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Glycemic Control With Diet, Sulfonylurea, Metformin, or
Insulin in Patients With Type 2 Diabetes Mellitus:
Progressive Requirement for Multiple Therapies (UKPDS
Robert C. Turner; Carole A. Cull; Valeria Frighi; et al. JAMA. 1999;281(21):2005-2012 (doi:10.1001/jama.281.21.2005) Glycemic Control With Diet, Sulfonylurea,
Metformin, or Insulin in Patients
With Type 2 Diabetes Mellitus
Progressive Requirement for Multiple Therapies (UKPDS 49)
Context Treatment with diet alone, insulin, sulfonylurea, or metformin is known to
improve glycemia in patients with type 2 diabetes mellitus, but which treatment mostfrequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown.
Objective To assess how often each therapy can achieve the glycemic control tar-
get 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
ONEOFTHEMAINGOALSOF 9yearsafterenrollment.
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 concen- levels to prevent the development of dia- tration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c 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, pa-
holm studies2 in white patients with type tients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin.
Main Outcome Measures Fasting plasma glucose and HbA
portion of patients who achieved target levels below 7% HbA (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis.
Results The proportion of patients who maintained target glycemic levels declined mark-
edly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfo- control will delay the progress of micro- nylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese pa- tients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c 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 HbA1c below 7% compared with diet alone. How- ever, the progressive deterioration of diabetes control was such that after 3 years ap- study in whites with 2-hour oral FPG tol- proximately 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, En-
(St Albans, England). Additional assistance was pro- gland. A complete list of the members of the UK Pro- vided by Boehringer Mannheim Corp (Livingston, Scot- spective Diabetes Study Group was published previ- land), Becton Dickinson Co (Oxford, England), Owen ously (Lancet. 1998;352:837-853).
Mumford (Woodstock, England), Securicor (London, Financial Disclosure: We received support from phar-
England), Eastman Kodak Co Health Imaging Divi- maceutical companies including Novo Nordisk Phar- sion (Hemel Hempstead, England), and Cortecs Di- maceuticals A/S (Bagsvaerd, Denmark), Bayer Phar- maceutical Division (Newbury, England), Bristol Myers Corresponding Author and Reprints: Robert C. Turner,
Squibb Co (Hounslow, England), Hoechst Marion FRCP, UKPDS Study Group, Diabetes Research Labo- Roussel (Bridgewater, NJ), Eli Lilly & Co (Indianapo- ratories, Radcliffe Infirmary, Woodstock Road, Oxford, lis, Ind), Lipha (Lyon, France), and Farmitalia Carlo Erba England OX2 6HE (e-mail: [email protected]).
1999 American Medical Association. All rights reserved.
JAMA, June 2, 1999—Vol 281, No. 21 2005
termed diet satisfactory. If the mean of termed delayed randomization as in the therapies can attain glycemic target lev- propriate numbers in each allocation.
Patients were seen at clinic visits every 7.0% in patients with type 2 diabetes has having diabetes, who are likely to be rep- different clinical presentations were me- lin regimen consisted of a once-daily dose 23 centers.12 All were initially treated by of long-acting or isophane insulin. If the lin therapy. Since type 2 diabetes is char- acterized by steady deterioration of glu- more difficult to attain near-normal gly- insulin doses at 6 and 9 years from diag- cemic control target levels. We report the scribed, by a dietitian, a low-fat, high- 34 U, respectively. At 9 years, the median these target levels with each of the agents months on this diet, patients were strati- fied into 1 of the following therapies ac- Patients
mia, termed primary diet failure were sive, termed main randomization, allo- doses, additional therapy was added.
an additional option, termed conven- tional therapy; (3) those with FPG con- min. This article evaluates the proportion 2006 JAMA, June 2, 1999—Vol 281, No. 21
1999 American Medical Association. All rights reserved.
below 7% or 8% at 3, 6, and 9 years after ses at each 3-year interval were of patients stratifications, primary diet failure group possible to estimate the proportion of the Statistical Analyses
proportions of patients allocated to each tain these target levels. Conversely, the sentative of all patients in that random- of patients within that stratification who were transferred to insulin therapy.
ity of failing to achieve the target lev- to take sulfonylurea alone, and of these, tiple therapies as a result of failing to variables interacted with the therapy al- 1999 American Medical Association. All rights reserved.
