Log in to MyACC
Hypoglycemia and CV Outcomes in Linagliptin Trials
Quick Takes
- Bidirectional associations were observed between hypoglycemia and CV events among participants enrolled in the CARMELINA study who had longer duration of type 2 diabetes and higher risk compared to those enrolled in the CAROLINA study.
- No such associations were noted between hypoglycemia and CV events among participants enrolled in the CAROLINA study.
- No associations were observed between hypoglycemia and CV events within 60 days of the hypoglycemic event, suggesting a lack of relationship.
Study Questions:
Is the association between hypoglycemia and cardiovascular (CV) events in type 2 diabetes (T2D) causal or reflective of individuals susceptible to both outcomes?
Methods:
The investigators conducted a secondary analysis of two trials: CARMELINA (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018), which were randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor, enrolling adults with T2D at high CV risk with or without high kidney risk. Participants enrolled in the CARMELINA trial had longer duration of T2D and a higher CV risk than those enrolled in the CAROLINA trial. The primary outcome (for both trials) was major adverse CV events (MACE), which included CV death, myocardial infarction, or stroke. An additional outcome of hospitalization for heart failure (HF) was added for this analysis. Hypoglycemia was defined as plasma glucose <54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode.
Results:
In the CARMELINA trial (6,979 patients; 4,390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and MACE (including HF hospitalization) with a hazard ratio [HR] of 1.23 (95% confidence interval [Cl], 1.04-1.46). A significant association was also observed between nonfatal CV events and hypoglycemia (HR, 1.39; 95% Cl, 1.06-1.83). In the CAROLINA trial (6,033 patients; 3,619 males [60.0%]; mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and MACE (including HF hospitalization) with an HR of 1.00 (95% Cl, 0.76-1.32). No significant association was noted between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% Cl, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze.
Conclusions:
The authors concluded that these analyses found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both.
Perspective:
These data suggest that patients with longer duration of T2D and higher CV risk may be at higher risk for either hypoglycemia or CV events. However, further research is warranted to confirm this observation. Furthermore, the data do not provide strong evidence of an association between the two.
Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention
Keywords: Diabetes Mellitus, Type 2, Hypoglycemia
< Back to Listings
