Richard C. Eastman

Model of Complications of NIDDM: II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia

OBJECTIVE To analyze the health benefits and economics of treating NIDDM with the goal of normoglycemia. RESEARCH DESIGN AND METHODS Incidence-based simulation model of NIDDM was used. Hazard rates for complications were adjusted for glycemia using risk gradients from the Diabetes Control and Complications Trial. Treatment costs were estimated from national survey data and clinical trials. Incremental costs and benefits were expressed in present value dollars (3% discount rate). Life-years were adjusted for quality of life, yielding quality-adjusted life-years (QALYs). RESULTS Comprehensive treatment of NIDDM that maintains an HbA1c value of 7.2% is predicted to reduce the cumulative incidence of blindness, end-stage renal disease, and lower-extremity amputation by 72, 87, and 67%, respectively. Cardiovascular disease risk increased by 3% (no effect of treating glycemia is assumed). Life expectancy increased 1.39 years. The cost of treating hyperglycemia increased by almost twofold, which is partially offset by reductions in the cost of complications. The estimated incremental cost/QALY gained is

Comparison of Diabetes Diagnostic Categories in the U.S. Population According to 1997 American Diabetes Association and 1980–1985 World Health Organization Diagnostic Criteria

16,002. Treatment is more cost-effective for those with longer glycemic exposure (earlier onset of diabetes), minorities, and those with higher HbA1c under standard care. CONCLUSIONS The incremental effectiveness of treating NIDDM with the goal of normoglycemia is estimated to be ∼

Early detection of undiagnosed diabetes mellitus: a US perspective.

16,000/QALY gained, which is in the range of interventions that are generally considered cost-effective.

Drug-resistant malaria: Molecular mechanisms and implications for public health

OBJECTIVE To compare the 1997 American Diabetes Association (ADA) and the 1980–1985 World Health Organization (WHO) diagnostic criteria in categorization of the diabetes diagnostic status of adults in the U.S. RESEARCH DESIGN AND METHODS Analyses are based on a probability sample of the U.S. population age 40–74 years in the 1988–1994 Third National Health and Nutrition Examination Survey (NHANES III). People with diabetes diagnosed before the survey were identified by questionnaire. For 2,844 people without diagnosed diabetes, fasting plasma glucose was obtained after an overnight 9 to < 24-h fast, HbA1c was measured, and a 2-h oral glucose tolerance test was administered. RESULTS Prevalence of diagnosed diabetes in this age-group is 7.9%. Prevalence of undiagnosed diabetes is 4.4% by ADA criteria and 6.4% by WHO criteria. The net change of −2.0% occurs because 1.0% are classified as having undiagnosed diabetes by ADA criteria but have impaired or normal glucose tolerance by WHO criteria, and 3.0% are classified as having impaired fasting glucose or normal fasting glucose by ADA criteria but have undiagnosed diabetes by WHO criteria. Prevalence of impaired fasting glucose is 10.1% (ADA), compared with 15.6% for impaired glucose tolerance (WHO). For those with undiagnosed diabetes by ADA criteria, 62.1% are above the normal range for HbA1c compared with 47.1% by WHO criteria. Mean HbA1c is 7.07% for undiagnosed diabetes by ADA criteria and 6.58% by WHO criteria. CONCLUSIONS The number of people with undiagnosed diabetes by ADA criteria is lower than that by WHO criteria. However, those individuals classified by ADA criteria are more hyperglycemic, with higher HbA1c values and a greater proportion of values above the normal range. This fact, together with the simplicity of obtaining a fasting plasma glucose value, may result in the detection of a greater proportion of people with undiagnosed diabetes in clinical practice using the new ADA diagnostic criteria.

