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Progressive Requirement for Multiple Therapies (UKPDS 49)

Robert C. Turner, FRCP; Carole A. Cull, PhD; Valeria Frighi, MD; Rury R. Holman, FRCP; for the UK Prospective Diabetes Study (UKPDS) Group

JAMA. 1999;281:2005-2012.

Context  Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A_1c(HbA_1c) below 7% is unknown.

Objective  To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association.

Design  Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment.

Setting  Outpatient diabetes clinics in 15 UK hospitals.

Patients  A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA_1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m².

Interventions  After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin.

Main Outcome Measures  Fasting plasma glucose and HbA_1c levels, and the proportion of patients who achieved target levels below 7% HbA_1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis.

Results  The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA_1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA_1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients.

Conclusions  Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA_1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Author Affiliations: Radcliffe Infirmary, Oxford, England. A complete list of the members of the UK Prospective Diabetes Study Group was published previously (Lancet. 1998;352:837-853).

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