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Where Do We Go from Here?
- From the Regenstrief Health Center, Richard L. Roudebush Veterans Affairs Medical Center, and the Indiana University School of Medicine, Indianapolis, Indiana. Note: This article is one of a series of articles comprising an Annals of Internal Medicine supplement entitled “Risks and Benefits of Intensive Management in Non-Insulin-dependent Diabetes Mellitus: The Fifth Regenstrief Conference.” To view a complete list of the articles included in this supplement, please view its Table of Contents.
Moving from research findings to clinical practice is a complex process involving the quality of the data; the readiness of the health care system to accept, implement, and pay for the changes recommended by the findings; and the diffusion of the technology and expertise necessary for implementation. Conference participants believe that the data reported here and by others represent an urgent call to recognize that non–insulin-dependent diabetes mellitus (NIDDM) is a serious disease with costly morbidity and mortality, which can be reduced by a comprehensive therapeutic approach. This approach, outlined in Table 3 of this supplement's introduction (see “Introduction: Risks and Benefits of Intensive Management of NIDDM. The Fifth Regenstrief Conference”), should be the goal of all practitioners. In many ways, the approach is similar to those recommended for hypertension and hyperlipidemia, the other chronic conditions underlying the risk for cardiovascular disease, which is disproportionately present in patients with NIDDM. Even in these areas, however, we are moving slowly [1].
Many patients with NIDDM do not realize the profound implications that this metabolic abnormality has on their survival. Our first step then is to ensure that all patients with NIDDM become aware of the risks inherent in that diagnosis and of the measures necessary to reduce those risks through initial and follow-up patient education. The principles of such educational programs have been extensively reviewed [2-6]. However, many patients do not receive such education, primarily because of limitations on reimbursement [7, 8]. In this supplement, Dr. Berger's article (see “Health Care for Persons with NIDDM: The German Experience”) shows how changes in the reimbursement system in Germany improved the implementation of patient education and outcomes.
In addition to comprehensive patient education, a thorough assessment of the patient's current risk status is needed, including assessment of the specific complications of diabetes, that is, retinopathy, nephropathy (including microalbuminuria), and neuropathy (primarily assessing sensation and circulation to the feet) [9]. The 10-gram monofilament is a simple method of measuring foot risk [10]. This assessment should be done as part of the initial evaluation because many patients with NIDDM have microvascular complications at diagnosis.
The initial evaluation also needs to include assessment of cardiovascular disease and risk factors. Patients with NIDDM who have hypertension or hyperlipidemia, or both, are more likely to develop cardiovascular disease no matter what their level of metabolic abnormality. In the Multiple Risk Factor Intervention Trial [11], the increased risk for cardiovascular disease caused by additional risk factors was arithmetic in patients without diabetes and multiplicative in patients with diabetes [11], which means that patients with diabetes and other cardiovascular risk factors need to be aggressively assessed and treated for hypertension and hyperlipidemia [12-14]. Additionally, as reviewed in the articles by Laakso (see “Glycemic Control and the Risk for Coronary Heart Disease in Patients with NIDDM: The Finnish Studies”) and Klein and colleagues (see “Relation of Glycemic Control to Diabetic Microvascular Complications in Diabetes Mellitus”) in this supplement, when hemoglobin A1c levels increase, so does the incidence of macrovascular disease.
Clinical trials in risk reduction have often excluded patients with diabetes. Although this rationale is logical from the perspective of the trials' designers, practicing clinicians must conclude that the benefits seen in these trial participants can also be expected for patients with NIDDM. We believe that this conclusion is warranted and recommend that hypertension and lipid guidelines and the use of aspirin prophylaxis [15] be vigorously addressed in patients with NIDDM.
Debate continues on the applicability of specific glycemic goals to various subsets of patients with NIDDM. The determining factor should be the outcome and side effects of hypoglycemic therapy in the individual patient. Perhaps the most important outcome of the Diabetes Control and Complications Trial (DCCT) [16] has been the determination that any decrease in hemoglobin A1 levels is beneficial [16]. Further, the more abnormal the level, the greater the net benefit for any given decrease in hemoglobin A1. Thus, a 1% decrease, for example, from 12% to 11%, decreases absolute risk more than does a decrease from 8% to 7%. Diabetic risk reduction, however, is the same regardless of the initial hemoglobin A1c level or therapeutic regimen (standard as compared with intensive DCCT treatment) and results in approximately a 40% reduction in risk for each 10% decrease in the hemoglobin A1c level.
