Volume 13 Number 4, 2000, Page 194
2 Diabetes Over Time:
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 -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 -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
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
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 1520 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
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 -cell failure in comparison to diet treatment alone. These observations challenge the widely held view that -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
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.
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 352:854865, 1998
3American Diabetes Association: Standards of medical care for patients with diabetes mellitus (Position Statement). Diabetes Care 23 (Suppl. 1):S32S42, 2000
4UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 317:703713, 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 317:714720, 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 20:16831687, 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 39:905912, 1990
8UK Prospective Diabetes Study Group: UK Prospective Diabetes 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 44:12491258, 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. 85116
10Cowie CC, Harris MI: Physical and metabolic characteristics of persons with diabetes. In Diabetes in America. 2nd ed. Harris MI, Ed. Beth
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 (19691971) and the second at the University of Washington in Seattle with Dr. Robert Williams (19711973). 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.
Copyright © 2000 American Diabetes Association
Last updated: 12/00