Genetic Variants May Personalize Diabetes Care

Two genetic variants predict the cardiovascular effects of intensive glycemic control, according to a study published online Aug. 15 in Diabetes Care. If validated with further studies, these genetic variants may function as a screening tool to help determine in which diabetic patients intensive glycemic control may be effective and in which patients the strategy may be harmful.

People with type 2 diabetes have substantially higher risk of cardiovascular disease than people without diabetes. Intensive glycemic control—an HbA1c less than 6.0 percent, rather than between 7.0 and 7.9 percent —was hoped to bring cardiovascular benefit. However, in the ACCORD trial's intensive treatment arm, benefits of intensive glycemic control were "surprisingly inconsistent." Intensive glycemic control reduced the risk of heart attack and major cardiovascular events, but actually increased cardiovascular mortality. This study, also by the ACCORD researchers, sought to determine if there was a way to genetically screen patients to identify those likely to be safely treated with intensive glycemic control.

The multi-institutional group of researchers analyzed more than 8 million common variants for genome-wide association with cardiovascular mortality among 2,667 white participants in the ACCORD intensive treatment arm. Significant loci were additionally examined in the entire ACCORD white genetic dataset (n = 5,360) and in a Joslin Clinic cohort (Boston; n= 422).

The researchers identified two loci—at 10q26 and 5q13—that achieved genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm. Participants with a genetic risk score (GRS) of zero (a low score) showed a four-fold reduction in cardiovascular mortality in response to intensive treatment, while those with GRS of one (an intermediate score) experienced no difference and those with a GRS of two (high score) experienced a three-fold increase in cardiovascular mortality without the reduction in nonfatal events.

The effect of these genetic markers was independent of other previously identified predictors of higher mortality. The modulating effect of these variants on cardiovascular mortality response to treatment held for the entire ACCORD white genetic dataset and in the real-world Joslin cohort ( P =0.029).

"After the report of increased mortality in response to intensive glycemic control in ACCORD, this intervention was dismissed as a viable strategy to decrease cardiovascular risk in high-risk patients with type 2 diabetes," writes lead author Hetal Shah, on behalf of the ACCORD trial researchers. "The results of our study suggest that it may be possible to revive this therapeutic approach by developing a precision medicine strategy, through which intensive treatment is prescribed for those patients who will benefit from it and who are at lower risk of being harmed. The fact that testing for two genetic markers is inexpensive and can be conducted at any point in time makes this possibility especially attractive, although the cost-effectiveness of this approach will have to be evaluated."

The applicability of these findings to non-white patients not at high risk for cardiovascular disease still needs to be evaluated.

Takeaway: While still requiring further validation, identification of two variants could mark an important discovery towards personalizing diabetes care.