Elsevier

Journal of Diabetes and its Complications

Volume 20, Issue 6, November–December 2006, Pages 395-401
Journal of Diabetes and its Complications

Original article
Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73

https://doi.org/10.1016/j.jdiacomp.2005.08.010Get rights and content

Abstract

The UK Prospective Diabetes Study (UKPDS) showed that a more intensive glucose control policy reduced risk of diabetic complications. As hypoglycemia is a barrier to achieving glycemic targets, we examined its occurrence and contributing factors in UKPDS patients randomized to and remaining for 6 years on diet, sulfonylurea, metformin (overweight subjects only), or insulin monotherapy from diagnosis of Type 2 diabetes. Self-reported hypoglycemic episodes were categorized as (1) transient, (2) temporarily incapacitated, (3) requiring third-party assistance, and (4) requiring medical attention, recording the most severe episode each quarter. Proportions of patients reporting at least one episode per year were calculated in relation to therapy, HbA1c, and clinical characteristics. In 5063 patients aged 25–65 years, only 2.5% per year reported substantive hypoglycemia (Grades 2–4) and 0.55% major hypoglycemia (Grade 3 or 4). Hypoglycemia was more frequent in younger (4.0% <45 years vs. 2.2% ≥45 years), female (3.0% vs. 2.2% male), normal weight (3.6% body mass index <25 kg/m2 vs. 1.9% ≥25 kg/m2), less hyperglycemic (5.2% HbA1c <7% vs. 2.3% ≥7%), or islet autoantibody-positive patients (4.3% vs. 2.1% negative) (all P<.0001). More on basal insulin reported hypoglycemia (3.8% per year) than diet (0.1%), sulfonylurea (1.2%), or metformin (0.3%) therapy, but less than on basal and prandial insulin (5.3%) (all P<.0001). Low hypoglycemia rates seen during the first 6 years of intensive glucose lowering therapy in Type 2 diabetes are unlikely to have a major impact on attempts to achieve guideline glycemic targets when sulfonylurea, metformin, or insulin are used as monotherapy.

Introduction

Intensive blood glucose control improves clinical outcomes in diabetes (DCCT Research Group, 1993, UKPDS Group, 1998), but most treatment regimens increase weight gain and risk of hypoglycemia. Information about hypoglycemia in diabetes is largely confined to Type 1 diabetes (Cryer, 2001) and insulin requiring Type 2 diabetes, where fear of hypoglycemia is often cited as a factor-limiting attempts to intensify therapy (Cryer, 2002). Severe hypoglycemia rates (episodes requiring third-party assistance) for people with Type 1 diabetes in the Diabetes Control and Complications Trial (DCCT) (DCCT Group, 1997) were approximately threefold greater in the intensive treatment group [61.2/100 person-years (pyrs)] than the conventional treatment group (18.7/100 pyrs). Although hypoglycemia is a concern also in Type 2 diabetes (Jennings, Wilson, & Ward, 1989), occurrence is much lower with rates of one or more episodes per year reported by the UK Prospective Diabetes Study (UKPDS) of 0.4% patients on chlorpropamide, 0.6% on glibenclamide (glibenclamide), and 2.3% on insulin (UKPDS Group, 1998), confirming an earlier report on a smaller subset of patients (UKPDS Group, 1995).

We have analyzed self-reported hypoglycemia in UKPDS patients according to their allocated monotherapy over 6 years from diagnosis of Type 2 diabetes and examined factors that might be associated with higher rates of hypoglycemia.

Section snippets

Patients

The UKPDS recruitment process and protocol have been reported previously (UKPDS Group, 1991). The study received ethical committee approval in 23 clinical centers and conformed to the guidelines of the Declarations of Helsinki (1975 and 1983). Briefly, 5102 of 7616 patients referred entered the study between 1977 and 1991. They gave informed consent, were aged 25–65 years, and had fasting plasma glucose (FPG) levels >6.0 mmol/l on two occasions after being diagnosed diabetic. Of the 5102, 81%

Results

Baseline characteristics, post-dietary run-in, for 5063 patients are listed in Table 1. The overall proportion of patients reporting at least one Grades 1–4 hypoglycemic episode (95% CI) per year was 11.0% (10.7 to 11.2), for a Grades 2–4 episode 2.5% (2.4 to 2.7), and for a Grade 3 or 4 episode 0.55% (0.50 to 0.60).

Table 2 shows annual percentages of patients reporting hypoglycemia, irrespective of current therapy or glycemic control, according to age, sex, ethnicity, body mass index (BMI),

Discussion

This evaluation of self-reported hypoglycemia over 6 years from diagnosis of Type 2 diabetes during the UKPDS trial emphasizes that compared with Type 1 diabetic patients (DCCT Research Group, 1991), the proportion of patients reporting hypoglycemia is substantially less, even in those allocated to intensive glucose monotherapies. The occurrence of major hypoglycemic episodes, requiring third-party or medical assistance, was especially low, and only one hypoglycemia-related fatality occurred (

Acknowledgments

The cooperation of patients and many NHS and non-NHS staff at the centers is much appreciated. The major grants for this study were from the UK Medical Research Council, British Diabetic Association, the UK Department of Health, The National Eye Institute and The National Institute of Digestive, Diabetes and Kidney Disease in the National Institutes of Health, USA, The British Heart Foundation, Novo-Nordisk, Bayer, Bristol Myers Squibb, Hoechst, Lilly, Lipha and Farmitalia Carlo Erba. Other

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