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United Kingdom Prospective Diabetes Study 17: A 9-Year Update of a Randomized, Controlled Trial on the Effect of Improved Metabolic Control on Complications in Non-Insulin-dependent Diabetes Mellitus

Robert Turner, FRCP; Carole Cull, PhD; and Rury Holman, FRCP for the United Kingdom Prospective Diabetes Study Group
[+] Article and Author Information

From the Radcliffe Infirmary, Oxford; Royal Infirmary, Aberdeen; General Hospital, Birmingham; St. George's Hospital and Hammersmith Hospital, London; City Hospital, Belfast; North Staffordshire Royal Infirmary, Stoke-on-Trent; Royal Victoria Hospital, Belfast; St. Helier Hospital, Carshalton; Whittington Hospital, London; Norfolk and Norwich Hospital, Norwich; Lister Hospital, Stevenage; Ipswich Hospital, Ipswich; Ninewells Hospital, Dundee; Northampton Hospital, Northampton; Torbay Hospital, Torquay; Peterborough General Hospital, Peterborough; Scarborough Hospital, Scarborough; Derbyshire Royal Infirmary, Derby; Manchester Royal Infirmary, Manchester; Hope Hospital, Salford; Leicester General Hospital, Leicester; and Royal Devon and Exeter Hospital, Exeter, United Kingdom. Note: This article is one of a series of articles comprising an Annals of Internal Medicine supplement entitled “Risks and Benefits of Intensive Management in Non-Insulin-dependent Diabetes Mellitus: The Fifth Regenstrief Conference.” To view a complete list of the articles included in this supplement, please view its Table of Contents. Acknowledgments: The authors thank the patients and many National Health Service (NHS) and non-NHS staff at the centers for their cooperation. They also thank Mrs. Irene Stratton, Professor Eva Kohner, and Drs. Sue Manley, David Matthews, Andrew Neil, and Jonathan Levy for their collaboration and advice and Ms. Ivy Samuel and Mrs. Caroline Wood for assistance with the manuscript. Grant Support: From the United Kingdom Medical Research Council; British Diabetic Association; United Kingdom Department of Health; National Eye Institute and National Institute of Digestive and Diabetes and Kidney Disease, National Institutes of Health; British Heart Foundation; Health Promotion Research Trust; Charles Wolfson Charitable Trust; Alan and Babette Sainsbury Trust; Oxford University Medical Research Fund Committee; various pharmaceutical companies, including Novo-Nordisk; Bayer Corporation; Bristol-Myers Squibb Company; Hoechst; Eli Lilly and Company; Lipha; and Farmitalia Carlo Erba; and other companies, including Boehringer-Mannheim, Becton Dickinson and Company, Owen Mumford, Securicor, Kodak, and Cortecs Diagnostics. Requests for Reprints: United Kingdom Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom. Current Author Addresses: Drs. Turner, Cull, and Holman: United Kingdom Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(1_Part_2):136-145. doi:10.7326/0003-4819-124-1_Part_2-199601011-00011
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Purpose: To report the progress (after 9-year follow-up) of a study designed to determine whether improved glucose control in patients with newly diagnosed non–insulin-dependent diabetes mellitus (NIDDM) is effective in reducing the incidence of clinical complications.

Data Source: A multicenter, randomized, controlled trial of different therapies for NIDDM. After initial diet therapy, 4209 asymptomatic patients who remained hyperglycemic (fasting plasma glucose levels, 6.0 to 15.0 mmol/L) were assigned to either a conventional therapy policy, primarily with diet alone, or to an intensive therapy policy, aiming for fasting plasma glucose levels of less than 6.0 mmol/L, with assignment to primary therapy with sulfonylurea or insulin (which increased insulin supply) or metformin (which enhanced insulin sensitivity).

