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United Kingdom Prospective Diabetes Study 24: A 6-Year, Randomized, Controlled Trial Comparing Sulfonylurea, Insulin, and Metformin Therapy in Patients with Newly Diagnosed Type 2 Diabetes That Could Not Be Controlled with Diet Therapy

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United Kingdom Prospective Diabetes Study Group. From Radcliffe Infirmary, Oxford, United Kingdom. For participants in the United Kingdom Prospective Diabetes Study Group, see Appendix. Acknowledgments: The authors thank the patients and the National Health Serviceand non-National Health Service staff at the centers for their cooperation. Grant Support: By grants from the United Kingdom Medical Research Council; the British Diabetic Association; the United Kingdom Department of Health; The National Eye Institute (5 U10 EY07049-11) and The National Institute of Diabetes and Digestive and Kidney Diseases (2 R01 DK33152-07), National Institutes of Health; The British Heart Foundation; The Health Promotion Research Trust; The Clothworkers' Foundation; Charles Wolfson Charitable Trust; The Alan and Babette Sainsbury Trust; and The Oxford University Medical Research Fund Committee. 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. Wright, Cull, Holman, and Turner: 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. 1998;128(3):165-175. doi:10.7326/0003-4819-128-3-199802010-00001
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Background: Uncertainty exists about the suitability of oral hypoglycemic drugs and insulin therapy for patients with newly diagnosed type 2 diabetes.

Objective: To assess and compare response to sulfonylurea, insulin, or metformin over 6 years in patients with newly diagnosed type 2 diabetes in whom disease could and could not be controlled with diet therapy alone.

Design: Multicenter, randomized, controlled trial.

Setting: Outpatient diabetes clinics of 15 hospitals in the United Kingdom.

Intervention: Sulfonylurea (chlorpropamide or glyburide), insulin, or metformin (if patients were obese).

Patients: 458 patients with newly diagnosed type 2 diabetes that could not be controlled with diet and had hyperglycemic symptoms or fasting plasma glucose levels greater than 15 mmol/L during the initial 3 months of diet therapy (primary diet failure group) and 1620 patients in whom disease was controlled by diet therapy and who had fasting plasma glucose levels of 6 to 15 mmol/L and no hyperglycemic symptoms while receiving diet therapy alone.

Measurements: Fasting plasma levels of glucose and insulin, hemoglobin A1c concentrations, body weight, and therapy required.

Results: Compared with the diet-controlled group, the primary diet failure group was younger and less obese and had more retinopathy, lower fasting plasma insulin levels, and reduced β-cell function. At 6 years, patients allocated to insulin had lower fasting plasma glucose levels than did patients allocated to oral agents, but hemoglobin A1c concentrations were similar. Forty-eight percent (95% CI, 37% to 58%) of patients in the primary diet failure group maintained hemoglobin A1c concentrations less than 0.08. By 6 years, 51% of patients (CI, 42% to 62%) allocated to ultralente insulin required additional short-acting insulin and 66% of patients (CI, 58% to 73%) allocated to sulfonylurea required additional therapy with metformin or insulin to control symptoms and maintain fasting plasma glucose levels less than 15 mmol/L. Patients allocated to insulin gained more weight and had more hypoglycemic attacks than did patients allocated to sulfonylurea. Obese patients allocated to metformin gained the least weight and had the fewest hypoglycemic attacks. For all therapies, control achieved at 6 years was worse in the primary diet failure group than in the diet-controlled group.

Conclusions: Because initial insulin therapy induced more hypoglycemic reactions and weight gain without necessarily providing better control, it may be reasonable to start with oral agents and change to insulin if goals for glycemic levels are not achieved.

Figures

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Figure 1.
Flow chart showing patients who were entered into the primary diet failure group.

After a 3-month run-in period of diet therapy alone, 560 of 4075 patients with newly diagnosed type 2 diabetes continued to have fasting plasma glucose levels greater than 15.0 mmol/L or hyperglycemic symptoms and were randomly assigned to different intensive therapies. Data from 458 patients allocated to insulin, sulfonylurea, or metformin therapy at 6 years are reported. The numbers of nonobese/obese patients in each group are shown. After the initial 3 months of diet therapy, 764 patients had fasting plasma glucose levels less than 6.0 mmol/L and 2769 patients had fasting plasma glucose levels of 6.0 to 15.0 mmol/L; the latter patients were allocated to diet alone or to insulin, sulfonylurea, or metformin therapy in the main randomization group.

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Figure 2.
Median fasting plasma glucose levels (top) and hemoglobin A1c concentrations (bottom) over 6 years in patients in the primary diet failure group who were allocated to insulin (squares), sulfonylurea (triangles), or metformin (Xs).1c

The left panels show data from nonobese patients; the right panels show data from obese patients. The horizontal dashed lines indicate plasma glucose levels of 6.0 and 7.8 mmol/L and hemoglobin A concentrations of 0.062 (the upper 97.5th percentile of the normal range in our laboratory).

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Figure 3.
Percentage of patients in the primary diet failure group who required additional therapy at 6 years, according to allocated therapy.

The number of patients included in each section is given inside the bar for each therapy group. The left panel shows data from nonobese patients; the right panel shows data from obese patients. C = chlorpropamide; G = glyburide; I = ultralente insulin; M = metformin; OHA = oral hypoglycemic agents.

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Figure 4.
Kaplan-Meier estimates of the survivor functions for the proportion of patients in the primary diet failure group who required additional therapy.Top.Bottom.2arrow2dashed line2dotted line

Estimated survivor functions for patients classified according to tertiles of age younger than 46 years, 46 to 57 years, and older than 57 years. Estimated survivor functions for patients classified by obesity according to tertiles of body mass index less than 23 kg/m ( ), 23 to 27 kg/m ( ), and greater than 27 kg/m ( ). The lighter dashed line indicates the estimated survivor function for all patients in the main randomization group (MR) who received intensive treatment. Numbers between the graphs are the numbers of patients at risk at annual intervals in the primary diet failure (PDF) and main randomization groups.

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Figure 5.
Mean changes in body weight (top) and fasting plasma insulin levels (bottom) over 6 years in patients in the primary diet failure group allocated to insulin (squares), sulfonylurea (triangles), or metformin (Xs).

Left panels show data from nonobese patients; right panels show data from obese patients.

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