Safety and efficacy of metformin in a restricted formulary.

OBJECTIVE: To assess the efficacy and safety of metformin (MET) in the Veterans' Administration Northern California Health Care System during the period from June 1995 through April 1996 when its use required approval by Endocrinology. STUDY DESIGN: A retrospective review of patient charts and computerized pharmacy and laboratory records. Patients served as their own historical controls. PATIENTS AND METHODS: Patients receiving MET (n = 251) were identified from the pharmacy database. On-line laboratory data, including the intermediate outcome variable HbA1c, were retrieved by computer for the interval 4 months prior to the initial prescription to May 1996. Clinical data including weight and blood pressure were obtained from chart review. RESULTS: Of 228 patients whose charts were available for review, 29 reported side effects, and 12 discontinued use due to these side effects. No patients were identified with lactic acidosis. Both baseline and treatment data on HbA1c were available on 164 patients. Mean HbA1c (%) data (unpaired), expressed as mean +/- SE, were as follows: between 4 months pretreatment and 1 month pretreatment, 9.41 +/- 0.19 (n = 103 tests); between 1 month pretreatment and baseline, 9.41 +/- 0.19 (n = 110 tests); 3 months of treatment, 8.79 +/- 0.16 (n = 157 tests, P < 0.05); 6 months of treatment, 8.30 +/- 0.17 (n = 79 tests, P < 0.0001); 9 months of treatment, 8.72 +/- 0.24 (n = 70 tests, P < 0.05), compared to pretreatment values. Similar analysis of unpaired weight and blood pressure data in 152 patients did not reveal any reduction in these clinical parameters over this treatment period. Serum lipids were unchanged on treatment (by paired analysis), but the number of tests was limited. CONCLUSION: In this setting, MET provided sustained beneficial effects on glycemic control and was well tolerated. Any effects on weight, blood pressure, and serum lipids were not demonstrable in this analysis. We conclude that MET can substantially improve outcome of diabetes care.

Postmarketing analysis of lovastatin use in the VA Northern California System of Clinics: a retrospective, computer-based study.

Prevention of coronary heart disease is a major public health goal. The efficacy of lovastatin in lowering serum cholesterol has been proven in research studies, but its efficacy in practice is unclear. To evaluate our practice patterns and outcome in the Veterans Administration Northern California System of Clinics, we reviewed computer-based records of 203 unselected patients issued lovastatin; 193 (95%) were men, and the average patient age was 66 +/- 9 years. The average daily dose of lovastatin was 24 +/- 10 mg, and average duration of therapy was 22 +/- 11 months. Only 72 patients (35%) were instructed on the prescription to take their medication with the evening meal, and only 59 patients (29%) had seen a dietitian during the observed (1 to 3 years) treatment period. Nevertheless, among the 124 patients with pretreatment lipid data, total serum cholesterol decreased by 18% from 271 +/- 45 to 221 +/- 41 mg/dL (P < 0.001), and low density lipoprotein (LDL)-cholesterol decreased by 23% from 185 +/- 43 to 143 +/- 37 (P < 0.001) mg/dL. High density lipoprotein-cholesterol and triglycerides were unchanged. Of the 168 patients with LDL-cholesterol data during the treatment period, only 74 (44%) achieved an LDL-cholesterol level of less than 130 mg/dL, the minimum goal for a population of older males with a high incidence of other cardiac risk factors. Safety surveillance with liver function testing was performed at least once in 192 patients (95%), but with creatine phosphokinase (CPK) testing in only 123 patients (61%) during the survey period. Enzyme elevations were minor, but occurred at least intermittently in approximately one quarter of patients. Only 5.7% of patients on lovastatin manifested an increase in transaminases on therapy. Due to incomplete baseline data, it is unclear how many patients had elevated CPK as a result of lovastatin. We conclude that: (1) lovastatin is effective in lowering total and LDL-cholesterol in practice, but is often used in dosage insufficient to lower LDL-cholesterol to goal levels; (2) patients are not being adequately educated on dosing schedules; (3) toxicity may be underestimated by infrequent and inconsistent surveillance; and (4) nonpharmacologic therapy is underutilized.

Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia.

Adrenal glands from a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol secretion in a dose-response manner in the absence of ACTH. Since immunoglobulins G from this patient did not stimulate corticosterone production in a mouse adrenal bioassay, an adrenal-stimulating immunoglobulin is unlikely to be the cause of adrenal hyperfunction in this case. This is the first description of estradiol stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome.

