.”

Statins, ACE inhibitors, and ARBs come with downsides as well. Research has shown that  statins have not been fully adopted for patients with type 2 diabetes, in part because of factors like provider unfamiliarity with clinical guidelines. In addition, for some patients treated with ACE inhibitors and ARBs, renin-angiotensin system blockers may not provide a full antiproteinuric response.

Siloed Care For Type 2 Diabetes

The total cost of diagnosing diabetes was $327 billion in 2017, with 30% of the total medical cost going to in-hospital patient care, according to the American Diabetes Association (ADA). The CDC states that heart failure costs the United States $30.7 billion each year, which includes health services and medications to treat heart failure. Treating end-stage renal disease costs the United States an additional $35 billion each year.

The cost of any one of these diseases on the health care system is already high. Taken together, complications resulting from type 2 diabetes represent a significant economic burden. If not properly managed, these complications can lead to fatal outcomes for patients.

“Dialysis and hospitalizations represent a significant financial burden on the health system and also importantly represent a decreased quality of life for the patient,” said S Russell Spjut, PharmD, clinical pharmacist, owner of Formulary Intel Consulting and First Report Managed Care editorial advisory board member. “The tough part with all of this is the highest costs for these patients come as the disease progresses, and helping everyone treating and supporting the patient understand the importance of early and effective treatment to prevent these terrible outcomes can be challenging.”

Organizations like the CDC and the Global Partnership for Effective Diabetes Management have championed efforts to provide interdisciplinary care and improve outcomes for patients with diabetes. But health care providers (HCPs) have traditionally operated in an isolated fashion and focused their efforts to treat the most urgent disease affecting the patient, Dr Khan noted. “Even though most HCPs recognize the interrelated risks of type 2 diabetes, cardiovascular, and renal disease, they may not be able to connect their patients to the appropriate specialists because of a complex system that can lead to fragmented care.”

Other providers may feel they are “overstepping their bounds” to treat conditions outside their specialty, said Dr Spjut. “In the best of circumstances, they may coordinate with the other providers treating the specific patient, or in the worst case, the patient may be on their own in trying to manage these conditions with separate providers.”

GLP-1 agonists and SGLT2 inhibitors

Results from several recent trials may help improve outcomes for patients with type 2 diabetes at risk for developing cardiovascular and renal disease. Glucagon-like peptide (GLP)-1 agonists and sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as type 2 diabetes treatments with cardioprotective and renoprotective properties, which could help reduce or prevent the risk of cardiovascular disease and renal disease in these patients.

In the REWIND trial sponsored by Eli Lilly, over 9900 patients with a previous cardiovascular event or at risk of cardiovascular disease who received the GLP-1 agonist dulaglutide showed reduced risk of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. REWIND also showed renal benefit in type 2 diabetes patients receiving dulaglutide, particularly in reduction of new macroalbuminuria.

In the DECLARE-TIMI 58 trial, patients with type 2 diabetes who received the SGLT2 inhibitor dapagliflozin were at a lower risk for heart failure hospitalization and cardiovascular death. “The majority of the patient population was without established cardiovascular disease and close to 50% of patients had normal renal function,” said Dr Khan, whose company, AstraZeneca, funded the trial. 

The CREDENCE trial sponsored by Janssen also showed the SGLT2 inhibitor canagliflozin reduced the risk of kidney failure in patients with type 2 diabetes in addition to lower risks of cardiovascular death, myocardial infarction, stroke, and heart failure hospitalization. “It should be standard of care in patients with diabetes,” said Dr Busch, who was an investigator in the CREDENCE trial. “One [prevention of] heart failure hospitalization might pay for years and years of therapy.

GLP-1 agonists and SGLT2 inhibitors have also gotten the attention of medical societies. The ADA updated their Standards of Medical Care in Diabetes to include data from the REWIND trial. The ADA, the American College of Cardiology, American Heart Association, the American Association of Clinical Endocrinologists, and the American College of Endocrinology have also updated their guidelines to reflect data from the DECLARE trial, said Dr Khan.

“These guideline updates are very important because they reinforce the role of SGLT2 inhibitors in reducing renal and cardiovascular risks, including heart failure, and help empower HCPs to provide evidence-based care and improve patient outcomes,” Dr Khan said.

Barriers to Care

At the moment, one of the largest barriers to care is not access to these classes of drugs, but the significant expense. Depending on the drug, the cost of GLP-1 agonists can range between $700 and $1200 per treatment, while SGLT2 inhibitors range between $300 and $500 per treatment, according to drug price tracking website GoodRx.

“Almost all of the plans I have had a chance to look at recently cover at least one or two of the currently available SGLT2 inhibitor medications,” said Dr Spjut. “Even with coverage though, I think there are many patients who may still struggle financially to pay for them.”

Prior authorization hurdles can also be an issue for patients, where insurance may require step therapy or have patients fail first with metformin before providing access to treatments. “As HCPs evaluate the variety of treatment options available to help
manage type 2 diabetes, cardiovascular disease, and renal disease, it’s important that they have the ability to determine which treatment options will have the greatest benefit for the patient without the current insurance hurdles,” said Dr Khan.

Some pharmaceutical companies offer vouchers to patients to make the drugs more affordable or even free, but patients on Medicare are not eligible to use these vouchers. Patients may also end up paying much more if they fall into the coverage “donut hole,” Dr Busch noted. “Medicare doesn’t routinely cover these drugs, and if they do, they don’t generously cover them…So, it’s a bigger deal for Medicare patients.”

Experts said they expect this situation to change as the benefits of both drug classes become more widespread.

“I would not be surprised to see some developments soon, such as a manufacturer releasing an authorized generic version of their product at a significantly reduced list price, such as we have seen in other high-profile therapeutic areas,” said Dr Spjut.

Dr Busch also said he has counseled patients on how to take these medications, including staying hydrated, reducing or stopping use of diuretics, tapering off insulin and other glucose-lowering drugs, and watching for signs of ketoacidosis—one of the side effects of SGLT2 inhibitors. “That is very rare, but preventable. If the patient can’t eat or drink, you would have them not take the therapy,” said Dr Busch.

Thinking Beyond HBA1C

If the long-term benefits of GLP-1 agonists and SGLT2 inhibitors persist, these medications should be “seriously considered” as part of therapy for patients with type 2 diabetes, said Dr Spjut. “If the results seen in these trials is consistent and long-lasting in the real world, they have a big potential to offset their costs over and over again if patients avoid the necessary treatments that come with the later stages of heart and renal failure,” he said.

“I think you’ll see our primary care providers writing a lot more in an unobstructed way, especially when they see the benefits in their own patients,” said Dr Busch. “In addition, both of these drug classes cause weight loss, and weight loss sells to the patients—they want to be on them.”

Measuring a patient’s HBA1C level has long been a mainstay of diabetes management, but GLP-1 agonists and SGLT2 inhibitors are already causing providers to rethink diabetes management beyond lowering HBA1C. 

“It’s not just HBA1C anymore,” Dr Busch said. It’s about the other benefits you get with the drug.”

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