Diabetes and Insulin Resistance

The criteria for the diagnosis of diabetes have been modified because evidence suggests that complications of hyperglycemia occur at plasma glucose levels below those previously used for diagnosis [1]. In the past, a fasting plasma glucose level of at least 140 mg/dL (7.71 mmol/L) was used as the general cutoff. This has been reduced to a level greater than 126 mg/dL (6.93 mmol/L). The diagnostic process is described in Table 1. Using this new guideline, the National Center for Health Statistics estimates that the prevalence of type 2 diabetes in the United States among adults 40 to 79 years of age is about 12.3%. Unfortunately, only about 50% of cases are diagnosed before end-organ damage occurs.

Troglitazone Improved Diabetes Control

Kumar S, Boulton AJ, Beck-Nielsen H, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia. 1996; 39:701-9.

Therapeutic options for patients with type 2 diabetes have exploded over the past 2 years. The most recently approved agent is troglitazone, an oral insulin-sensitizing agent. Troglitazone reduces insulin resistance and enhances insulin sensitivity by increasing insulin-dependent glucose disposal in skeletal muscle and decreasing hepatic glucose output.

Kumar and colleagues sought to determine the metabolic effects of troglitazone in patients with type 2 diabetes. In a 31-center clinical trial, 330 patients with fasting capillary blood glucose levels between 125 and 270 mg/dL (6.93 and 14.98 mmol/L) were randomly assigned to receive placebo or one of four troglitazone doses. All patients had been treated with diet therapy and oral antihyperglycemic agents, and therapy with the drugs was stopped 3 to 4 weeks before the study began. The major outcome was glycemic control, as measured by hemoglobin A_1c levels after 12 weeks of treatment.

Mean hemoglobin A_1c levels were 0.07 to 0.074 in the treated groups and 0.08 in the placebo group. Fasting glucose levels paralleled this difference. In addition, insulin sensitivity improved by about 30% in the patients treated with troglitazone, and triglyceride and nonesterified fatty acid concentrations decreased. No episodes of hypoglycemia occurred when troglitazone was used as monotherapy. In addition, the drug was not associated with weight gain, a common side effect of sulfonylurea agents.

No differences were noted in adverse events, although troglitazone was associated with some degree of neutropenia in about 20% of patients. Troglitazone has been associated with cardiac enlargement in animals, but there have been no reports of cardiac failure in humans. Since the drug became clinically available, at least 35 cases of liver failure have occurred among the 600 000 patients receiving troglitazone. This has prompted the U.S. Food and Drug Administration to advise physicians to monitor liver function test results.

Troglitazone should be taken with breakfast, starting at a dose of 200 mg; 400 mg is the usual maintenance dose. If insulin is required, the insulin dose can often be reduced by adding troglitazone. This is currently the major role of troglitazone. The Food and Drug Administration has approved the drug for use in patients with type 2 diabetes receiving insulin whose hemoglobin A_1c levels continue to be greater than 0.085.

Troglitazone is the latest option for the treatment of type 2 diabetes, but it is an expensive drug with unknown long-term effects. Thus, its precise role in treatment remains undetermined.

In 1998, the goals of treatment for type 2 diabetes remain unclear [2]. Some argue that the benefits of tight glucose control shown to occur in patients with type 1 diabetes are likely to apply to patients with type 2 diabetes [3]. Others cite a smaller, 27-month study that directly showed that tight glycemic control in patients with type 2 diabetes was associated with a 50% increase in the incidence of cardiovascular events [4]. An American Diabetes Association consensus paper suggested that a goal might be a hemoglobin A_1c level less than 0.07 and that therapeutic action should probably be taken with a hemoglobin A_1c level greater than 0.08 [5]. The issue may be settled later this year, when the United Kingdom Prospective Diabetes Study concludes. This study is carefully monitoring the association of glycemic control and clinical outcomes in patients with type 2 diabetes.

