Diabetes Spectrum
Volume 13 Number 4, 2000, Page 194
From Research to Practice / Lessons From the UKPDS

Managing Type 2 Diabetes Over Time:
Lessons From the UKPDS


Preface


Matthew C. Riddle, MD


Twenty-three years ago, the Oxford University group and their collaborators started the United Kingdom Prospective Diabetes Study (UKPDS), and since then they have reported its results in more than 40 publications. The UKPDS has taught us a lot. Best publicized has been the randomized comparison between a "conventional" treatment policy using diet alone and an "intensive" policy beginning with a sulfonylurea, metformin, or insulin.

This part of the trial confirmed the glucose hypothesis for type 2 diabetes,1,2 as the Diabetes Control and Complications Trial did for type 1 diabetes. Although they were designed differently, both trials showed that reducing glycosylated hemoglobin (HbA1c) values by 1% reduces microvascular complications of diabetes by about 30%. In the UKPDS, the subjects started their assigned treatments when their mean HbA1c was about 7%, and the HbA1c in the intensive treatment groups averaged 7% during the next 10 years. These findings leave little refuge for the view that glucose control is unimportant or unattainable and support 7% HbA1c as a realistic and desirable target for glycemic control.3

Other findings of the UKPDS have deservedly received attention. For example, the trial showed that sulfonylureas, metformin, and insulin are equally effective in reducing microvascular complications and that (contrary to fears about sulfonylureas and insulin) none of these agents caused harm through cardiovascular or other toxicity.1,2 It also showed that treating blood pressure with either an angio-tensin-converting enzyme (ACE) inhibitor (captopril) or a beta.gif (968 bytes)-sympathetic blocker (atenolol) sharply reduced microvascular and macrovascular complications.4,5

These are huge contributions. However, another aspect of the UKPDS deserves more press than it has received. This concerns the natural history of type 2 diabetes and its implications for the people who experience it in their own lives and for those of us who support, teach, and advise them. At its outset, the trial collected a large, representative group of people with newly diagnosed diabetes.6 Various characteristics of this group have been described in detail, and important subgroups have been identified. The effectiveness of vigorous efforts to improve lifestyle has been reported, and this information is of great interest.7 Similarly, the relative effectiveness of various drug therapies over time has become evident from this trial.8 "Secondary failure" was not specific to any single treatment, but rather reflected progressive decline of beta.gif (968 bytes)-cell function.

These insights go beyond proving that controlling hyperglycemia and hypertension is important and beyond setting therapeutic targets. They lead to new tactics for coping with type 2 diabetes. Let's consider each more closely.

The Typical Person Newly Diagnosed With Diabetes
Of course, the subjects of the UKPDS were all from the United Kingdom, but they were not as different from people in the United States as is sometimes assumed. Of 5,012 people recruited for the UKPDS, 82% were described as white,6 while about 70% of people with diabetes in the United States are described as non-Hispanic white.9 The mean age at diagnosis and entry to the UKPDS was 52 years, and the mean body mass index (BMI, kg/m2) was 29. Both figures are very similar to those in the United States.9,10 Mean fasting plasma glucose at diagnosis was 209 mg/dl for men and 223 mg/dl for women, and the corresponding HbA1c values were 9.0% and 9.3%, respectively. Mean blood pressure was 134/82 mmHg for men and 140/84 mmHg for women, and mean low-density lipoprotein (LDL) cholesterol was 139 mg/dl for men and 151 mg/dl for women. Given the differences in geography and time from patients newly diagnosed in the United States today, these exact values should not be overemphasized, but the general pattern should hold true.

The pertinence of these numbers is obvious when they are compared to accepted targets for treatment.3 A BMI of 30 reflects weight about 30% above the desirable level and mandates an effort to lose weight for nearly everyone. A >2% reduction in HbA1c is needed to get from 9% to the <7% target range. If the blood pressure target is <130 mmHg systolic and the mean in a large population is above that value, then more than half of these people should start (or intensify) antihypertensive treatment. Similarly, if the LDL cholesterol level that triggers active treatment is 130 mg/dl and the population mean is well above that, then more than half should be treated.

These figures are alarming, especially if you have just learned you have diabetes. There is a lot to learn, many lifestyle changes to make, many pills to take, and a long way to go to reach the metabolic targets. How can you do it all? Where should you start?

What A Typical Person Can Expect From Lifestyle Changes
The conventional answer to the last question above has been: dietary therapy. All subjects enrolled in the UKPDS entered an intensive 3-month dietary program as initial treatment. An early UKPDS report focused on the response of the first 3,044 subjects to undertake this program.7 Even though people with ketonuria had been excluded in the selection process, 447 of this group (15%) had a fasting glucose >270 mg/dl and started drug treatment before completing the dietary program. After 3 months, only 482 (16%) reached the predefined target for fasting plasma glucose, which was <108 mg/dl, a value very similar to the currently recommended range (90–130 mg/dl).3

Thus, 15% responded so little to diet alone that they were given early drug treatment, and 69% responded incompletely and were eligible for the main randomized trial of conventional treatment (continued diet) versus intensive treatment (drugs). Only 16% achieved the glycemic target with diet alone. Those who did succeed with diet lost weight (from 132% of ideal body weight at the start to 121% after 3 months, or about 15–20 lb), but after another year of dietary effort, only about half of them (9% of the starting group) maintained fasting glucose values <108 mg/dl.

Although it challenges traditional thinking, the message from this experience is clear. Dieting does control glucose if it is extremely effective in reducing weight, but this is rarely achieved or maintained. Eating less and exercising more and continuing to do so is too hard, and at the same time the glycemic improvement typically needed is too great.