Symptoms of Sensory Neuropathy in Adults with NIDDM in the U.S. Population

Undiagnosed Type 2 diabetes has become a common condition in the US, comprising one‐third of all cases of the disease. We believe that screening for and detection of undiagnosed Type 2 diabetes is an important endeavor. In this review we provide evidence that diabetes is a condition that is appropriate for population screening and detection. This includes evidence that: 1 Type 2 diabetes is a significant health problem. It affects more than 16 million adults in the US and places these individuals at high risk for serious complications of the eyes, nerves, kidneys, and cardiovascular system. 2 There is a latent phase before diagnosis of Type 2 diabetes. During this period of undiagnosed disease, risk factors for diabetic micro‐ and macrovascular complications are markedly elevated and diabetic complications are developing. 3 Diagnostic criteria for diabetes have been established and are based on plasma glucose values. These criteria define a group of individuals with significant hyperglycemia who also have a high frequency of risk factors for micro‐ and macrovascular disease. 4 The natural history of Type 2 diabetes is understood. In most patients, diabetes proceeds inexorably from genetic predisposition, through the stage of insulin resistance and hyperinsulinemia, to beta cell failure and overt clinical disease. 5 There are effective and acceptable therapies available for Type 2 diabetes and its complications. Treating hyperglycemia to prevent complications is more effective than treating these complications after they have developed. Furthermore, guidelines for treatment to prevent cardiovascular disease in people known to have diabetes are more stringent than in those individuals who are not known to have diabetes. 6 There is a suitable test for screening for undiagnosed Type 2 diabetes that has high sensitivity and specificity – measurement of fasting plasma glucose. Guidelines for identifying persons at high risk for diabetes have been established. Copyright

Acanthosis nigricans in Obese Women with Hyperandrogenism: Characterization of an Insulin-Resistant State Distinct from the Type A and B Syndromes

Resistance to antimalarial drugs has often threatened malaria elimination efforts and historically has led to the short‐term resurgence of malaria incidences and deaths. With concentrated malaria eradication efforts currently underway, monitoring drug resistance in clinical settings complemented by in vitro drug susceptibility assays and analysis of resistance markers, becomes critical to the implementation of an effective antimalarial drug policy. Understanding of the factors, which lead to the development and spread of drug resistance, is necessary to design optimal prevention and treatment strategies. This review attempts to summarize the unique factors presented by malarial parasites that lead to the emergence and spread of drug resistance, and gives an overview of known resistance mechanisms to currently used antimalarial drugs.

The Effects of Treatment on the Direct Costs of Diabetes

OBJECTIVE To ascertain the prevalence and determinants of sensory neuropathy symptoms through structured interview of a representative sample of people with diabetes in the U.S. population. RESEARCH DESIGN AND METHODS The 1989 National Health Interview Survey consisted of a representative sample of 84,572 persons in the U.S. ≥ 18 yr of age. A household respondent identified all people in the household believed to have diabetes (n = 2829). Subjects who could not be personally interviewed (n = 129) and individuals who stated they did not have diabetes (n = 295) were excluded. A detailed questionnaire was administered to 99.3% of the remaining 2405 subjects. Questions on symptoms of sensory neuropathy included whether during the past 3 mo the subjects had experienced numbness or loss of feeling, pain or tingling, or decreased ability to feel hot or cold. The neuropathy questions were also administered to a representative sample of 20,037 subjects who were not known to have diabetes. RESULTS Prevalence of symptoms of sensory neuropathy was 30.2% among people with IDDM. This prevalence was 36.0% for men with NIDDM and 39.8% for women with NIDDM, compared with 9.8 and 11.8% for nondiabetic men and women, respectively. In logistic regression, factors independently related to symptoms of sensory neuropathy in people with NIDDM included duration of diabetes, hypertension, hyperglycemia, and glycosuria. Long duration of NIDDM (>20 yr) was associated with a twofold increased risk of symptoms of sensory neuropathy compared with those with 0-4 yr of diabetes. Hypertension was associated with a 60% higher likelihood of symptoms. Diabetic individuals whose blood glucose was high all or most of the time or whose urine tests showed glucose all of the time were > 2 times as likely to have symptoms of sensory neuropathy than those who did not report hyperglycemia or glycosuria. Age, sex, ethnicity, cigarette smoking, and height were not determinants of sensory neuropathy. CONCLUSIONS Symptoms of sensory neuropathy affect 30–40% of diabetic patients in the U.S. Men and women are affected equally. Prevalence of these symptoms increases with longer duration of diabetes; hypertension and hyperglycemia predispose to symptoms of sensory neuropathy.