Whichever treatment goals are chosen, the cornerstone of treatment remains diet therapy. In obese patients, weight reduction is paramount to regaining metabolic control. Among leaner patients, diet is still critical to optimize control of hyperglycemia and hyperlipidemia. The American Diabetes Association now recommends that less than 10% of calories should come from saturated fats and that cholesterol intake should be limited to less than 300 mg/d. Fiber has received much attention, and the American Diabetes Association recommends that daily fiber intake be 20 to 35 g [2]. Because diets must be individualized and because compliance is probably less than 50%, diabetic patients will benefit from consultations with a registered dietitian.

Exercise, too, is part of every diabetic treatment plan. It helps maintain weight loss, improves glycemic control, reduces cardiovascular risks overall, and promotes general well-being. Optimal exercise should be aerobic (50% to 70% of maximal heart rate), last 20 to 45 minutes, and be done at least 3 times weekly [2].

The first-line drugs are still the sulfonylureas. Second-generation sulfonylureas are the most widely used, but their long half-lives need to be considered in patients prone to hypoglycemic episodes, especially elderly persons [6].

Metformin was approved for use in the United States in 1995 after being used in many other parts of the world for more than 20 years. Although the drug's mechanism of action is unclear, it reduces both fasting and postprandial glucose levels in diabetic patients (but not in euglycemic persons). It also reduces hepatic gluconeogenesis. Unlike the sulfonylureas and insulin, it does not promote weight gain. Taken with a sulfonylurea, it reduces hemoglobin A_1c levels by about 1% to 2%. The most common side effect, gastrointestinal discomfort, is dose related and tends to remit after several weeks. A rare but ominous adverse effect is lactic acidosis. As a result, metformin should not be given to patients with renal, hepatic, or major cardiovascular diseases or hypoxia because these patients have a predisposition to high lactate levels. Because radiologic dye can depress renal function, metformin therapy should be stopped at least 2 days before such radiologic studies are done.

Acarbose was approved for use early in 1996. It acts by tightly binding to the intestinal disaccharidase enzymes, thus competing with digestion of carbohydrates and sucrose. This drug decreases post-prandial hyperglycemia by 30% to 50%, but it reduces hemoglobin A_1c levels by only about 0.5% to 1%. Acarbose must be given with the first bite of a meal, and its side effects-such as flatulence from microbial digestion of the sugars not absorbed from the gut-are predictable.

Little information exists about the combination of troglitazone and metformin or about the sulfonylureas. Figure 1 shows a stepwise plan that summarizes a reasonable approach to therapy for type 2 diabetes.

View larger version (18K): [in this window] [in a new window]   Figure 1. Therapeutic approach to type 2 diabetes mellitus. * Typical goal would be a hemoglobin A1c level of 0.07 or less.

Troglitazone Altered Course in Polycystic Ovary Syndrome

Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996; 81:3299-306.

The polycystic ovary syndrome affects about 5% of premenopausal women [7]. Typical clinical characteristics include chronic anovulation, infertility, elevated plasma testosterone levels, hyperinsulinemia, obesity, and hirsutism. The cause of the syndrome is unknown, but patients typically show resistance to insulin's effects, and diabetes commonly develops.

Dunaif and colleagues hypothesized that insulin resistance may be one cause of the polycystic ovary syndrome. In a 3-month clinical trial, 25 women with this syndrome were randomly assigned to receive troglitazone, either 200 mg/d or 400 mg/d.

Dose-related decreases in insulin levels and improvement in hyperglycemia occurred with treatment. Perhaps more important, these changes were associated with significant decreases in levels of free testosterone and related hormones. Two of the 21 women who completed the study now also have ovulatory menses.

Dunaif and colleagues suggest that troglitazone may have a major role to play in the treatment of the polycystic ovary syndrome. However, because this study was small and had no placebo group, a more comprehensive trial is needed before troglitazone can be recommended for routine use in patients with this syndrome.

Hyperlipidemia

The deleterious effects associated with elevated serum LDL cholesterol levels are well known. The association of hypertriglyceridemia and atherosclerotic vascular disease has been controversial, however, and disagreement seems to be growing again. Fortunately, a single agent seems to be effective in both hypercholesterolemia and hypertriglyceridemia.