Diabetic nephropathy: hemodynamic basis and implications for disease management.

New evidence shows that systemic and intrarenal hemodynamic abnormalities are major factors in the initiation and progression of diabetic nephropathy. Genetic predisposition to elevated systemic blood pressure may contribute to its development. Glomerular vasodilation and hyperfiltration, mediated in part by prostaglandins, may play a role in glomerular damage early in the course of diabetes, but clinical studies are limited. The development of more sensitive assays for albuminuria now allows early diagnosis of incipient nephropathy in the "microalbuminuria" phase. Treatment during this phase with antihypertensive agents, including angiotensin-converting enzyme inhibitors, or with dietary protein restriction, can decrease the degree of albuminuria, but data on their long-term effects on disease progression are limited. In hypertensive patients with established clinical diabetic nephropathy characterized by proteinuria in excess of 0.3 to 0.5 g/d, antihypertensive therapy has a major impact on delaying renal failure. Modalities that lower both systemic and intraglomerular pressure may be more beneficial in preserving renal function than those that primarily lower systemic pressure. Any therapeutic intervention should be monitored meticulously to establish its efficacy and safety in the individual patient. Therapy specifically directed against hemodynamic abnormalities throughout the course of diabetic renal disease may significantly delay and decrease the negative impact of this diabetic complication on survival and quality of life.

University of California, Davis, conference: Mild hypertension.

Prevalence of "higher than normal" blood pressures in a community is inversely related to the magnitude of the elevation; the milder grades of elevation are far more prevalent. A multifactorially inherited tendency to develop hypertension is modulated by multiple environmental influences. Autonomic nervous and behavioral factors plausibly appear to contribute to the initiating mechanisms of hypertension; the associated hemodynamic changes and the resulting cardiovascular structural changes interact to perpetuate the process. The complex interaction of hypertension and atherosclerosis is further complicated by direct as well as secondary effects of antihypertensive drugs on atherogenesis. Attributable cardiovascular risk is generally proportional to the degree of hypertension across the entire range of elevated blood pressure; this kind of relationship holds also for normal versus subnormal blood pressure values. Pharmacologic lowering of blood pressure, however, does not confer proportional benefit. Thus, such lowering of blood pressure to normotensive levels does not reduce the risk level to that in the normotensive population. Therapeutic outcome is influenced by the interaction of blood pressure lowering, type of antihypertensive agents used, existing risk factors, and target organ damage. Benefits of lowering blood pressure in established mild hypertension (diastolic blood pressure greater than 95 mm Hg) are confirmed. Drug treatment of patients with lower diastolic blood pressure or with isolated elevations of systolic blood pressures continues to be controversial as does the choice of initial therapeutic agent(s). The large-scale experience of clinical trials encompassing the long-term risks and benefits of the drug treatment of mild hypertension is limited to the use of diuretics and adrenergic beta blockers. A variety of new and promising therapeutic agents for use as alternate choices for initial therapy needs to undergo comparative evaluation.

Primary hyperaldosteronism.

Primary hyperaldosteronism is a challenging diagnosis because of its low incidence and variable pathophysiology. Serum potassium, properly done, is the routine screening test, but is not without its limitations. Confirmation of the diagnosis requires demonstration of abnormally high and nonsuppressible values for aldosterone in plasma and urine and low plasma renin activity. Sophisticated biochemical profiling and localization procedures often are required to identify those subtypes that will benefit from surgical management, including aldosterone-producing adenomas, primary adrenal hyperplasia, unilateral hyperplasia, and aldosterone-producing renin responsive adenomas. Glucocorticoid-suppressible hyperaldosteronism and isolated aldosterone-producing adrenal carcinoma are rare additional subtypes to be identified. Differentiation among these subtypes is a developing process that can be expected to continue to improve with new techniques and new understanding of underlying pathophysiology.

Age and the endocrine system.

The pattern of age-induced changes in each endocrine system is unique. Both hormone levels and target organ responsivity are altered in the aging endocrine-cardiovascular system. Serum levels of vasopressor hormones both increase (norepinephrine) and decrease (renin, aldosterone). Target organ responses to beta-adrenergic stimulation in the heart and probably also in vascular smooth muscle decrease due to postreceptor changes. These effects contribute to the clinical problems of hypertension and orthostatic hypotension which characterize the elderly. Aging produces mild carbohydrate intolerance and a minimal increase in fasting serum glucose in healthy, nonobese individuals, primarily due to decreasing postreceptor responsiveness to insulin. Aging decreases the metabolism of thyroxine, including its conversion to triiodothyronine, but clinically significant alterations of thyroid hormone levels do not occur. Changes in the end-organ response to thyroid hormones, however, significantly alter the clinical presentation of thyroid diseases. Aging shifts the serum vasopressin-serum osmolality relationship toward higher serum vasopressin levels probably due to altered baroreceptor input, probably contributing to the tendency toward hyponatremia in the elderly. Aging slows the metabolism of cortisol, but glucocorticoid levels in the human are essentially unaltered by age. However, recent data indicate that delta-5 adrenal steroids decrease markedly in both men and women. Nodules in the anterior pituitary, the thyroid, and the adrenal increase in frequency with aging. Finally, the reproductive system is primarily altered by endocrine cell death, by unknown mechanisms, resulting in decreased estrogen and testosterone levels in women and men. This most obvious age-related endocrine change turns out to be incompletely understood and is not representative of most age-related endocrine changes. Despite characterization of these many age-related alterations in endocrine systems, therapeutic issues often remain unexplored, and more data are needed in many areas.

The effects of alcohol on the endocrine system.

Male hypogonadism is the best documented endocrine effect of chronic alcoholism. A reversible clinical syndrome resembling Cushing's syndrome has also recently been described in some chronic alcoholics. The pituitary-thyroid axis is relatively resistant to the effects of ethanol, although mild abnormalities in various thyroid tests are frequently noted in the presence of alcoholic liver disease.

The effects of alcohol on blood pressure and electrolytes.

The interaction between alcohol abuse, changes in blood pressure, and electrolyte abnormalities is complex. Some effects of alcohol are seen only with acute ingestion, some during withdrawal, and some only in chronic drinkers. Careful attention to the interactions between the metabolism of various electrolytes can prevent unnecessary morbidity and mortality in alcoholic patients.

Frequent falsely negative renal vein renin tests in unilateral renal parenchymal disease.

A retrospective analysis of 12 hypertensive patients with unilateral renal parenchymal disease was done to evaluate the roles of renal vein renin testing and an operation. The patients were considered to have renal parenchymal disease on the basis of radiographic and/or pathologic findings. Only 2 patients had positive renal vein renin studies. Both of these patients were improved after unilateral nephrectomy but 1 had subsequent progression of disease and renal failure. Of the 10 patients with negative studies 5 had unilateral nephrectomy: 4 of them, nevertheless, experienced substantial improvement in the hypertension. It is concluded that hypertensive patients with unilateral renal parenchymal disease often can benefit from an operation and that renal vein renin testing in such patients can be misleading.

Low plasma renin activity in normotensive patients with diabetes mellitus: relationship to neuropathy.

To determine the effect of diabetes mellitus on the renin-aldosterone system, independent of age, nephropathy, or hypertension, 16 normotensive diabetics with long-term disease (mean duration, 15 years) and no (14) or minimal (2) proteinuria, were compared to nine age-matched, normotensive controls. Plasma renin activity (PRA) measured supine and after 4 hours of quiet ambulation, both on an ad libitum diet and on Day 4 of a 10 mEq low sodium diet, was always lower in the diabetics (31%-56% of control values). After the combined stimulus of sodium depletion and ambulation, PRA was 2.2 +/- 0.4 in the diabetics compared to 3.4 +/- 0.2 ng/ml/hr in controls (p less than 0.025). On the low sodium diet, PRA and the postural response of PRA correlated directly with the degree of autonomic dysfunction as quantitated by the velocity of esophageal peristalsis (r = 0.60, p less than 0.05; r = 0.75, p less than 0.005 respectively), suggesting that autonomic neuropathy was an important factor contributing to low PRA in these patients. No other parameters correlated with PRA. Plasma renin substrate (PRS) tended to be lower in diabetics (1053 +/- 95 vs 1358 +/- 132 ng AI/ml; p less than 0.07) but not sufficiently so to account for the substantial difference in PRA. Furthermore, PRS did not correlate with PRA. Fasting blood sugar, while higher in diabetics (209 vs 96 mg/dl), and creatinine clearance, which was lower (112 +/- 13 vs 78 +/- 4 ml/min; p less than 0.01), also did not correlate with PRA. Other factors, including serum creatinine, serum potassium, urinary aldosterone, blood pressure, and body weight, and the responses of these parameters to sodium depletion, were similar in diabetics and controls. These data implicate visceral neuropathy as a major factor in the hyporeninemia of these diabetics.