Non-Insulin-Mediated Glucose Disappearance in Subjects With IDDM: Discordance Between Experimental Results and Minimal Model Analysis

Acanthosis nigricans and hyperandrogenism are commonly found in patients with extreme target cell resistance to insulin, as in the type A and B syndromes of insulin resistance. However, the significance of concurrent acanthosis nigricans and hyperandrogenism in other clinical settings is not clear. We observed acanthosis nigricans to be present in 5% (15 of 300) of patients being evaluated for hyperandrogenism, and carried out studies of insulin binding and action in a group (7) of these women. Although none were diabetic, all were insulin resistant as assessed by hyperinsulinemia when fasting and after oral glucose administration. All patients were obese (mean IBW, 169%). However, when matched to hyperandrogenized women of similar body weight, patients with acanthosis nigricans were clearly more hyperinsulinemic. Insulin binding to monocytes and red cells was decreased in patients with acanthosis, and the extent of decrease was predicted by the fasting insulin level. There was also marked resistance to exogenous insulin during euglycemic insulin clamp studies in the two patients so tested. Anti-insulin receptor antibodies were not detectable, ruling out the type B syndrome. Unlike the type A syndrome, insulin binding to monocytes of these patients increased after acute (2/2) and chronic (1/1) caloric restriction. In the latter patient, acanthosi nigricans remitted as insulin resistance and the insulin binding defect improved. We conclude that acanthosis nigricans is present in as many as 5% of women with clinically significant hyperandrogenism. These women, although not diabetic, have fairly marked insulin resistance. Despite a number of clinical similarities to patients with the type A and B syndromes, the insulin resistance of these women seems more likely to be a consequence of their obesity, and caloric restriction would appear to be the most appropriate therapy. The basis for apparent interrelationships between insulin, androgens, and acanthosis nigricans in these and other patients is discussed.

Specificity spillover at the hormone receptor exploring its role in human disease

Treatment of diabetic complications consumes health care resources. Intensive therapy was shown by the Diabetes Control and Complications Trial (DCCT) to avert complications. Economic analyses and models have been used to evaluate the cost-effectiveness of intensive therapy for people with type 1 and type 2 diabetes. An economic analysis of the DCCT estimated the cost of intensive therapy to be two to three times greater than that of conventional therapy. In contrast, an economic model predicts that intensive therapy, as compared with conventional therapy, could reduce blindness from 34 to 20% or by 41%, end-stage renal disease from 24 to 7% or by 71%, and lower-extremity amputations from 7 to 4% or by 43%. Although intensive therapy is more expensive, when the costs of complications are factored in, it becomes cost-effective for treatment of type 1 diabetes. Similarly, a model to evaluate the cost-effectiveness of intensive therapy for people with type 2 diabetes found that the lifetime costs of general and diabetes-related medical care would be approximately two times greater. However, the reduction in lifetime costs of complications, which would produce substantial reductions in costs of treatment, largely offsets the difference. Intensive therapy for type 1 and type 2 diabetes may be more expensive than conventional therapy, but from an economic perspective, it is comparable in cost to pharmacological therapies for people with hypertension and hypercholesterolemia. From a health system viewpoint, intensive therapy represents a fruitful long-term financial investment.

Receptors for Peptide Hormones: New Insights into the Pathophysiology of Disease States in Man

Both insulin and glucose contribute to the regulation of glucose metabolism in vivo. We directly measured the ability of glucose per se to promote glucose disposal in subjects with insulin-dependent diabetes mellitus (IDDM). We compared our results with predictions of the minimal model of glucose metabolism. To identify minimal model parameters, a frequently sampled intravenous glucose tolerance test (FSIVGTT) was administered to each subject while they were connected to a Biostator (a device that monitors blood glucose and gives insulin to mimic normal insulin secretion). Data from this test reflected normal glucose tolerance and were in excellent agreement with minimal model predictions. The FSIVGTT was then repeated without the Biostator in the same diabetic subjects in order to directly measure the effect of glucose per se to promote glucose disposal in the absence of an incremental insulin effect (a basal insulin drip was maintained). To compare these results with minimal model predictions, the equations describing glucose disappearance in the absence of an incremental insulin effect were solved using parameters identified from the Biostator experiment. The glucose disappearance measured in the absence of an incremental insulin response was much slower than the minimal model predictions. Thus, the minimal model appears to overestimate the effect of glucose per se on glucose uptake and underestimate the contribution of incremental insulin.