Atorvastatin Decreased Low-Density Lipoprotein Cholesterol and Triglyceride Levels

Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA. 1996; 275:128-33.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors-the "statins"-have been shown to reduce both the incidence of acute coronary artery events and overall mortality rates. Studies have shown that pravastatin is effective in primary prevention [8] and that simvastatin is effective in secondary prevention [9]. In 1995, the newest agent, atorvastatin, was shown to reduce LDL cholesterol levels by as much as 46% [10].

The question of whether hypertriglyceridemia is an independent risk factor for atherogenic vascular disease remains unanswered. However, many diseases that are associated with hypertriglyceridemia are also associated with vascular disease, including diabetes mellitus, chronic renal disease, and some primary lipid disorders [11].

Bakker-Arkema and colleagues assessed the effect of atorvastatin on levels of triglycerides and lipoprotein fractions in patients with primary hypertriglyceridemia. They also sought to determine whether decreasing triglyceride levels would result in a redistribution of various lipoprotein fractions.

In a clinical trial, 56 patients with fasting hypertriglyceridemia (mean triglyceride level, 603 mg/dL [6.80 mmol/L]) were randomly assigned to receive either placebo or one of three atorvastatin regimens (5, 20, or 80 mg). All patients were also prescribed a cholesterol-lowering diet and were followed for 4 weeks while receiving the combined drug and diet regimens. Results are shown in Table 2. Maximal reduction in triglyceride levels was observed by week 2. Changes in LDL and very low-density lipoprotein cholesterol triglyceride levels were similar; this finding indicates that triglyceride levels were not decreased at the expense of elevated lipoprotein levels.

Atorvastatin is approved as an adjunct to diet in patients with hypercholesterolemia to reduce elevated cholesterol and triglyceride levels. It is also useful in patients who are homozygous for familial hypercholesterolemia; these patients have no LDL receptor activity. Atorvastatin, with a starting dose of 10 mg, can be administered once a day with or without meals. Figure 2 compares the performance of the drug with that of other HMG-CoA reductase inhibitors, as reported by the manufacturers.

View larger version (25K): [in this window] [in a new window]   Figure 2. Comparison of effects of four HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors.

In summary, atorvastatin produces a strong, dose-dependent, rapid reduction in LDL cholesterol and triglyceride levels.

Human Growth Hormone

Human growth hormone has been used to increase height in children with growth hormone deficiency, and there is increasing interest in the use of growth hormone in adults. Some have supported its use to maintain metabolic function in elderly persons because levels of circulating growth hormone decline with advancing age. But more attention has recently been given to the hormone's anabolic effect on various wasting syndromes and to its use in adults with pituitary disease.

AIDS-Associated Wasting Was Blunted

Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med. 1996; 125:873-82.

Body wasting is highly prevalent among patients with AIDS and probably results from several factors, including viral infection, intercurrent infections, tissue cytokines, and poor caloric intake. Wasting is an important clinical problem in patients with AIDS, both because it compromises quality of life and because it is an independent risk factor for death. Short-term treatment with growth hormone has shown promise both in patients with AIDS and in persons with other major stressors, such as surgery and trauma.

Schambelan and colleagues evaluated the long-term effect of treatment with human growth hormone in patients with HIV-associated wasting. In a clinical trial, they randomly assigned 178 patients to receive injections of either recombinant human growth hormone, 0.1 mg/kg of body weight per day (mean dosage, 6 mg/d), or placebo for 12 weeks. Among the major outcomes measured were weight, body fat, lean body mass, work output, quality of life, and safety of treatment.

Patients receiving growth hormone gained mean (±SD) of 1.7 ± 3.7 kg, compared with a 0.1 ± 3.1 kg increase in those receiving placebo. Lean body mass increased similarly and body fat decreased in patients in the treatment group compared with those in the placebo group. At 12 weeks, all three outcomes were beyond the limits of generally recognized statistical significance. Work output improved more among patients receiving growth hormone, but quality-of-life scores did not differ between the groups. Days of disability and use of medical resources were also similar for both groups. Growth hormone did not seem to affect clinical progression of AIDS, lymphocyte counts, or viral burden. Common adverse effects were edema, arthralgia, and diarrhea. Treatment did not affect glucose or hemoglobin A_1c levels.

Human growth hormone seems to be metabolically active in patients with HIV-associated wasting. However, therapy costs at least $40 000 a year. There is also a theoretical concern, especially in patients with HIV, about a tumor-promoting effect of the growth hormone, although no tumors occurred in this 12-week study.

Responses Were Reported in Adults with Hypopituitary Diseases

Baum HB, Biller BM, Finkelstein JS, et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann Intern Med. 1996; 125:883-90.

In contrast to children with growth hormone deficiency, patients with adult-onset growth hormone deficiency generally have not received replacement therapy. Patients with hypopituitarism are typically given glucocorticoid, thyroid, and gonadal hormone replacement. However, some patients with hypopituitarism have reduced bone density and increased fat mass.

Baum and colleagues sought to determine whether long-term growth hormone therapy at a physiologic dose-one adjusted to maintain normal insulin-like growth factor 1 levels-has clinical effects in patients with adult-onset growth hormone deficiency. They recruited 32 men with adult-onset growth hormone deficiency caused by pituitary disease not due to malignancy. The patients were randomly assigned to receive growth hormone or placebo. Growth hormone therapy was initiated at 0.01 mg/kg, and the dose was decreased by 25% if insulin-like growth factor 1 levels increased. Primary outcome variables were body composition and bone density of the lumbar spine, femoral neck, and radius.

Over a period of 18 months, the growth hormone group had 5% increases in mean bone density of the lumbar spine and 2.4% increases in bone density of the femoral neck. In the placebo group, lumbar spine density did not change and femoral neck density decreased by 1.5%. Biochemical markers of bone metabolism paralleled these changes. Body fat decreased by about 13% in the treated group and by about 7% in the placebo group. Lean body mass increased 5% and 3%, respectively. Fasting glucose levels increased slightly in the growth hormone group, but hemoglobin A_1c levels did not. Cardiac function also did not change.

In patients with adult-onset growth hormone deficiency, replacement therapy increased bone density at two skeletal sites and increased lean body mass. However, long-term outcomes, such as rates of fracture and death, remain unknown. Longer and larger studies in both women and men need to be done before clinical practice is changed.

Baum and colleagues' attempt to deliver physiologic doses of growth hormone by titrating doses on the basis of serum insulin-like growth factor 1 levels was intriguing. If these levels were high, growth hormone dose was decreased. The authors also reported fewer adverse events than occurred in Schambelan and colleagues' study of growth hormone therapy in HIV-infected patients, in which doses were standardized. However, both studies showed that sodium retention and edema can be problems.

Despite the excitement over growth hormone treatment, many questions remain unanswered. It still is unclear which patients, if any, will gain meaningful clinical benefit from long-term therapy. This uncertainty is complicated by the drug's extremely high cost.

Bone Disease

The bisphosphonates have substantially changed the approach to the prevention and treatment of bone diseases. It is now clear that the clinical morbidity of osteoporosis can be mitigated with alendronate. Paget disease of bone also seems to respond favorably to this agent.

Alendronate Generally Reduced the Incidence of Fractures

Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996; 348:1535-41.

Alendronate, available in the United States since 1995, has been shown to decrease the risk for vertebral fractures in women with osteoporosis. The drug has also been shown to increase bone mineral density throughout the body [12]. However, previous studies have had insufficient statistical power to determine whether alendronate has a significant effect on fractures other than radiologically evident vertebral fractures.

Black and colleagues enrolled 2027 women who had low femoral bone density in a multicenter randomized trial. The women received either placebo or alendronate, 10 mg/d, and were followed for 36 months. The primary study end point was the effect on vertebral fractures. Eight percent of the women receiving alendronate had radiologically evident vertebral fractures compared with 15% of those receiving placebo (number needed to treat for 3 years to prevent one fracture, 14).

