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Association of Severe Hypoglycemia and Cardiovascular Outcomes in Type 2 Diabetes

Jan 12, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy

Trial assesses if link exists between severe hypoglycemia and adverse cardiovascular outcomes in veterans.

Due to the increased prevalence of type 2 diabetes, a large amount of research efforts has been devoted to determining appropriate glycemic goals and various ways of achieving them. Intensification of glycemic management has been a topic of interest in several studies; however, many trials are ended early due to increased incidence of death in the intervention group. The cause of these deaths is thought to be severely low blood sugars or hypoglycemia. The association between hypoglycemia and cardiovascular risk has been the topic of several studies, but the results have been inconsistent. Additionally, the observed risk factors and consequences of severe hypoglycemia appear to vary from study to study. Consequently, this study aims to determine if an association exists between severe hypoglycemia and serious cardiovascular events and all-cause mortality.

This study utilizes the data from the Veterans Affairs Diabetes Trial (VADT) and re-analyzes it in order to achieve its aim. The VADT encompassed 20 Veterans Administration hospitals and enrolled a total of 1,791 participants, 97% of which were male. It was a randomized-controlled trial whose aim was to determine the micro- and macrovascular effects of intensive glycemic management in veterans with type 2 diabetes. Once deemed eligible, to participate in the VADT, patients were randomized into either the intervention or control group. Patients were initiated on maximal doses of metformin and rosiglitazone or glimepiride and rosiglitazone (combination based on baseline BMI) in the intervention arm or half maximum dose of the same combination of medications in the control group.

During the course of the VADT study, severe cardiovascular events and death (both cardiovascular-related and otherwise) were recorded and patients were assessed at 3-month intervals where incidence of severe hypoglycemia, HbA1c, and other lab values were assessed. The data collected over the median 5.6 years of follow-up provided an excellent foundation for a re-analysis of this type. From the data collected during the VADT study, the incidence of severe hypoglycemia was compared against the occurrence of major cardiovascular events, cardiovascular death, and all-cause mortality. Incidence of severe hypoglycemia was also compared against age, presence of proteinuria, neuropathy, insulin use, BMI, race, HbA1c, and study arm, in an effort to determine associated risk factors for severe hypoglycemia. Statistical significance was determined with the use of cox proportional hazards regression model (for association with cardiovascular events and mortality) and mixed logistic regression (for hypoglycemic risk factors).

Of the 1,791 participants included in the VADT study, 35 were excluded due to missing data and were thus excluded from the re-analysis. When the data was analyzed, it was found that severe hypoglycemic events within the previous 3 months were correlated with an increased risk of serious cardiovascular events (P = 0.032), as well as cardiovascular and all-cause mortality (P = 0.012 and 0.024 respectively). It was noted, however, that the risk of all-cause mortality was increased in the control group compared to the intervention group after a severe hypoglycemic event (P = 0.01). It was also found that proteinuria, neuropathy, and insulin use were determined to be risk factors for severe hypoglycemic events (P = 0.009, 0.01, and 0.02 respectively).

The findings of this study suggest that incidence of severe hypoglycemia can significantly increase risk of cardiovascular and all-cause mortality in the 3 months following the event. These results further highlight the known dangers of hypoglycemia. Consequently, intensive glycemic management should be undertaken cautiously, on a case-by-case basis, in order to decrease the likelihood of severe hypoglycemia and resultant risk of cardiovascular and all-cause mortality.

Practice Pearls:

  • Intensive glycemic management has been proposed by several recent studies as a viable method of preventing micro- and macrovascular complications of diabetes; however, it is associated with increased incidence of severe hypoglycemia when compared to maintenance of a more standard glycemic goal.
  • The results of this study suggest that episodes of severe hypoglycemia can increase the risk of cardiovascular and all-cause mortality up to 30 days after the event.
  • Intensive glycemic management should be undertaken carefully and on a case-by-case basis in order to decrease the likelihood of severe hypoglycemia and resultant risk of cardiovascular and all-cause mortality.

Reference:

Davis, Stephen N., et al. “Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial.” Diabetes Care, 2018, p. dc181144., doi:10.2337/dc18-1144.

Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy