CV benefits of type 2 diabetes agents may extend to type 1, but more data needed
Type 2 diabetes agents with proven cardiovascular benefit may be useful for patients with type 1 diabetes to prevent atherosclerotic CVD, but more robust data are needed for the type 1 population.
CVD is more common among individuals with type 1 diabetes compared with those without diabetes, and risk for a CV event is large, Richard E. Pratley, MD, the Samuel E. Crockett chair in diabetes research and medical director of AdventHealth Diabetes Institute, told Healio. CVD occurs on average 10 to 15 years earlier among people with type 1 diabetes and type 1 diabetes status essentially eliminates the cardioprotection seen among premenopausal women, Pratley said.
“CVD is the leading cause of death among people with type 1 diabetes, and our approach [to reducing CV risk] really is extrapolated from studies in type 2 diabetes and nondiabetic patients,” Pratley said. “That seemed to work out well for lipids, but what about these other medications?”
The addition of SGLT2 inhibitors or GLP-1 receptor agonists — currently FDA approved only for type 2 diabetes — to intensive insulin therapy provides minimal benefits, with no demonstrated gain for CVD, and poses the risk for “substantial harm,” according to David M. Nathan, MD, director of the Massachusetts General Hospital Diabetes Center and professor of medicine at Harvard Medical School.
“Until there are any credible data showing a benefit with these classes of drugs in type 1 diabetes, there are only increased adverse effects, risk and costs to recommend them,” Nathan told Healio. “In particular, the SGLT-2 inhibitors pose an increased risk for [diabetic ketoacidosis] when used in type 1 diabetes.”
Translating SGLT2, GLP-1 benefits
To prevent excess risk for atherosclerotic CVD in type 1 diabetes, Pratley said, clinicians should manage key CV risk factors by targeting smoking cessation, an HbA1c to 7% or less and blood pressure to 130/80 mm Hg or less; considering high-intensity statin therapy to lower LDL cholesterol; reducing hypoglycemia; and recommending weight loss.
However, data from T1D Exchange show that only about 28% of adults aged at least 50 years — those at higher risk for CVD — have an HbA1c of less than 7%, Pratley said.
Since 2008 when the FDA mandated CV outcomes trials for any diabetes therapies, a “cottage industry” of trials, particularly for SGLT2 inhibitors and GLP-1 receptor agonists, have demonstrated sometimes surprising CV benefits for those with type 2 diabetes with and without preexisting CVD. To date, 28 such trials have been completed for eight classes of medications, with more than 200,000 planned participants with type 2 diabetes. Data from smaller studies have previously suggested that as many as 7% of adults diagnosed with type 2 diabetes are positive for glutamic acid decarboxylase (GAD65) antibodies, indicating that they actually have a form of autoimmune diabetes, such as latent autoimmune diabetes in adults, or LADA, Pratley said.
“For example, in a post-hoc analysis, 7.6% of participants with ‘type 2 diabetes’ enrolled in the AWARD 2, 4 and 5 trials for the GLP-1 receptor agonist dulaglutide [Trulicity, Eli Lilly], were positive for GAD65 antibodies,” Pratley told Healio.
The AWARD participants experienced a reduction in HbA1c of about 1% when assigned dulaglutide, Pratley said. He noted that the drug appeared safe for that subset.
“We understand that these patients are not the same as those who developed type 1 diabetes as a youth,” Pratley said. “However, they are also different from patients with “classic type 2 diabetes, more often requiring insulin therapy to achieve glycemic targets.”
The GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) was also associated with reductions in HbA1c and body weight for those with type 1 diabetes in small studies, suggesting that GLP-1 receptor agonists are effective and can be used safely by people with autoimmune diabetes, Pratley said.
Some moderate-term trials of SGLT2 inhibitors among people with type 1 diabetes showed reductions in HbA1c and body weight and no increase in symptomatic or severe hypoglycemia, although DKA was observed in some participants.
Four CV outcomes trials assessing risk for major adverse CV events with GLP-1 receptor agonists demonstrated a benefit, with HRs ranging from 0.74 to 0.88 for the LEADER, SUSTAIN-6, HARMONY and REWIND trials, Pratley said.
Studies with SGLT2 inhibitors have consistently shown as much as a 30% reduction in hospitalization for heart failure for people with type 2 diabetes. Two studies, CANVAS and EMPA-REG OUTCOME, showed a significant reduction in major adverse CV events; EMPA-REG OUTCOME showed a reduction in CV death, Pratley said.
Risks for DKA, adverse events
The idea of prescribing SGLT2 inhibitors or GLP-1 receptor agonists for people with type 1 diabetes has been suggested since the classes first showed CV benefits; Pratley and Nathan debated the issue in December during an online presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Nathan said agents labeled to reduce CVD for people with type 2 diabetes should not be extended to those with type 1 diabetes.
“The balance between the benefits and the risks of adding an SGLT2 inhibitor or a GLP-1 receptor agonist clearly weigh against using these drugs,” Nathan said. “HbA1cs are about the same. Modest weight loss, more so on the GLP-1 side, are balanced against the nausea, vomiting, diarrhea and other GI symptoms. There are minimal [observed] reductions in insulin doses, minimal increase in time-in-range, no difference in hypoglycemia and no CVD benefit has been demonstrated.”
On the risk side with such medications are genital mycotic infections, DKA and fatal DKA in the setting of SGLT2 inhibitors, drug costs and adverse GI effects, Nathan said.
“Results in clinical trials that minimize the risk for DKA at baseline and try to mitigate risk during the studies likely represent an idealized outcome,” Nathan said. “That is to say that the results in clinical practice will certainly be worse, with less benefit, and I suspect greater risk.”
Pratley said researchers must build an evidence base for preventing CVD in type 1 diabetes, with regard to factors such as diet and weight loss, statins and hypertensive drugs, glycemic control and the newer agents shown to have a CV benefit, including SGLT2 inhibitors and GLP-1 receptor agonists.