However, a more important finding was a secondary outcome: Fewer nonvertebral fractures occurred in women receiving alendronate (Table 3).

Adverse effects, especially erosive esophagitis, have been worrisome for many clinicians, but these authors showed no differences in adverse effects between groups. More than 500 000 patients have received prescriptions for alendronate. Although the manufacturer has issued warnings about the risk for esophagitis, a worldwide review found only 51 serious episodes among 475 000 patients taking the drug (number needed to harm, approximately 9000) [13, 14]. Most patients noted symptoms within 2 months of beginning treatment, and more than half, despite instructions, had taken alendronate with little or no water. In all, about 61% of the patients who developed esophagitis in this postmarketing study had taken the drug incorrectly. Although alendronate can cause serious gastrointestinal side effects, these effects seem to be unusual and can generally be avoided with instruction and compliance with these instructions: The drug should be taken with at least 8 ounces of water, and patients should not lie down within 30 minutes of taking the drug or until they have consumed food for the first time that day. If a patient has a preexisting esophageal disorder, alendronate either should not be used or should be given with close monitoring.

A major question is whether alendronate affects the progression of osteoporosis caused by pharmacologic doses of glucocorticoids. No clinical trial results on this subject have yet been published, but some trials are in progress. At this point, it seems prudent to consider alendronate treatment (along with gonadal hormone replacement) for patients who have low bone density and must continue to receive glucocorticoids.

Alendronate Was More Effective in Paget Disease

Siris E, Weinstein RS, Altman R, et al. Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. J Clin Endocrinol Metab. 1996; 81:961-7.

Paget disease of bone (osteitis deformans) is a chronic progressive disease that affects about 3% of persons older than 50 years of age. In a substantial proportion of patients, it causes deep bone pain. It can also lead to kyphosis, a propensity to fractures, hypercalcemia, high-output congestive heart failure, deafness, and renal stones. In about 2% of patients, Paget disease lesions may undergo sarcomatous changes.

One mainstay of treatment has been the bisphosphonates, especially etidronate. In higher doses, etidronate is associated with osteomalacia. Alendronate is more potent than etidronate in inhibiting osteoclast-mediated bone resorption, and it is not associated with abnormal mineralization.

Siris and colleagues compared the clinical efficacy of etidronate and alendronate. They recruited 89 patients with clinical Paget disease and randomly assigned them to receive either etidronate (400 mg/d) or alendronate (40 mg/d). Follow-up lasted 6 months. Primary outcomes were changes in serum alkaline phosphatase levels; other variables included pain and functional impairment scores.

Alkaline phosphatase levels returned to normal in 63% of patients receiving alendronate compared with 17% of those receiving etidronate. Pain decreased in the alendronate group but increased in the etidronate group; neither change, however, reached the generally accepted level of statistical significance. The two drugs were well tolerated. Histomorphometric analyses of bone showed no negative effects of alendronate treatment. Osteomalacia developed in one etidronate recipient.

Thus, this small study suggests that alendronate is at least as effective as, and probably more effective than, etidronate for the treatment of Paget disease. The costs of the two drugs are similar.

Estrogen Increased Bone Density

Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. The Writing Group for the PEPI Trial. JAMA. 1996; 276:1389-96.

Alendronate is being used with increasing frequency, but estrogen remains the primary therapy for postmenopausal osteoporosis, which is defined as bone density that is at least 2 SDs below a reference mean. Yet much remains unknown about how estrogen affects bone density. It is not clear whether estrogen simply slows the loss of bone, whether it maintains bone density, or whether it actually increases it. If estrogen could be shown to increase bone density, the consensus to recommend it would be further solidified.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was designed to assess the effects of various estrogen-containing regimens on heart disease. The investigators also assessed the effects on bone density. This 3-year, multicenter trial involved 875 women between 45 and 64 years of age. The regimens and results are shown in Table 4. In general, according to an intention-to-treat analysis, women taking the combined estrogen-medroxy-progesterone daily had the best outcomes. (They also had the lowest dropout rates [22%].) Older women, women with initially low bone mineral density, and those who had not previously received hormone therapy had relatively better outcomes. No major differences were seen in the total number of fractures.

