Koska J, Nuyujukian DS, Bahn GD, et al. - In advanced type 2 diabetes, an association of low C-peptide levels with elevated cardiovascular (CVD) risk exists. The link is independent of increases in glucose variation or severe hypoglycemia.

• A total of 1,565 Veterans Affairs Diabetes Trial participants were analyzed for fasting C-peptide levels at baseline, composite CVD outcome, severe hypoglycemia, and visit-to-visit fasting glucose coefficient of variation (CV) and average real variability.

• The association between C-peptide and CVD risk was U-shaped, with elevated risk with decreasing levels in the low range (< 0.50 nmol/l, HR 1.30) and with increasing levels in the high range (> 1.23 nmol/l, 1.27).

• Inverse association of C-peptide levels with the risk of severe hypoglycemia (OR 0.68) and visit-to-visit glucose variation was identified.

• The link between low C-peptide levels and CVD risk was independent of cardiometabolic risk factors and continued to be related to CVD when evaluated in the same model with severe hypoglycemia and glucose CV.

• C-peptide levels not only could predict future glucose control patterns and CVD risk but also detect phenotypes impacting clinical decision making in advanced type 2 diabetes.