SGLT2 Inhibitors Changed the Treatment Paradigm for T2D, Have Implications for Managed Care

The treatment paradigm for type 2 diabetes (T2D) is increasingly complex as the introduction of sodium glucose co-transporter 2 (SGLT2) inhibitors has impacted guidelines for managing the disease and managed care in general, said Richard E. Pratley, MD, the Samuel E. Crockett Chair in Diabetes Research and medical director of the AdventHealth Diabetes Institute, and adjunct professor of medicine at the Johns Hopkins University School of Medicine, during his presentation at the National Association of Managed Care Physicians Virtual Spring Managed Care Forum.

SGLT2 inhibitors “are changing our previous paradigm in diabetes in ways that really benefit patients with type 2 diabetes,” Pratley said.

Currently, there are more than 34 million patients with diabetes in the United States, or 10.5% of the US population, according to the CDC. The majority (90%-95%) of adult cases are T2D. In addition, 88 million adults in the United States, or 34.5% of the adult population, have prediabetes and are at risk for developing diabetes.

“We've seen literally an explosion in the number of patients with diabetes over the last 2 to 3 decades or so—it's truly another pandemic,” Pratley said. “Not the one we're currently obsessed with, but one that's been going on for 30 years.”

Diabetes also presents a high risk of chronic complications and the CDC has estimated that the total annual cost of diabetes is $327 billion (2017 data) broken down as $237 billion for direct medical costs and $90 billion in reduced productivity.

In the United States, diabetes management could be better. According to Pratley, more than 14 million patients have glycated hemoglobin (A1C) ≥ 7%, which is above the target. On top of that, 16 million patients are obese and more than 4 million have severe obesity, which has “its own set of complications and is making diabetes and its management much worse,” he said.

Stroke, cardiovascular disease (CVD), and diabetic neuropathy are expensive complications of diabetes that are associated with morbidity and mortality in diabetes. “These are the ones that, increasingly, we’re paying attention to,” Pratley said.

One-fourth of adults with diabetes also have CVD and it affects men and women equally. Heart failure is also increasingly being seen with diabetes, and it is an age-related issue with increasingly prevalence as people get older. Hospitalizations for heart failure in patients with diabetes are more prevalent than admissions for coronary syndrome, dysrhythmia, or stroke.

There has also been an increase in the prevalence of end-stage kidney disease (ESKD) in patients with diabetes.

“This is really a worrisome trend because end-stage kidney disease is associated with higher mortality and is also a very costly disease for many years,” Pratley said.

Patients with diabetes on dialysis have a worse life expectancy than people with leukemia, bladder cancer, or colorectal cancer. Approximately 40% of patients with diabetes have a 5-year survival rate on dialysis.

In the last 25 years, research has suggested that there have been reductions in the United States in myocardial infarction (MI), stroke, and amputation and in patients with diabetes, which is good news, except the trend is slowing down among younger individuals with diabetes.

After years of hospitalizations for cardiorenal events among patients with T2D declining, they started picking back up between 2010 and 2015 for patients younger than 65 years. However, in the older patient population, there is still progress in reducing hospitalizations for cardiorenal events among patients with T2D.

“We may be winning that battle, but we’re losing the war,” Pratley said. “The actual burden of cardiovascular disease is increasing overall.”

As of 2008, there has been a more concerted effort to address CVD in patients with diabetes after a study suggested that rosiglitazone was associated with an increase risk of MI.¹ The findings led the FDA to convene a group of experts to provide guidance on evaluating cardiovascular (CV) risk. The resulting guidance was that the drugs in development had to do robust CV outcomes trials on postmarketing conditions to assure the FDA that they will not increase the risk of CVD.

Since then, there have been more than 28 trials initiated for 8 drug classes. The studies included more than 200,000 patients with diabetes. Among those trials, 8 were for SGLT2 inhibitors:

• EMPA-REG OUTCOME studying empagliflozin in 7000 patients for 5 years
• CANVAS-R and CANVAS studying canagliflozin in 5826 patients for 3 years and 4418 patients for more than 4 years, respectively
• SOLOIST-WHF studying sotagliflozin in 4000 patients for approximately 2.7 years
• SCORED studying sotagliflozin in 10,500 patients for approximately 4.5 years
• VERTIS CV studying ertugliflozin in 8000 patients for approximately 6 years (Pratley worked on this study)
• CREDENCE, a cardiorenal trial, studying canagliflozin in 4464 patients for 5.5 years
• DECLARE-TIMI studying dapagliflozin in 17,160 patients for approximately 6 years

So far, 4 of these drugs were approved by the FDA for type 2 diabetes: empagliflozin, canagliflozin, ertugliflozin, and dapagliflozin. The CV outcomes trials for these drugs had very similar designs and all the patients in them either had established CVD or risk factors for CVD. The age was very similar across all the studies (approximately 63 years), and A1C was also high in all the studies (between 8.1 and 8.3).

Some of the benefits that have been seen with the SGLT2 inhibitors have been reductions in A1C by 0.6% to 0.9%, a low risk of hypoglycemia, and modest reductions in weight and blood pressure. Some of the risks are polyuria/dehydration, genital mycotic infections, and increased risk of diabetic ketoacidosis.

In EMPA-REG OUTCOME and the 2 CANVAS trials, there were significant 14% reductions in relative risk for the major adverse cardiovascular events (MACE) of CV death, nonfatal MI, and nonfatal stroke.^2,3 DECLARE-TIMI and VERTIS CV did not show significant reductions.^4,5

These trial results have all impacted local and international guidelines. First-line therapy remains metformin alongside lifestyle changes, but patients who have high risk for or established chronic kidney disease (CKD) or heart failure have other options. These patients should be started on an SGTL2 inhibitor, Pratley explained.

These new therapies and the guideline changes have implications for managed care. CKD has a 97% higher risk for all-cause mortality, a 119% higher risk for CV mortality, and an 87% higher risk of MACE, plus the disease is very costly. Similarly, the rate for hospitalization is 2-fold higher in patients with T2D and heart failure and CVD is the primary cause of mortality and morbidity in these patients. Both heart failure and CVD also have excess costs.

“Prevention and effective management of these conditions is of paramount importance to improving outcomes and reducing costs in managed care populations,” Pratley said.

However, SGLT2 inhibitors are not for every patient, as the guidelines suggest. Yet, survey results of patients with T2D worldwide seen by primary care providers or specialists found that there are identical rates of SGTL2 inhibitor use regardless of whether the patient had CVD.

“People are not yet up to the guidelines for starting the SGLT2 inhibitors,” Pratley said. “So, this is a real opportunity to personalize therapy with these newer and more expensive therapies.”

References

1. Nissen ST, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-71. doi:10.1056/NEJMoa072761

2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28. doi:10.1056/NEJMoa1504720

3. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925

4. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389

5. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. doi:10.1056/NEJMoa2004967