This is the largest completed clinical trial of the effects of estrogen and progesterone on spinal and hip bone density in postmenopausal women. Several conclusions can be drawn. First, the average bone density of the spine and the hip was increased with 3-year use of estrogen. This is in contrast to what many had believed-that estrogen simply retarded bone loss. Second, a daily combined estrogen-progesterone agent was tolerated best. Third, in the analysis of women who adhered to the regimens, combined estrogen-progesterone therapy provided no added benefit over unopposed estrogen therapy, but the combined regimen was also not less effective than unopposed estrogen. Finally, among the patients who adhered to therapy, only age, initial bone density, and previous hormone use influenced the effect of hormone therapy on bone density. The other factors that clinicians often care about-smoking, alcohol use, and calcium intake-did not modify the effect of estrogen on change in bone density.

This study also had limitations. First and most important, the participants were too young and the follow-up was too short for the researchers to observe an effect on fracture rate. Second, only one estrogen dose was tested, and one might wonder whether smaller doses might be as effective.

In summary, the finding that estrogen seems to actually increase bone density in postmenopausal women will help in efforts to decrease the prevalence of osteoporosis and the major morbidity associated with it.

Estrogen and alendronate, along with appropriate calcium intake, are the most efficacious drugs currently available for preventing and treating osteoporosis. Evidence is beginning to accumulate that alendronate (with dietary calcium) may be effective preventive therapy if the patient cannot take estrogen. Some clinicians have also considered calcitonin therapy, but calcitonin has not been shown to be as efficacious as estrogen and bisphosphonates in increasing bone mass, decreasing bone loss, or preventing fractures. Calcitonin can mitigate the pain associated with vertebral compression fractures, but when given as a nasal spray can irritate the nasal mucosa. Etidronate, given in cycles every few months, has also been shown to be less effective than alendronate in preventing fractures.

Estrogen Was Not Associated with Weight Gain

Kritz-Silverstein D, Barrett-Connor E. Long-term postmenopausal hormone use, obesity, and fat distribution in older women. JAMA. 1996; 275:46-9.

A major concern among postmenopausal women considering estrogen therapy is whether this therapy will cause weight gain. Previous studies of such an association have had mixed results, but it is a common perception that estrogen induces weight gain.

Kritz-Silverstein and Barrett-Connor performed a 15-year prospective, cross-sectional cohort study to examine the association of long-term estrogen use with obesity, fat distribution, and body composition in older women. Between 1972 and 1974, 82% of the adult residents of Rancho Bernardo, a predominately white, upper-middle-class southern California community, were surveyed to determine the prevalence of risk factors for heart disease. Participants were 671 women aged 65 to 94 years who participated in the initial study between 1972 and 1974 and attended a clinic visit between 1988 and 1991. Height and body weight were recorded at the beginning and end of the study. Of the women, 194 had never used hormone replacement therapy, 331 had used hormones intermittently, and 146 had used hormones continually for 15 years.

At baseline, women who had intermittently and continually used hormones had lower mean body mass index scores than women who had never used hormone replacement therapy. After 15 years, no differences were seen in weight change, body mass index change, waist-to-hip ratio, or fat mass between women who used estrogen and those who did not.

The authors conclude that hormone replacement therapy, whether used intermittently or continually for 15 or more years, is not associated with weight gain or central obesity. However, the results of this study must be interpreted with caution. Because the study was not randomized, there is a serious risk for self-selection. Furthermore, the study was done in a white, relatively affluent community, and the results may not be generalizable to other ethnic and socioeconomic groups.

Dr. Kreisberg: Department of Internal Medicine, Baptist Health System, 800 Montclair Road, Birmingham, AL 35213.

Dr. Roberts (Series Editor): Madrona Medical Group, 4370 Cordata Parkway, Bellingham, WA 98226-8075.