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Severe Hypoglycemia Increases Premature Death and Cancer Risk in T2DM

A look at whether type 2 diabetes patients with severe hypoglycemia exhibit certain phenotypes that may predict premature death and all-site cancer….

Hypoglycemia is common in many diabetics, especially with intensive blood glucose lowering strategies. Previous studies have shown hypoglycemia to increase the risk of CVD and mortality in diabetic patients as a result of arrhythmia, abnormal hemostasis, neurohormonal dysregulation, and other conditions. The nature of the relationship between hypoglycemia and increased risk of death remains somewhat unclear, though the 1.3-2.3 fold increased risk of all-site cancer and related death in type 2 diabetes has researchers looking for answers. Kong, APS et al. therefore designed a study to examine the associations of clinical profiles of type 2 diabetics who developed severe hypoglycemia with their clinical outcomes, including death and all-site cancer. This group of researchers was also the first to report associations of HbA1c, lipids, and BMI with all-site cancer in type 2 diabetics in previous research.

This study, occurring from 1995-2009, was a consecutive cohort consisting of 8,767 type 2 diabetic patients with and without hypoglycemia in the year before enrollment. Data was obtained from the Hong Kong Diabetes Registry, which records the outcomes, including hospital admissions, of all those enrolled until the time of their death. Researchers used ICD-9 codes indicating hospitalization from hypoglycemia to determine occurrence of severe hypoglycemia. The average age of participants was 57.4 years, and median diabetes duration was 5 years. Patients underwent a 4-hour assessment for diabetes-related complications and risk factors at enrollment and regularly thereafter. The assessment consisted of an interview by diabetes nurses and various physical measurements and examinations. Blood was also sampled after an 8-h overnight fast to measure fasting lipids, glucose, HbA1c, and perform liver and renal function tests. Spot urinary albumin-to-creatinine ratio was used to define albuminuria.

Results showed patients with severe hypoglycemia to be older and more likely to be previous smokers and drinkers, have longer disease duration, and lower BMI than those without severe hypoglycemia. They also had higher HbA1c and BP, but lower TG and LDL-C levels. Those with severe hypoglycemia also had worse renal function and were more likely to have a history of CVD and insulin use at time of enrollment. After adjustment for confounding variables, old age, low BMI, high HbA1c, high BP, low LDL-C and triglycerides, albuminuria and CKD were found to be independent risk factors for severe hypoglycemia. Though patients with and without severe hypoglycemia at enrollment had similar cancer rates, patients with severe hypoglycemia had a higher incidence of all-site cancer and mortality at follow-up.

A major limitation of this study was the definition of a severe hypoglycemic event as an ICD-9 code for hospitalization due to hypoglycemia. Events not requiring or resulting in hospital admission were not accounted for, and therefore the occurrence of hypoglycemia could have been underestimated. The results of this study allowed researchers to identify risk factors predictive of severe hypoglycemia in type 2 diabetics, and showed that those experiencing severe hypoglycemia were more likely to die prematurely and/or develop all-site cancer. The findings also have some implications for clinical management of these patients. Patients with severe hypoglycemia were less likely to meet HbA1c and BP goals and were more likely to have renal dysfunction despite the increased likelihood that they were pharmacologically treating these conditions. This suggests that other issues such as treatment noncompliance, psychological distress, or depression could be contributing to poor health outcomes, necessitating comprehensive assessment for individualized care. Future research to improve understanding of the complex interrelationships that exist between renal impairment, dyslipidemia, severe hypoglycemia and cancer would be beneficial in furthering our knowledge of the nature of the comorbidities that exist with type 2 diabetes.

Practice Pearls:
  • The following were identified as risk factors for severe hypoglycemia: old age, low BMI, high HbA1c, low triglycerides, low LDL-C, albuminuria, and CKD.
  • Patients with severe hypoglycemia were more likely to die and develop all-site cancer than those without severe hypoglycemia.
  • The following are recommended to practitioners: individualizing treatment goals, co-management of primary and specialist care, and periodic phenotyping.

Kong, APS et al. "Severe Hypoglycemia Identifies Vulnerable Patients With Type 2 Diabetes at risk for Premature Death and All-Site Cancer: The Hong Kong Diabetes Registry" Diabetes Care. 2014; 37: 1024-1031.