SGLT2 inhibitors were designed to lower glucose, but clinical trials uncovered unexpected cardiovascular and renal benefits. Updated guidelines from the American Diabetes Association now recommends SGLT2 inhibitors in type 2 diabetes patients to lower glucose.
The evidence is clear that SGLT2 inhibitors should be added to the drug regimen of many type 2 diabetes patients, according to recent revisions of the American Diabetes Association’s standards of care for diabetes.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors interfere with glucose reuptake in the proximal tubules of the kidneys, increasing urinary excretion of glucose and thereby lowering glucose in the bloodstream. The drugs were brought to market with the thought that lowering glucose levels through this new mechanism should have favorable effects in treating diabetes.
But they’ve been found to have unexpected benefits — a discovery that has been called serendipitous. In 2008, the U.S. Food and Drug Administration added long-term cardiovascular outcomes trials (CVOTs) as another safety step in the approval process for diabetes agents because of the possible adverse cardiovascular effects of some diabetes drugs that came to light well after they had been approved.
- The latest update of the American Diabetes Association’s standards of care recommends use of SGLT2 inhibitors in type 2 diabetes patients as an additional agent for lowering glucose — and perhaps more importantly, for lowering cardiovascular and renal risk in patients predisposed to these complications.
- SGLT2 inhibitors’ positive effects do not seem to be mediated through their glucose-lowering action and may extend to patients without diabetes.
- SGLT2 inhibitor’s benefits were revealed unexpectedly in cardiovascular outcomes trials as part of the drug-approval process.
The CVOTs for SGLT2 inhibitors had unexpected results that quickly got people’s attention when they began to appear in 2015. The first published trial tested empagliflozin against placebo among type 2 diabetes patients at risk of cardiovascular events — nearly all of whom had established cardiovascular disease — who were receiving the standard of care. Among the benefits were a significant reduction in the risk of cardiovascular mortality and a 35% relative risk reduction in hospitalization for heart failure. The CVOTs published for canagliflozin in 2017 and dapagliflozin in 2018 reported similarly positive heart failure outcomes.
A meta-analysis of the CVOT results published in the Lancet in January 2019 concluded: “SGLT2 inhibitors have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalization for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.”
In the year since that analysis, more results have appeared that have generally reinforced and broadened the benefits as the drugs have been tested in more diverse patient groups.
“It is important for endocrinologists — and even more important for primary care doctors, nephrologists, and cardiologists — to think about using these drugs early in many patients with diabetes. The indications for the use of SGLT2 inhibitors are expanding rapidly.” – Jennifer Green, MD, endocrinologist, Duke University, Durham, N.C.
What the New Guidelines Say
SGLT2 inhibitors are now part of the mix for glucose lowering in the section of the standards on glycemic treatment. But perhaps the most significant references come in section 10 (“Cardiovascular Disease and Risk Management”) of the 2020 guidelines, which recommend:
- “Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or established kidney disease, a sodium–glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen.”
- “In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, multiple atherosclerotic cardiovascular disease risk factors, or diabetic kidney disease, a sodium–glucose cotransporter 2 inhibitor … is recommended to reduce the risk of major adverse cardiovascular events and heart failure hospitalization.”
Jennifer Green, MD, an endocrinologist at Duke University and member of the ADA professional practice committee that regularly revises the standards, says that metformin remains the recommended first-line treatment for type 2 diabetes. But she says that when it comes to adding another drug, “the main change this year was the removal of a need for tighter glycemic control to add a medication with cardio-renal benefit. If you have a patient with established atherosclerotic cardiovascular disease, or, in particular, with chronic kidney disease or heart failure, you should preferentially add an SGLT2 inhibitor irrespective of the need for additional glucose lowering. The reason for the change is that the benefits of the drugs don’t seem to be mediated through glucose lowering. Benefits were seen irrespective of patients’ hemoglobin A1c at baseline, and in fact some of the benefits may extend to patients without diabetes. So, it is important for endocrinologists — and even more important for primary care doctors, nephrologists, and cardiologists — to think about using these drugs early in many patients with diabetes. The indications for the use of SGLT2 inhibitors are expanding rapidly.”