JAMA, June 2, 1999—Vol 281, No. 21 2007
Figure 1. Glucose Stratification at Entry and Randomization to Different Therapies During the UK Prospective Diabetes Study
Subjects With Newly Diagnosed Type 2 Diabetes Mellitus For subjects marked with an asterisk, numbers changed with duration of the study since those with fasting plasma glucose levels of less than 6 mmol/L (108 mg/dL)after 3-month diet progressively become higher than 6.0 mmol/L (108 mg/dL) and were randomized to the different therapy options. Others were removed followingdeath or loss to follow-up. The numbers in each group are those included in the cohorts analyzed at 3, 6, and 9 years. Those marked with a dagger remained less than6.0 mmol/L (108 mg/dL) and are not included in the analysis. To convert millimoles per liter to milligrams per deciliter, multiply by 18.
Table 1. Proportion of Patients Who Attain Goals*
Fasting Plasma Glucose
Hemoglobin A Ͻ
7.8 mmol/L
Proportions Attaining Goals
mg/dL). TABLE 1 and FIGURE 2 summa-
rize the results for 3, 6, and 9 years for mg/dL) for patients allocated and remain- *Values are proportions (95% confidence intervals) expressed as percentages. To convert fasting plasma glucose to milligrams per deciliter, multiply by 18.
els below 7.0%. However, each thera-peutic agent, given as a monotherapy, ap-proximately doubled the proportion of justed for the effect of sex; PՆ.05 was patients who could attain HbA1c levels be- FIGURE 1 shows, in outline, the strati-
vious publications.12,13,19,20 Numbers of sponse over the first 6 years, but by 9 years 2008 JAMA, June 2, 1999—Vol 281, No. 21
1999 American Medical Association. All rights reserved.
target level as those taking sulfonylurea tently achieved the target levels more of- ever, the response for HbA1c after 9 years was similar for both therapies (for HbA1c Ͻ7%: 28% vs 24%, respectively). Pa- formin (Table 1) showed a similar re- (140 mg/dL) compared with 41% tak- Figure 2. Proportions of Patients in Each Therapy Allocation
Values are for patients who remained receiving monotherapy and achieved different control targets after 3, 6, and 9 years.
Table 2. Univariate Logistic Regression Analysis of Predictive Factors*
Fasting Plasma Glucose
Hemoglobin A
7.8 mmol/L
Odds Ratio
Odds Ratio
Variable
P Value
P Value
Subjects
Subjects
*After 3 months’ diet for likelihood of requiring multiple therapies since glycemic goals were not achieved at 3 years after allocation in 1775 patients. CI indicates confidence interval.
†To convert fasting plasma glucose to milligrams per deciliter divide by 0.05551.
‡Adjusted for sex differences.
§Values are for overweight subjects only.
1999 American Medical Association. All rights reserved.
JAMA, June 2, 1999—Vol 281, No. 21 2009
sity (assessed as either BMI or waist cir- ter 9 years. In relation to the HbA1c tar- significantly associated with the likeli- hood of requiring multiple therapies. The P = .46), but not as well by 9 years (13% carboxylase status of the patients was not associated with either of the targets.
