Hypoglycemia: a review of definitions used in clinical trials evaluating antihyperglycemic drugs for diabetes

Abstract

ObjectiveTo understand the severity and potential impact of heterogeneity in definitions of hypoglycemia used in diabetes research, we aimed to review the hypoglycemia definitions adopted in randomized controlled trials (RCTs).MethodsWe reviewed 109 RCTs included in the Canadian Agency for Drugs and Technologies in Health reports for the second- and third-line therapy for the patients with type 2 diabetes (T2D).ResultsNearly 60% (n=66) of the studies reviewed presented the definitions for overall hypoglycemia, and another 20% (n=22) of the studies reported the results for hypoglycemia but did not report a definition. Among these 66 studies, only 9 (14%) followed the American Diabetes Association/European Medicines Agency specified guidelines to define hypoglycemia, with an exact threshold of plasma glucose ≤3.9 mmol/L. Fifty-two of the 66 studies (79%) used a threshold considerably lower than the recommended ≤3.9 mmol/L, and 16 studies used a threshold between 3.8 and 4.0 mmol/L. The proportion of the trials that used a cutoff value of <3.1 mmol/L appeared to be slightly similar among the more commonly used non-insulin treatments, GLP-1s (7 of 18 [39%]), thiazolidinediones (TZDs; 6 of 11 [55%]), DPP-4s (12 of 19 [64%]), and sulfonylureas (11 of 20 [55%]). Among trials with intermediate-long-acting insulins (neutral protamine Hagedorn insulin, detemir, glargine), 7 of 26 trials (27%) used a cutoff of <3.1 mmol/L. The definition of severe hypoglycemia was also subject to substantial heterogeneity, in both the utilized threshold and accompanying soft definitions.ConclusionThis review demonstrates that substantial heterogeneity exists in the definition of overall, severe/major, and nocturnal hypoglycemia across RCTs investigating T2D interventions.

Risk of any hypoglycaemia with newer antihyperglycaemic agents in patients with type 2 diabetes: A systematic review and meta‐analysis

“…There were a number of limitations to this study. As anticipated, the definitions of hypoglycaemia were heterogenous and included varying classifications of severity, symptomology, documentation, ascertainment, collection, reporting and handling of patients with hypoglycaemia . To overcome this, our primary outcome was any hypoglycaemia, irrespective of the definitions and classifications used by each study.…”

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

“…Thiazolidinediones are agonists of the peroxisome‐proliferator active receptor (Balijepalli et al, ), which may reduce IR and promote the expression of growth factors such as BDNF (Kariharan et al, ). Clinical studies indicate that in patients with cognitive impairment or AD in early stages, thiazolidinediones improve long‐term memory functioning (Galimberti & Scarpini, ) .…”

Reporting of hypoglycaemia in clinical trials of basal insulins: A need for consensus

“…However, important heterogeneity exists among these guidelines (Table ), which has contributed to differences in the way hypoglycaemia has been reported across clinical trials . A meta‐analysis of trials included in the Canadian Agency for Drugs and Technologies in Health Reports examined the way hypoglycaemia was reported in trials of glucose‐lowering drugs, including oral antihyperglycaemic drugs, fast‐acting insulins and BIs . This revealed that definitions of hypoglycaemia were included in only 60% of these trials, and few of these definitions followed American Diabetes Association (ADA) and European Medicines Agency (EMA) recommendations for definition of hypoglycaemia as blood glucose (BG) of ≤3.9 mmol/L (≤70 mg/dL), or <3.1 mmol/L (<56 mg/dL), which was recommended by the EMA prior to 2012 …”

“…7 A meta-analysis of trials included in the Canadian Agency for Drugs and Technologies in Health Reports examined the way hypoglycaemia was reported in trials of glucose-lowering drugs, including oral antihyperglycaemic drugs, fast-acting insulins and BIs. 36 This revealed that definitions of hypoglycaemia were included in only 60% of these trials, 36 and few of these definitions followed American…”

“…Diabetes Association (ADA) 37 and European Medicines Agency (EMA) 38 recommendations for definition of hypoglycaemia as blood glucose (BG) of ≤3.9 mmol/L (≤70 mg/dL), or <3.1 mmol/L (<56 mg/dL), which was recommended by the EMA prior to 2012. 36 The differences in BG thresholds for non-severe hypoglycaemia can be seen in the examples of treat-to-target trials shown in non-severe hypoglycaemia, but the glycaemic threshold no greater than 3.9 mmol/L (≤70 mg/dL), now designated as an "alert level," has been considered for some time to be indicative of non-severe hypoglycaemia. 39,40 Ideally, in line with recent guidelines, both thresholds should be reported routinely.…”