March 15, 2021
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Type 2 diabetes agents with proven cardiovascular benefits may be useful for patients with type 1 diabetes to prevent atherosclerotic CVD. However, more robust data are needed for the type 1 population.
Richard E. Pratley
CVD is more common in people with type 1 diabetes than in people without diabetes, and the risk of a CV event is high. Richard E. Pratley, MD, The Samuel E. Crockett Chair of Diabetes Research and Medical Director of the AdventHealth Diabetes Institute told Healio. CVD occurs on average 10 to 15 years earlier in people with type 1 diabetes, and type 1 diabetes status essentially eliminates the cardioprotection seen in pre-menopausal women, Pratley said.
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“CVD is the leading killer of people with type 1 diabetes and our approach [to reducing CV risk] is really extrapolated from studies in type 2 diabetes and nondiabetic patients, ”said Pratley. “That seemed to work well for lipids, but what about these other drugs?”
David M. Nathan
Adding SGLT2 inhibitors or GLP-1 receptor agonists – currently only approved by the FDA for type 2 diabetes – to intensive insulin therapy offers minimal benefits with no proven benefit for CVD and harbors noisy David M. Nathan, MD, Director of the Massachusetts General Hospital Diabetes Center and Professor of Medicine at Harvard Medical School.
“Until there is credible data to show a benefit for these classes of drugs in type 1 diabetes, there are only increased side effects, risks, and costs to recommend them,” Nathan told Healio. “The SGLT-2 inhibitors in particular pose an increased risk for [diabetic ketoacidosis] when used in type 1 diabetes. “
The translation of SGLT2 and GLP-1 benefits
To avoid undue risk of atherosclerotic CVD in type 1 diabetes, clinicians should manage key CV risk factors through targeted smoking cessation, an HbA1c level of 7% or less, and a blood pressure of 130/80 mm Hg or less. Consider high-intensity statin therapy to lower LDL cholesterol; Reduction in hypoglycemia; and recommend weight loss.
However, data from T1D Exchange shows that only about 28% of adults aged 50 or over – those at higher risk for CVD – have HbA1c less than 7%, Pratley said.
Since 2008, when the FDA mandated studies of CV outcomes for diabetes therapies, a “home industry” of studies, particularly for SGLT2 inhibitors and GLP-1 receptor agonists, has had sometimes surprising CV benefits for patients with type 2 diabetes shown with and without pre-existing CVD. To date, 28 such studies have been completed for eight drug classes with more than 200,000 planned participants with type 2 diabetes. Data from smaller studies previously showed that up to 7% of adults diagnosed with type 2 diabetes are positive for glutamic acid decarboxylase (GAD65) antibodies, suggesting that they actually have some form of autoimmune diabetes such as latent autoimmune diabetes in adults. or LADA, said Pratley.
“In a post-hoc analysis, for example, 7.6% of the participants with type 2 diabetes took part in the AWARD 2, 4 and 5 studies for the GLP-1 receptor agonist dulaglutide [Trulicity, Eli Lilly]were positive for GAD65 antibodies, ”Pratley told Healio.
AWARD attendees experienced about a 1% reduction in HbA1c when they received dulaglutide, Pratley said. He noted that the drug seemed safe for this subgroup.
“We understand that these patients are not the same as those who developed type 1 diabetes as adolescents,” said Pratley. “However, they are also different from patients with” classic type 2 diabetes, who more often need insulin therapy to achieve glycemic goals. “
The GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) has also been associated with reductions in HbA1c and body weight in patients with type 1 diabetes in small studies, suggesting that GLP-1 receptor agonists are effective and in humans Autoimmune diabetes can be safely used with, Pratley said.
Some medium-term studies with SGLT2 inhibitors in people with type 1 diabetes showed reductions in HbA1c and body weight, and no increases in symptomatic or severe hypoglycemia, although DKA was seen in some participants.
Four CV outcome studies assessing the risk of serious adverse CV events with GLP-1 receptor agonists showed a benefit, with HRs for the LEADER, SUSTAIN-6, HARMONY and REWIND studies in between 0.74 and 0.88, Pratley said.
Studies with SGLT2 inhibitors have consistently shown that hospital admissions for heart failure have decreased by up to 30% in 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 was suggested because the classes were the first to show CV benefits. Pratley and Nathan discussed the topic in December during an online presentation at the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.
Nathan said funds marked for reducing CVD in people with type 2 diabetes should not be extended to people with type 1 diabetes.
“The balance between the benefits and risks of adding an SGLT2 inhibitor or a GLP-1 receptor agonist clearly has a negative impact on the use of these drugs,” said Nathan. “HbA1cs are roughly the same. Modest weight loss, even more on the GLP-1 side, will counteract nausea, vomiting, diarrhea, and other GI symptoms. There are minimal [observed] A decrease in insulin doses, a minimal increase in time, no difference in hypoglycemia, and no CVD benefit have been demonstrated. “
On the risk side with such drugs, genital mycotic infections, DKA and fatal DKA are associated with setting SGLT2 inhibitors, drug costs and adverse GI effects, Nathan said.
“Results in clinical trials that minimize the risk of getting DKA at the start of the study and try to reduce the risk during the studies are likely an idealized outcome,” said Nathan. “What that means is that in clinical practice, the results will certainly be worse, with less benefit, and I suspect greater risk.”
Pratley said researchers are building an evidence base for the prevention of CVD in type 1 diabetes in terms of factors such as diet and weight loss, statins and high blood pressure drugs, blood sugar control, and the newer drugs shown to have CV benefits including SGLT2 inhibitors and GLP, must build -1 receptor agonists.
For more informations:
David M. Nathan, MD, can be reached at dnathan@mgh.harvard.edu. Richard E. Pratley, MD, can be reached at richard.pratley.md@AdventHealth.com.
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