Severe hypoglycaemia and absolute risk of cause-specific mortality in individuals with type 2 diabetes: a UK primary care observational study

Abstract

Aims/hypothesis Several pathophysiological mechanisms would suggest a causal link between hypoglycaemia and cardiovascular death; conversely, current knowledge would not support a causal relationship with other causes of death. To clarify the nature and the magnitude of the association between hypoglycaemia and death, we investigated the 5 year mortality risks for cardiovascular disease, cancer and other causes in individuals with type 2 diabetes admitted to hospital for a severe hypoglycaemic episode. Methods We defined in the UK Clinical Practice Research Datalink database a prevalent cohort of adults with type 2 diabetes diagnosed between 1 January 1998 and 1 January 2011 (index date), with available linkage to the Office for National Statistics (ONS) and the Hospital Episode Statistics (HES). A hospital admission reporting hypoglycaemia as the underlying cause was identified before the index date in the HES; date and underlying cause of death were obtained from the ONS. We quantified the 5 year risk of cause-specific death in people with and without admission to hospital for severe hypoglycaemia, adjusting for potential confounders and accounting for competing risk. Results Of the 74,610 subjects included in the cohort, 388 (0.5%) were admitted at least once for a severe hypoglycaemic episode; subjects admitted were older, with higher HbA1c and a greater prevalence of multimorbidity. During a median follow-up of 7.1 years, 236 (60.8%) and 18,539 (25.0%) deaths occurred in subjects with and without a previous severe hypoglycaemia, respectively. Non-cardiovascular causes accounted for 71% of all deaths in both subjects with and without hypoglycaemia. In a 60-year-old person with severe hypoglycaemia, the 5 year absolute risk of death, adjusted for age, sex, ethnicity, systolic blood pressure, total cholesterol, HbA1c, BMI, eGFR, smoking status, alcohol consumption and deprivation (Townsend score), was 6.6%, 1.1% and 13.1% for cardiovascular, cancer and other causes, respectively, while the 5 year absolute risk difference compared with a subject without severe hypoglycaemia was 4.7% (95% CI 1.0, 8.3) for cardiovascular, −1.4% (−4.1, 1.4) for cancer and 11.1% (6.1, 16.1) for other causes of death. Results were consistent in models further adjusted for medications and comorbidities (myocardial infarction, stroke, peripheral artery disease, heart failure, atrial fibrillation, cancer), with sulfonylurea and insulin associated with increased mortality rates (from cause-specific hazard ratio of 1.06 [95% CI 0.99, 1.14] for cancer death with use of sulfonylurea to 1.42 [1.29, 1.56] for cardiovascular death with use of insulin). Results were robust to missing data. Conclusions/interpretation The results of this study indicate severe hypoglycaemia as a marker of, rather than causally linked to, an increased risk of long-term mortality. Regardless of the nature of the association, a severe hypoglycaemic episode represents a strong negative prognostic factor in patients with type 2 diabetes.

Severe hypoglycaemia in adults presenting to a hospital emergency department: Clinical characteristics, comorbidities, and mortality outcomes

“…The relationship between SH and cardiovascular mortality continues to generate controversy as to whether it is a direct cause, or is a marker of serious underlying illness that predisposes to this metabolic event. 38 Although this relationship may be bi-directional, 39 the present study supports SH as a marker of poor prognosis in those with high comorbidity burden, particularly in people with T2D and non-DM individuals. Most deaths were from non-cardiovascular causes, particularly sepsis, multi-organ failure, cancer and advanced frailty, and the comorbidity burden was significantly greater among those who died.…”

Sulfonylureas in the Current Practice of Type 2 Diabetes Management: Are They All the Same? Consensus from the Gulf Cooperation Council (GCC) Countries Advisory Board on Sulfonylureas

“…Historically, the use of SUs as a monotherapy or in combination has, in general, been perceived to increase the risk for major hypoglycemic events as compared to other diabetes medications [71][72][73]. The risk is higher for most insulin secretagogues than for other DM drugs, and is in fact a strong indicator of poor prognosis among T2D patients [74]. Accumulating evidence has, however, consistently demonstrated that, among SU drugs, gliclazide poses the lowest risk for episodes of major hypoglycemia [30,75,76], and that this risk is comparable to those posed by other commonly used secondline therapeutic drugs [32,34,55].…”

Relative protein intake and associations with markers of physical function in those with type 2 diabetes

“…Our sample is broadly representative of our larger cohort of people with type 2 diabetes and when compared with a population level cohort including those with type 2 diabetes ( n = 74,222) derived from the Clinical Practice Research Datalink (CPRD) in the United Kingdom, the average BMI (30.6 kg/m 2 (CODEC) vs. 30.1 kg/m 2 (CPRD)), HbA1c (6.9% (CODEC) vs. 6.9% (CPRD)) and age (65 (CODEC vs. 67.7 (CPRD)) were broadly similar 40 . However, our study does have limitations.…”