SC Connecticut News

Almost 500 million adults worldwide are living with type 2 diabetes, and over 200 million of them take metformin, an oral medication that reduces blood sugar levels. Despite metformin’s widespread use, many type 2 diabetes patients eventually require second-line medications to maintain control of their blood sugar levels when metformin’s efficacy fades.

These second-line medications can impact more than just blood sugar. Growing evidence suggests that these treatments could benefit type 2 diabetes patients who also have cardiovascular disease by reducing their risk for heart attack and stroke.

Despite these known positive effects, the main second-line diabetes medications—older drugs such as sulfonylureas (SUs) and dipeptidyl peptidase-4s (DPP-4s), and newer drugs including glucagon-like peptide-1 (GLP-1RAs) analogs and sodium-glucose cotransporter 2 (SGLT-2is) inhibitors—have never been compared against each other for their cardiovascular benefits.

“The challenge now, for clinicians, is to decide which therapy to use in a patient, especially those with an elevated risk of cardiovascular adverse events,” says Rohan Khera, MD, MS, assistant professor of medicine (cardiovascular medicine) and director of the Cardiovascular Data Science (CarDS) Lab at Yale School of Medicine (YSM), and assistant professor of biostatistics (health informatics) at the Yale School of Public Health. “Some of the older drugs were never even tested for whether they were safe and effective or actually improve cardiovascular risk, and the newer drugs were never compared head-to-head.”

Khera, his co-principal investigator Marc Suchard, MD, PhD, at UCLA, and CarDS Lab members Arya Aminorroaya, MD, MPH; Lovedeep Dhingra, MBBS; Phyllis Thangaraj, MD, PhD; and Aline Pedroso Camargos, PhD; along with a large international team of scientists published the first study directly comparing these second-line diabetes drugs and their cardiovascular benefits in the Journal of the American College of Cardiology on August 26. The study draws from ten international datasets and spans nearly two decades of data from almost 1.5 million patients with type 2 diabetes and cardiovascular disease. The study is notable not only for its clinically relevant findings but also for the rigorous scientific methods used.

Using datasets from the United States, Germany, Spain, and the United Kingdom, Khera's team compared how well each of four different second-line diabetes medication classes reduced adverse cardiovascular events among type 2 diabetes patients with cardiovascular disease. They found that newer SGLT-2i and GLP-1RA drugs were most effective at reducing cardiovascular risk while older sulfonylurea drugs were least effective: SGLT-2is and GLP-1RAs had a 24% and 28% lower risk for cardiovascular events than sulfonylureas respectively.

“The older generation drugs do seem to be inferior on cardiovascular risk reduction,” Khera says. “I think that’s an important key takeaway while we make these decisions in practice especially among those who have high risk whether continued use of some old drugs is appropriate.”

Sulfonylureas such as glipizide and glimepiride are among the most commonly used second-line diabetes medications. Khera believes this finding should be taken into clinical consideration since newer drugs contain blood glucose levels as effectively as old ones but have lower risks for adverse side effects such as hypoglycemia and weight gain.

The scientific methodology was equally important according to Khera. His team performed a “comparative effectiveness study” which compares evidence on benefits versus harms across different treatment methods using observational research rather than controlled conditions typical in clinical trials thereby addressing more confounding variables like treatment timing choices availability etc., influencing results through advanced methods ensuring robustness reliability enough guiding decisions better trusting principles domains work making determinations recommended changes practices trust-building mechanisms incorporation guidelines suggestions vital importance future efforts transparency codes programming publicly available adaptations encouraging further rigorous comparative studies reliable robust data driving best available guiding clinical practices.

“We need more studies like these done rigorously incorporating mechanisms ensuring FDA guidelines recommendations changing practices trusting domain principles building trust robust reliable guiding decisions,” he adds.