Meta-Analysis: Association Between Hypoglycemia and Serious Adverse Events in Older Patients Treated With Glucose-Lowering Agents

Abstract

AimsWe conducted a meta-analysis of serious adverse events (dementia, macro- and micro-vascular events, falls and fractures, and death) associated with hypoglycemia in older patients treated with glucose lowering drugs.Materials and MethodsMeta-analysis of studies reporting on hypoglycemia and adverse events. The search included studies from two previously published systematic reviews, and an updated search of MEDLINE and EMBASE from April 2014 to November 2019. We assessed study validity based on ascertainment of hypoglycemia, adverse events and adjustment for confounders, and conducted a random effects meta-analyses, assessing heterogeneity using the I2 statistic.ResultsWe included 44 studies involving 2,507,434 participants. Most of the studies used adjusted analysis for confounders and hypoglycaemic events were typically identified based on healthcare databases (severe events). Hypoglycemia was associated with increased likelihood of death in a meta-analysis of eighteen studies, pooled OR 2.02 (95% Confidence Interval 1.75–2.32). Studies assessing mortality signal a time-response relationship with a higher risk of adverse events occurring within the first 90 days after hypoglycemia. Our meta-analysis of nine studies demonstrated that hypoglycaemic episodes were associated with dementia – pooled OR 1.50 (95% CI 1.29–1.74). Our meta-analysis of nineteen studies demonstrated associations between hypoglycaemia and macrovascular complications, pooled OR 1.81 (95% CI 1.70–1.94), and microvascular complications (two studies) pooled OR 1.77 (95% CI 1.49–2.10). There is also an association between hypoglycemia and cardiovascular death (six studies) – pooled OR 2.11 (95% CI 1.55 to 2.87). Similarly, our meta-analysis of six studies demonstrated an association between hypoglycemia and falls and fractures, pooled OR 1.78 (95% CI 1.44–2.21) and 1.68 (95% CI 1.37–2.07) respectively.ConclusionThis meta-analysis confirms previously reported concerns of serious harm following hypoglycemia, especially in the immediate time period after a hypoglycaemic event. Avoidance of hypoglycaemic episodes should be a priority in this vulnerable population.

Association between hypoglycemia and dementia in patients with diabetes: a systematic review and meta-analysis of 1.4 million patients

“…However, one of the included studies was cross-sectional in design, reporting risk of mild cognitive impairment and not dementia [ 11 ]. Another review [ 9 ] published by the same authors in 2019 also demonstrated a statistically significant increased risk of dementia with prior hypoglycemic events (OR: 1.50 95% CI: 1.29, 1.74). Nonetheless, our study is a significant update from their review as we excluded two studies [ 27 , 28 ] from the past review (due to overlapping data) and included three new studies which significantly raised the statistical power of our analysis.…”

“…While hypoglycemia is easily treatable and a transient complication, it is not without other short and long-term adverse effects. Hypoglycemia has been shown to increase the risk of micro and macrovascular complications of DM along with the increased risk of falls and fractures [ 9 ]. Research also suggests a heightened risk of cardiovascular and all-cause mortality due to hypoglycemia in diabetics [ 10 ].…”

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

“…In addition, hypoglycemia is an independent risk factor for dementia [ 104 , 105 ]. Treatment with glucose lowering pharmacotherapy has an inherent risk for iatrogenic hypoglycemia, especially in older T2DM patients with a long diabetes duration treated with insulin or sulfonylurea [ 106 ].…”

Risk factors associated with mortality in individuals with type 2 diabetes following an episode of severe hypoglycaemia. Results from a randomised controlled trial

“… 3 However, intensification of glycaemic treatment increases hypoglycaemic exposure, which is believed to be associated with an increased risk of cardiovascular events. 4 – 6 As such, guidelines suggest individualising HbA1c targets while also focusing on hypoglycaemic avoidance and acknowledging that more research in this area is required. 7 …”