Results: All three modes of pharmacologic therapy in the intensively treated group—sulfonylurea, insulin, and metformin—had similar efficacy in reducing the fasting plasma glucose and glycated hemoglobin levels. Over 9 years, patients assigned to intensive therapy with sulfonylurea or insulin had lower fasting plasma glucose levels (median, 7.3 and 9.0 mmol/L, respectively) and lower hemoglobin A1c levels (6.7% and 7.5%, respectively) than patients assigned to conventional therapy. Regardless of the assigned therapy, however, the fasting plasma glucose and hemoglobin A1c levels increased, and maintaining near-normal glycemia was, in general, not feasible. Even insulin therapy did not achieve the therapeutic goal of near-normal glycemia because of the difficulty in treating marked hyperglycemia and the risk for hypoglycemic episodes. Nine years after the diagnosis of diabetes, 29% of the patients had had a diabetes-related clinical end point, 20% had had a macrovascular complication, and 9% had had a microvascular complication.

Conclusions: A report will be published in 1998 after a median duration from randomization of 11 years (range, 6 to 20 years) with an 81% power at a 1% level of significance of detecting whether the obtained improvement in glucose control causes a 15% decrease or increase in the incidence of major complications and whether any specific therapy is advantageous or disadvantageous.

Figures

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Figure 1.
A flow diagram of randomization.

The main analysis compares patients assigned to conventional therapy with diet with patients assigned to intensive therapy with sulfonylurea or insulin (dotted box). Obese patients assigned to conventional therapy are compared with those assigned to metformin therapy (marked by an asterisk). Additionally, patients assigned to sulfonylurea are compared with those assigned to insulin and patients assigned to the first-generation sulfonylurea chlorpropamide are compared with those assigned to second-generation glyburide or glipizide. fpg equals fasting plasma glucose level.

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Figure 2.
The left-hand panels show the median fasting plasma glucose (A) and hemoglobin A1c (B) in patients assigned to conventional therapy (●) and those assigned to intensive therapy with sulfonylurea or insulin (fill diamond) in all patients studied each year up to 9 years of follow-up.1c1c1c1c

The histograms show the total number of patients with data at each year in this cross-sectional analysis. The dotted lines for fasting plasma glucose show 7.8 and 6.0 mmol/L, the apparent thresholds from epidemiologic studies for microvascular and macrovascular complications, and for hemoglobin A , the upper end of the normal range, 6.2%. The right-hand panels shows the median fasting plasma glucose level (C) and hemoglobin A level (D) in obese patients assigned to conventional therapy ○ and those assigned to intensive therapy with metformin (+) and with sulfonylurea or insulin (open diamond). FPG equals fasting plasma glucose level; HbA equals hemoglobin A level.

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Figure 3.
A 9-year comparison of hemoglobin A1c levels in the conventional and intensive therapy groups in patients with insulin-dependent diabetes in the Diabetes Control and Complications Trial (DCCT)[21]and in the cohorts of patients with non–insulin-dependent diabetes mellitus in the United Kingdom Prospective Diabetes Study (UKPDS).1c

Both studies used the Biorad HPLC analyzer method and were analyzed by assignment to therapy. For the first 3 years, hemoglobin A levels in the UKPDS patients had a lower range than in the DCCT patients, but after 7 years, UKPDS levels were in the lower DCCT range.

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Figure 4.
A 9-year comparison of fasting plasma glucose (FPG) levels in the patients of the University Group Diabetes Program (UGDP)[7]who were taking either placebo or variable-insulin doses and in the cohorts of the conventional and insulin therapy groups of the United Kingdom Prospective Diabetes Study (UKPDS) studied for 9 years[33], both analyzed by assignment to therapy.

The UGDP measured blood glucose levels and a correction of × 1.1 was used to give equivalent fasting plasma glucose values. The two studies have shown similar deterioration of blood glucose control over 9 years.

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Figure 5.
Proportion of patients developing diabetes-related clinical end points over 9 years, as shown by a Kaplan-Meier plot.

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