GLP-1 and Genes Linked to CV Risk with Intensive DM Therapy

A new study has shown light on why some people treated with intensive glycemic control may be at increased risk for cardiac events, while others seem to benefit.

Results were published online on November 28, 2017 in Diabetes Care, and “highlight the importance of GLP-1 as a cardioprotective factor,” according to first author Hetal Shah, MBBS, of Harvard Medical School, and colleagues.¹
Intensive glycemic control has been proposed as one strategy to decrease the risk of CVD in T2D, but the approach is controversial. Results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that patients with T2D who were at high CV risk and received intensive glycemic control had significantly lower rates of myocardial infarction than those treated with standard therapy. However, the trial was stopped early due to a seemingly paradoxical increase in CV mortality with intensive therapy.²

Researchers later conducted a genome-wide association study (GWAS) in a subset of ACCORD participants. That study identified two genetic variants (rs57922 and rs9299870) significantly associated with increased CV mortality in patients treated with intensive glycemic control.³ 

Further work resulted in the development of a genetic risk score (GRS) derived from these two genetic variants. In patients with a GRS of 0, intensive therapy was protective from cardiac events.  In patients with a GRS ≥2, intensive therapy was associated with increased cardiac mortality.³

To begin to understand underlying mechanisms, researchers evaluated a subset of 351 participants who were part of the ACCORD study or a related study called ACCORD-MIND. Included participants had both GWAS data and data on 65 biomarkers related to metabolism, CVD, endocrine and immune function, and sepsis/apoptosis at baseline and 12 months after randomization to intensive glycemic control or standard therapy.

Statistical modeling was used to investigate the link between GRS at baseline and 12-month change in biomarker levels. 

• Results in the intensive therapy arm showed that each unit increase in GRS was linked to 22% decrease in change in active GLP-1 levels from baseline to 12 months (P = 3 x 10-4), with the effect driven by rs57922 (P = 5 x 10-4). The standard therapy arm showed no such association.   
• Furthermore, C/C homozygotes previously found to derive CV benefits from intensive treatment had a 22% increase in active GLP-1 levels between baseline and 12 months. Active GLP-1 levels were unmodified in C/T heterozygotes. And, T/T homozygotes found to have increased CV mortality with intensive treatment, had a 28% decrease in GLP-1 levels.
• Adjusting for baseline CVD, diabetes duration, HbA1c, fasting plasma glucose, heart rate, smoking, age, and sex did change the results.
• Carriers of rs9299870 showed a tendency toward higher active GLP-1 at baseline, but there was no significant change at 12 months.

Next: Possible explanations

While the mechanisms of how rs57922 may affect active GLP-1 levels remains unclear, one possibility is that it may be associated with lower expression of genes involved in GLP-1 synthesis, secretion and/or processing during intensive glycemic control. Having a genetic variant that decreases GLP-1 levels may decrease the cardioprotective effects GLP-1 appears to have on glucose metabolism, as well as on acute and chronic stress. It may also affect GLP-1’s anti-inflammatory effects on cells involved in atherogenesis.

However, the authors pointed out that the changes in GLP-1 seen in this study were much smaller than those associated with therapeutic doses.  Whether or not such small changes can influence CV risk is open to question.
Other limitations include a relatively small sample size, precluding the evaluation of CV outcomes. Also, the study included only Caucasian participants with an average age of 62-63 years, and the results may not apply to other populations.

Nevertheless, the authors concluded: “[O]ur results suggest a possible role of diminished GLP-1 activity as a factor for increased cardiac mortality during intensive glycemic therapy in rs57922 T/T homozygotes, possibly via impaired cardio- and/or stress-protective mechanisms or enhanced inflammatory pathways. Further studies seeking replication of this observation in other data sets and exploring the underlying mechanisms are warranted.”

Take Home Points

• Analysis of a subset of participants from ACCORD and ACCORD-MIND found that GLP-1 activity may explain why some patients but not others have increased cardiac mortality with intensive glycemic control
• Over 12 months, people with two copies of the T variant (T/T) previously been found to have increased cardiac mortality with intensive treatment had a decrease in active GLP-1 levels
• Over 12 months, people with two copies of the C variant (C/C) previously been found to derive CV benefits from intensive treatment, had an increase in active GLP-1 levels
• Further research is needed to confirm these findings in more varied populations

References:

1. Shah HS, Morieri ML, Marcovina SM, et al. Modulation of GLP-1 levels by a genetic variant that regulates the cardiovascular effects of intensive glycemic control in ACCORD. Diabetes Care. 2017 Nov 28. pii: dc171638.

2. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–2559

3. Shah HS, Gao H, Morieri ML, et al. Genetic predictors of cardiovascular mortality during intensive glycemic control in type 2 diabetes: findings from the ACCORD clinical trial. Diabetes Care. 2016;39:1915–1924.