The limitations of diet, exercise, and the currently available oral hypoglycemic therapies have been reported [17]; many, if not most, patients with NIDDM eventually require insulin therapy for metabolic control. These limitations are being reduced through introduction of new therapeutic agents with differing mechanisms of action. Metformin—which lowers hepatic glucose output and peripheral insulin resistance—was introduced to the American market last year, and acarbose—which interferes with intestinal carbohydrate absorption—was recently approved by the Food and Drug Administration and should be available in 1996 [18, 19]. Introduction of these agents raises the possibility of treating NIDDM with combined oral agents similar to the treatment of hypertension and hyperlipidemia. More recently, a new class of agents, the thiazolidinoliones, have entered clinical trials. These agents have a unique mechanism of action—they reduce insulin resistance. In preliminary studies, troglitazone reduced hypertension and hyperlipidemia in addition to reducing hyperglycemia [20, 21].
No current or planned European or North American studies directly address microvascular disease and neuropathy in NIDDM. However, a recently published report of an ongoing study from Japan is directly relevant [22]. The study followed patients with NIDDM who were receiving multiple insulin injections as compared with patients who were receiving a conventional insulin injection regimen for 6 years. Although the study was small, with 55 patients in each of four groups (control groups with and without baseline complications and experimental groups with and without baseline complications), it showed a decrease in the cumulative incidence or the progression of retinopathy, nephropathy, and neuropathy similar to that seen in the DCCT. The investigators concluded that there was a glycemic threshold for fasting blood glucose of 6.11 mmol/L (110 mg/dL) and a 2-hour postprandial blood glucose concentration of 10.0 mmol/L (180 mg/dL), which corresponded to a hemoglobin A1c level of 6.5% below which these complications did not progress. The results of this study are consistent with those predicted by both the DCCT and the data from Klein and coworkers (see “Relation of Glycemic Control to Diabetic Microvascular Complications in Diabetes Mellitus”). Thus, the scientific basis for lowering glycemia to prevent the specific complications of NIDDM is greatly enhanced by this controlled clinical trial.
The only current major trial on macrovascular disease in NIDDM is the United Kingdom Prospective Diabetes Study described by Dr. Turner in this supplement (see “United Kingdom Prospective Diabetes Study 17: A 9-Year Update of a Randomized, Controlled Trial on the Effect of Improved Metabolic Control on Complications in NIDDM”). The study addresses the question of whether current therapy reduces macrovascular or microvascular disease, or both (they are combined in the primary analysis), in NIDDM. However, the study may not address the question of prevention completely because the patients' hemoglobin A1 levels are increasing and may reach a point where even in the intensively treated group they are too high to answer unequivocally the primary prevention question. The Veterans Affairs trial discussed by Dr. Colwell (see “The Feasibility of Intensive Insulin Management in NIDDM: Implications of the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM”), if extended, would directly address that question, but its continuation depends on future funding. Another recently funded trial, the NIDDM Primary Prevention Trial, will address the question of whether early intervention in high-risk patients prevents the development of clinical NIDDM and will also study the effect of interventions on macrovascular disease and its risk factors.
Two other studies that should assist us in understanding current diabetes practices should be mentioned. The first is the Diabetes Patient Outcomes Research Team (PORT) study, directed by Dr. Sheldon Greenfield and funded by the Agency for Health Care Policy and Research. This 5-year observational study examines current diabetes practices and outcomes at three geographical sites. Preliminary data presented by Dr. Greenfield did not show an improvement in outcomes as of function of hemoglobin A1. We await further analysis and publication of those data. Also, the Health Care Finance Administration is initiating a large multisite study of diabetes care in their patient population in both health maintenance organization and fee-for-service sites (Fleming B. Personal communication).
Two other major questions need to be answered: Who will carry out this comprehensive care, and who will pay for it? Most patients with NIDDM are cared for by primary care physicians, a situation that is likely to continue. A collaborative model involving the expanded use of nurses, dietitians, diabetes educators, and subspecialist physician consultation for specific complications appears the most likely to develop, particularly under managed care. The DCCT used this approach with considerable success. Others have also described successful use of collaboration among health professionals, both generalists and specialists [23-25]. Dr. Harris and associates have published the second edition of Diabetes in America, a scholarly compendium of current diabetes morbidities, care practices, and costs [26]. Given the enormous cost of diabetes complications today, the benefit of comprehensive management should outweigh its cost in a relatively brief period.
A major new initiative to communicate the importance of comprehensive treatment of diabetes, particularly of NIDDM, has been the creation of the National Diabetes Education Program (NDEP). The NDEP, modeled on the National Hypertension and Cholesterol Education Programs, has as its goal the education of practitioners, patients, and the public as to the seriousness of diabetes and the measures that can be taken to reduce future complications. The program is jointly funded by the National Institutes of Health and the Centers for Disease Control and Prevention. The NDEP is anticipated to enlist the aid of professional, governmental, and lay organizations involved in diabetes care and policy to develop and disseminate data and guidelines that address the strategies for reducing diabetes complications.
Requests for Reqrints: Charles M. Clark, MD, Regenstrief Health Center, 1001 W. Tenth Street, 5th Floor, Indianapolis, IN 46202.
- Copyright ©2004 by the American College of Physicians