Univariate Analysis
of Predictors of Requirement
for Additional Therapy
TABLE 2 shows the results of a logistic
dL), but lower was not significantly dif- (Table 2). FIGURE 3 shows these odds
multiple therapies due to HbA1c levels of years. In this univariate analysis, a young age at diagnosis, increased baseline obe- Multivariate Analysis
of Response to Therapies
A multivariate logistic regression analy-
Figure 3. Univariate Analysis of Multiple Therapies to Achieve HbA1c Below 7%
sis for intensive therapy with insulin orsulfonylurea compared with conven- tional therapy was performed in rela-tion to the requirement for additionaltherapy at 3 years, in which covariatesfor inclusion in the model were those significant in the univariate analysis,with a stepwise selection process toidentify the final model.
gave a lower likelihood of requiring ad-ditional therapy for HbA1c levels be-low 7% (OR, 0.55; 95% CI, 0.43-0.69; PϽ.001), and for FPG concentrationsof less than 7.8 mmol/L (140 mg/dL) (OR, 0.34; 95% CI, 0.27-0.44; PϽ.001)
(TABLE 3). In relation to the FPG goal,
The patients allocated to and remaining on diet alone formed the reference group for the comparison with insulin, sulfonylurea, and metformin. When the 95% confidence interval about the odds ratio is less than 1.0,that therapy has a significantly decreased requirement for additional therapy to achieve HbA1c of less than 7%. tant factor entering into the model be- fore other covariates. Higher baselinelevels of FPG or HbA1c gave a greater Table 3. Conventional vs Intensive Therapy With Insulin or Sulfonylurea*
Fasting Plasma Glucose
Hemoglobin A
7% (n = 1589)
7.8 mmol/L (n = 1651)
Odds Ratio
P
Odds Ratio
P
Variable
Intensive vs conventional 0.55 (0.43-0.69) *Stepwise logistic regression model for likelihood of requiring multiple therapies as glycemic goals were not achieved at 3 years after allocation. CI indicates confidence interval; ellipses, variable not inlcuded in model.
2010 JAMA, June 2, 1999—Vol 281, No. 21
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tions,4 the progressive decline in ␤-cell 1.08-1.72; P = .01) after inclusion of 1.18-1.53; PϽ.001), age (OR, 0.74; 95% CI, 0.65-0.86; PϽ.001), and BMI (OR, Funding/Support: We received funding from the UK
1.15; 95% CI, 1.02-1.30; PϽ.001) in the used, in clinical practice they have simi- Medical Research Council (London, England), British Diabetic Association (London), the UK Department of Health (London), the National Eye Institute (Bethesda,Md), the US National Institute of Digestive, Diabetes and Kidney Disease (Bethesda), the British Heart Foun- dation (London), the Health Promotion Research Trust(London), Charles Wolfson Charitable Trust (Lon- don), the Clothworkers’ Foundation (London), the Alan and Babette Sainsbury Trust (London), and the Ox- ford University Medical Research Fund Committee (Ox- (OR, 0.44; 95% CI, 0.27-0.72; PϽ.001), Acknowledgment: We appreciate the cooperation that
1.40-2.75; PՅ.005), high plasma tri- was given by the patients and many National HealthService and non–National Health Service staff at the fol- lowing centers: Radcliffe Infirmary (Oxford, England), 3.27; PϽ.001), and young age (OR, Royal Infirmary (Aberdeen, Scotland), General Hospi- tal (Birmingham, England), St George’s Hospital and 0.53; 95% CI, 0.39-0.72; PϽ.001) also have been anticipated. This is partly be- Hammersmith Hospital (London, England), City Hos- pital (Belfast, Ireland), North Staffordshire Royal Hos-pital (Stoke-on-Trent, England), Royal Victoria Hospi- tal (Belfast), St Helier Hospital (Carshalton, England), Whittington Hospital (London), Norfolk & Norwich Hos-pital (Norwich, England), Lister Hospital (Stevenage, En- gland), Ipswich Hospital (Ipswich, England), Ninewells Hospital (Dundee, Scotland), and Northampton Hos- REFERENCES
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Affairs Cooperative Study on glycemic control and Scientific truth, which I formerly thought of as fixed,as though it could be weighed and measured, is change-able. Add a fact, change the outlook, and you have anew truth. Truth is a constant variable. We seek it,we find it, our viewpoint changes, and the truthchanges to meet it.
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