Solid Evidence Base
The decision to include SGLT2 inhibitors in the ADA guidelines was not difficult because it is based on consistent and solid evidence from large, well-conducted outcome trials, according to Mikhail Kosiborod, MD, of Saint Luke’s Mid America Heart Institute in Kansas City, and an American College of Cardiology representative on the ADA committee.
He says that additional information has come from the DAPA-HF trial, which studied the effects of dapagliflozin in patients with heart failure and a reduced ejection fraction. The study included patients with and without diabetes and found similar cardiovascular benefits — significant reduction in the risk of cardiovascular death and worsening heart failure — regardless of the presence of diabetes. The findings provide additional evidence that the drugs provide benefits not related to lowering glucose and could have as-yet unestablished mechanisms of action conferring direct cardiovascular benefits. The speed with which benefits manifest — in relatively short-term trials — is another piece of evidence that they are not due to lowering glucose or hemoglobin A1c.
Which Drug to Choose?
The outcomes benefits are pretty consistent across the SGLT2 inhibitor class, Green says, so the choice of which SGLT2 inhibitor to prescribe may well be guided by the patient’s insurance coverage and ease of access. For example, the VA includes one SGLT2 inhibitor on its formulary and Medicaid coverage varies by state. Private insurance often specifies one drug in the class for coverage or lower copays, and discovering which drug is covered can be a hit-or-miss process of writing a prescription for the patient to take to a pharmacy.
The Expense Hurdle
Like many other new drugs, the value of SGLT2 inhibitors has been questioned because of their high price. But Green notes: “There are currently patients with diabetes being treated with other expensive medications without a demonstrated cardiovascular outcomes benefit. It may be worth turning a critical eye on the regimen of patients at risk for cardio-renal complications to see if you could substitute an SGLT2 inhibitor for an existing expensive medication without a demonstrated outcomes benefit, for a financially net neutral change, but a positive change with respect to their risk of serious complications.”
Reasons for Caution
Of course, like any drug, SGLT2 inhibitors have their contraindications and side effects. In 2015, the FDA added warnings to their labels about the risks of urinary tract infections and ketoacidosis. The FDA has consistently turned down applications for the use of SGLT2 inhibitors in type 1 diabetes, with the main concern being an increased risk of ketoacidosis in these patients.
Green notes that a canagliflozin study raised concerns about an increased risk of fractures and amputations, so she is cautious about starting an SGLT2 inhibitor in a patient already at high risk for amputation, such as a patient with ongoing foot ulceration.
“Many cardiologists now see these medications as drugs to prevent heart failure and cardiovascular death, with purely incidental effects on blood glucose. Their real benefit, and the reason we should use them, is because of their effects on heart failure, diabetic kidney disease, and cardiovascular death.” – Brendan M. Everett, MD, MPH, associate professor, Harvard Medical School, Boston, Mass.
The nephrology community has also greeted SGLT2 inhibitors with enthusiasm because of strong evidence that the drugs slow the progression of diabetic kidney disease. However, as kidney decline continues, their use is not recommended when a patient’s estimated glomerular filtration rate drops below 45 or 30, with the cutoff number varying by drug.
Brendan M. Everett, MD, MPH, an associate professor at Harvard Medical School and co-chair of the American College of Cardiology’s expert clinical decision pathway committee on the use of these drugs, also endorses the ADA’s new guidelines: “In the empagliflozin CVOT, there was a 40% reduction in cardiovascular death, and that drove a reduction in all-cause mortality. That’s important clinically to both doctors and patients. That finding has been validated in trials of canagliflozin and dapagliflozin. The benefits of these drugs for the cardiovascular system are so substantial that they have changed the way we think about treating patients who have both diabetes and cardiovascular disease. Many cardiologists now see these medications as drugs to prevent heart failure and cardiovascular death, with purely incidental effects on blood glucose. Their real benefit, and the reason we should use them, is because of their effects on heart failure, diabetic kidney disease, and cardiovascular death.”
Seaborg is a Charlottesville, Va.-based freelance writer and a frequent contributor to Endocrine news. He wrote about the benefits of Medicare coverage for continuous glucose monitors in the April issue.