By Annette M. Boyle
The search has been on for decades: A medication that can help reduce the risk of cardiovascular disease in Type 2 diabetes patients. Late last year, an existing drug was approved by the FDA for that additional a usage, potentially benefiting the more than million veterans with high blood sugar.
PHOENIX—Finding a way to substantially reduce the risk of cardiovascular disease (CVD) in Type 2 diabetes mellitus (T2DM) has been a nearly mythic quest for endocrinologists.
Patients with diabetes have a substantially increased risk of myocardial infarction, stroke and CVD-related mortality that controlling serum glucose alone does not appear to eliminate. Recent studies, however, indicate that an existing antidiabetic agent, empagliflozin, may help diabetics reduce both glycated hemoglobin levels and cardiovascular disease risk.
That could be good news for the 1 in 4 veterans with a diagnosis of diabetes.
Last winter, the U.S. Food and Drug Administration added an indication for the sodium-glucose co-transporter 2 (SGLT2) inhibitor. “Empagliflozin is now approved for use to treat blood glucose in type 2 diabetes as well as to reduce CVD in patients with T2DM. The agent, therefore, can be effective in two very important areas of concern for our patients with T2DM,” said Peter Reaven, MD, director of the Diabetes Research Program at the Phoenix VA Health Care System.
By blocking the SGLT2 protein that drives glucose reabsorption in the kidneys, SGLT2 inhibitors increase glucose excretion in urine and lower glucose levels in the blood. They also have a slight diuretic effect, which appears to reduce blood pressure, without increasing heart rate.
“Although there are now a wide variety of effective glucose lowering agents for diabetes, the SGLT2 inhibitor class of medications offers some unique advantages that complement other diabetes medications, making it a valuable add-on medication,” Reaven told U.S. Medicine.
The Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial found that empagliflozin reduced the risk of death from cardiovascular disease 38% and all-cause death by 32%. The risk of hospitalization for heart failure dropped 35%, while the risk of transient ischemic attack declined 15% and the rate of stroke rose 18%.1
The trial produced significantly better results in terms of reduction of CVD risk than several other large randomized clinical trials over the last decade. Those studies, which included the VA Diabetes Trial (VADT), the United Kingdom Prospective Diabetes Study (UKPDS), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, had mixed results in terms of identifying a clear relationship between tight glucose control and CVD. UKPDS found some evidence of benefit, while ADVANCE did not. ACCORD showed improvement in non-fatal cardiovascular events, but also an increase in mortality.
Reaven was an author of the initial VADT study and its follow-up study. The initial trial enrolled 1,791 veterans with diabetes who also had cardiovascular disease or were at high risk for CVD. Half received intensive intervention to reduce A1c to below 7, while the others received standard care and had a mean A1c of 8.4. The groups had equivalent blood pressure and blood lipid control and received the same antidiabetic medications, just at different intensities. Patients continued in the study for a median of 5.6 years.2
“The outcomes in terms of cardiovascular disease were somewhat surprising, in that there was a modest by not statistically significant 12% reduction in cardiovascular events in the intensive control group,” Reaven explained in the VA Research Quarterly Update. Microvascular outcomes also improved only slightly. Veterans who had shorter duration of diabetes and less advanced disease seemed to benefit more from tighter glycemic control.
The VADT follow-up study included an additional nine years of information on the study participants. While the researchers found that aggressive management of serum glucose with a multidrug regimen reduced the rate of cardiovascular events 17% compared to standard therapy, it had no impact on overall mortality. The researchers cautioned that “in the absence of a reduction in total mortality, a small-to-moderate reduction in the rate of cardiovascular events needs to weighted against potential harm due to overly aggressive care and the burden, long-term safety profile, and side effects of treatment, including weight gain and hypoglycemia.”3
Given the relatively small benefit of intensive glycemic control for reducing cardiovascular disease risk seen in VADT and other studies, the approval of empagliflozin could change the standard of care for diabetic patients at high risk of CVD, according to Reaven.
“As CVD death is the leading cause of death in our T2DM population, having the ability to add on a medication that also significantly reduces the risk of this very important outcome is a major step forward in diabetes care,” he added.
SGLT2 inhibitors might not be appropriate for all patients, Reaven cautioned. Adverse effects of SGLT2 inhibitors can include dehydration, hypotension, serious urinary tract infections, urogenital infections, ketoacidosis, acute kidney injury and hypoglycemia, when used with insulin or sulfonylureas.
Still, “patients with T2DM with moderate to good renal function, and with a CVD history, or at high risk for CVD, who have inadequate glucose control on metformin and/or other combinations of oral agents are very reasonable candidates” for SGLTs inhibitors, he pointed out, adding, “Patients without CVD risk may also benefit from the glucose lowering effect of this class of medication, although it typically lowers A1c .5-1%, so those who have glucose levels substantially above goal targets may need additional medications to achieve their goals.”
- Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1094. doi:10.1056/NEJMc1600827.
- Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with Type 2 diabetes. N Engl J Med. 2009;360:129-139.
- Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266. Erratum in: N Engl J Med. 2015 Jul 9;373(2):198.
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