Why Cardiologists Should Become Diabetologists, With Paul D. Thompson, MD

Paul D. Thompson, MD

I studied the August 5, 2021, New England Journal of Medicine report of a trial comparing semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), versus tirzepatide, a drug that has both GLP-1a and glucose-dependent insulinotropic polypeptide activity.¹ GLP-1 RA’s stimulate insulin secretion during hyperglycemia and decrease glucagon secretion during euglycemia and hypoglycemia.GLP-1 RA’s also decrease gastric emptying thereby decreasing appetite and body weight. Tirzepatide has GLP-1 RA activity, but also stimulates insulin release and decreases glucagon levels during euglycemia and hypoglycemia via its glucose-dependent insulinotropic activity. This dual-action has theoretical advantages. The study compared semaglutide 1 mg SQ weekly, versus tirzepatide 5, 10, or 15 mg SQ weekly. Tirzepatide has not yet been FDA approved.

All 3 tirzepatide doses decreased mean hemoglobin A1c (A1c) by 2.01 to 2.3% versus 1.86% for semaglutide. Bodyweight decreased 1.9 to 5.5 kg more with tirzepatide than with semaglutide over the 40-week study. But this was not a fair comparison because STEP 2 or the Semaglutide Treatment Effect in People with Obesity study used a semaglutide dose of 2.4 mg weekly,² and higher semaglutide doses probably would have reduced hemoglobin A1c and body weight more.

But here’s the real question. Why is a cardiologist (me) studying an article on new diabetes treatments? I remember similar thoughts about why cardiologists were interested in lipid metabolism when lovastatin was FDA approved in November 1987. And look where cardiologists are now in managing lipids using statins, PCSK9 inhibitors, ezetimibe, and bempedoic acid. Cardiologists, like all clinicians, get interested in problems they can fix easily. Metformin, sodium-glucose transport type 2 inhibitors (SGLT2i), and GLP-1 RAs (as the oral semaglutide, Rybelsus) are now all available orally. Even when using GLP1a’s as injection is not difficult. They are easy to use because they rarely cause hypoglycemia unless administered with insulin or a sulfonylurea. This means they are “smart drugs” in that their glucose-lowering effect dissipates as the glucose levels fall. All reduce A1c and reduce body weight, and the latter effect can make you a hero to your patients!

I’ll bet that our experience with LDL management, that “even lower is even better”, will also ultimately be applied to A1c management. The Fourier Trial demonstrated a 2% absolute risk reduction in cardiovascular events after only 3 years when high-risk coronary patients reduced their median LDL-C from 92 to 30 mg/dl using the PCSK-9 inhibitor, evolucamab.³ I realize that available diabetes trials show no difference in outcomes with A1c’s above or below 7%, but these trials used insulin to achieve the A1c levels, and insulin causes hypoglycemia and has many atherogenic properties. Furthermore, someone with “borderline diabetes” has already lost 50% of his/her insulin-secreting capacity. The Diabetes Prevention Program demonstrated that treating patients with prediabetes, defined as an oral glucose tolerance 2-hour value above 140 mg/dl, but less than 200 mg/dl, decreased the onset of diabetes by 31%.⁴ Hyperglycemia not only glycosylates hemoglobin, but also glycosylates proteins in the LDL particle making LDL more inflammatory and atherogenic. In the Early ACS Trial, among 879 patients with non-ST segment elevation MIs (NSTEMI), 32.5% had known diabetes, 12.2% had undiagnosed diabetes but fasting glucose values at or above 126 mg/dL or an A1c greater than 6.5%, and 8% had prediabetes diagnosed by a glucose of 110 to 126 mg/dL. 5Only 44.4% had normal glucose metabolism. Prediabetes is dangerous. It leads to diabetes and causes cardiac events along the way.

Maybe it’s time for cardiologists to know more, do more, and be more aggressive about treating diabetes, borderline or otherwise.

References:

1. Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med 2021;385:503-15.
2. Davies M, Faerch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971-84.
3. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713-22.
4. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
5. Giraldez RR, Clare RM, Lopes RD, et al. Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome. Am Heart J 2013;165:918,925.e2.