Perhaps we should rethink our approach. Should people newly found to have diabetes always rely on nutritional therapy alone for a long and often unhappy time before considering the addition of drug therapy? When lifestyle efforts fail, the person who is trying them can hardly avoid feeling that it is a personal failure, which is not true and not a message we want to convey. Another option would be to teach lifestyle tactics immediately, with high priority, but also with ancillary drug treatment to overcome glucose toxicity, restore glycemic control, and allow the person to enjoy success. The drug dosage can always be reduced, or the drug can be stopped entirely later. Lifestyle management begins now and continues lifelong, but it rarely does the job alone.

Short-Term and Long-Term Prospects for Drug Treatment
After randomization of the subjects not entirely successful with diet alone, all of the drug treatments used in the UKPDS were, at first, very successful. They all achieved mean HbA1c values <7%.8 However, as reported in an analysis of 4,209 subjects followed for the first 6 years after randomization, all the treatment groups, including the conventional (diet) group, showed deterioration of glycemic control over time. The rate of increase of HbA1c was remarkably similar in all the groups, about 0.2–0.3% of HbA1c yearly. Analysis of the data available suggests that the rise of HbA1c was mainly due to a progressive decline of beta.gif (968 bytes)-cell function rather than worsening of insulin resistance or lack of adherence to medications.8

These findings were not widely expected and have led to some important conclusions. First, type 2 diabetes is intrinsically a progressive disorder that, if treated in a simple way, will outgrow its response to therapy. Second, none of the drug treatments used in the UKPDS (sulfonylurea, metformin, and insulin) showed any tendency to alter the progression of diabetes. Metformin limited weight gain and modestly reduced serum insulin levels, but it did not protect against the decline of endogenous insulin. Sulfonylureas, which stimulate insulin secretion, showed no tendency to accelerate beta.gif (968 bytes)-cell failure in comparison to diet treatment alone. These observations challenge the widely held view that beta.gif (968 bytes)-cells fail because they are "exhausted" by overuse. Third, over time most people with type 2 diabetes will need combinations of drugs to maintain control. And fourth, with progression of type 2 diabetes, many people will eventually need insulin and often not just one or two injections of long-acting insulin but a full-scale multiple injection regimen.

Revising Tactics for the Newly Diagnosed
These insights from the UKPDS have implications for action. In my view, they have not yet been assimilated into practice, but they should be. The typical patient who is found, at age 50 and BMI 29, to have high random glucose values and an HbA1c of 9%, untreated blood pressure of 140/85 mmHg, and LDL cholesterol of 145 mg/dl needs to know what lies ahead. Such a person usually is told that many complications are possible and that they are more likely if treatment is not taken seriously. The importance of lifestyle change is emphasized, but it is seldom disclosed that the early success rate is only 15% and the longer-term rate is less than that. The person rarely learns at the outset how many different kinds of treatments are likely to become necessary and when. Insulin is typically mentioned as something that may be needed in the distant future, if at all, with the implication that with good behavior this unpleasant remedy can be avoided.

I think most people will benefit from a more accurate, positive, and complete description of the natural history of type 2 diabetes and the means now available to deal with it. There is no better time to start than in the teachable moment that follows diagnosis. This From Research to Practice section is designed to develop this point of view.

Three seasoned experts have agreed to write on three important (and interconnected) aspects of managing type 2 diabetes. Virginia Valentine, RN, MSN, CDE, (p. 197) covers teaching people who are newly found to have diabetes what this diagnosis means for the future, starting at the beginning but not neglecting the long view. Wendy Satin-Rapaport, LCSW, PsyD, Rebecca Taylor Cohen, MA, and I (p. 201) address the emotional challenges from the escalating demands of diabetes, especially at diagnosis and when starting insulin. John B. Buse, MD, PhD, CDE, FACE (p. 211) describes step-wise use of antihyperglycemic agents to match the progressive need and to avoid the rise of HbA1c seen in the UKPDS with its overly simple scheme of treatment.

We hope you find these articles useful.


References
1UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998

2UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998

3American Diabetes Association: Standards of medical care for patients with diabetes mellitus (Position Statement). Diabetes Care 23 (Suppl. 1):S32–S42, 2000

4UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 317:703–713, 1998

5UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ 317:714–720, 1998

6UK Prospective Diabetes Study Group: UK Prospective Diabetes Study 27: plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 20:1683–1687, 1997

7UK Prospective Diabetes Study Group: UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients. Metabolism 39:905–912, 1990

8UK Prospective Diabetes Study Group: UK Prospective Diabetes 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258, 1995

9Cowie CC, Eberhardt MS: Sociodemographic characteristics of persons with diabetes. In Diabetes in America. 2nd ed. Harris MI, Ed. Bethesda, Md., National Institutes of Health (NIH Publ. No. 95-1468), 1995, p. 85–116

10Cowie CC, Harris MI: Physical and metabolic characteristics of persons with diabetes. In Diabetes in America. 2nd ed. Harris MI, Ed. Beth


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Guest Editor

Matthew C. Riddle, MD, earned a bachelor's degree from Yale University in 1960 and a medical degree from Harvard Medical School in 1964. He served his internship and residency in internal medicine at Rush-Presbyterian-St. Luke's Medical Center in Chicago and completed two fellowships in endocrinology and metabolism, the first at Rush with Dr. Theodore Schwartz (1969–1971) and the second at the University of Washington in Seattle with Dr. Robert Williams (1971–1973). He is a professor of medicine and head of the Section of Diabetes at Oregon Health Sciences University in Portland. His interests include the physiology and treatment of type 2 diabetes, newer therapeutic agents, and the organization of care for diabetes.


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