Tonic dopaminergic suppression of plasma aldosterone.

To investigate the interaction between dopamine and aldosterone in man, either the dopamine antagonist, metoclopramide [methoxy-2-chloro-5-procainamide (M)], or a placebo was given by an iv bolus in a random, double blind fashion to nine supine volunteers on a hospital diet (mean urinary sodium excretion, 135 +/- 17 vs. 145 +/- 26 meq/24 h; P = NS). After M (10 mg), plasma aldosterone (PA) rose from 6.4 +/- 1.1 to 14.0 +/- 2.2 (SEM) ng/dl (P less than 0.01) within 15 min. PRA, potassium, and cortisol were unchanged. PRL increased 10-fold, but individual increments in PA and PRL did not correlate significantly. Oral M (10 mg) produced a rise in PA in only two of five volunteers. To determine whether the increase in PA was due to the dopamine antagonist properties of M, the iv study was repeated in four of the volunteers during an ongoing dopamine infusion. The integrated incremental change in PA during the hour after M administration was markedly blunted (399 +/- 56 vs. 69 +/- 32 ng/dl.min; P less than 0.05), and the PRL response was totally abolished. Assuming no major effects of M on the MCR of aldosterone, these data suggest a tonic inhibitory influence of dopamine on aldosterone secretion.

Tryptic activation of plasma renin activity.

Trypsinization of human plasma, like acid activation or cryoactivation, increases renin activity, as determined by subsequent enzymatic assay. In three plasma pools, tryptic activation was maximal within 2 min at a trypsin concentration of 500 micrograms/ml, decreasing at higher concentrations. Neither prolongation of trypsin exposure for up to 1 h nor temperature (0 or 37 C) mattered. In plasmas from 26 healthy volunteers ambulatory for 3 h, trypsin increased PRA 3-fold from 2.8 +/- 0.4 to 8.3 +/- 0.7 ng/ml.h (P less than 0.001). Plasma renin reactivity (the amount of angiotensin I generated in plasma by the addition of active renin) and plasma renin substrate were unaltered by trypsin in concentrations up to 500 micrograms/ml. By exclusion, these data support the concept that an inactive precursor form of renin normally exists in human plasma. At concentrations of trypsin of 1 mg/ml or greater, tryptic activation diminished due to degradative effects of trypsin on the renin assay system, indicating the need for careful selection of conditions to maximize tryptic activation.

Deoxycorticosterone and 17-ketosteroids. Elevated levels in adult hypertensive patients.

Plasma 11-deoxycorticosterone levels were manyfold elevated in three adult patients with hypertension and elevated urinary excretion levels of 17-ketosteroids but without Cushing's syndrome. Dexamethasone therapy resulted in suppression of these steroids and in improvement of blood pressure in two of the patients. A partial adrenal 11beta-hydroxylase deficiency appears to best explain these findings.

Incidence of pituitary tumors following adrenalectomy. A long-term follow-up study of patients treated for Cushing's disease.

The long-term follow-up of 21 patients who had undergone bilateral adrenalectomy for Cushing's disease has revealed eight definite and two suspected cases of pituitary tumors. The average time from adrenalectomy to the diagnosis of the pituitary tumor was 6 1/2 years, with a range of 1 1/2 to 12 years. The incidence of tumors in this study (38%) is higher than that reported by others and may reflect (1) that none of these patients received pituitary irradiation in addition to adrenalectomy, (2) the length of follow-up, and (3) the high index of suspicion and early diagnosis of pituitary tumors in recent years. These data raise the question of whether bilateral adrenalectomy alone is an acceptable form of therapy for Cushing's disease. For patients treated in this way, a life-long commitment should be made to undergo annual reexamination for the possible occurrence of a pituitary neoplasm.

Is low-renin hypertension an overdiagnosed syndrome?

The controversy surrounding low-renin hypertension ranges from the concept that it carries a favorable prognosis to the therory that it a form of nephrosclerosis. At least a part of the debate may result from the use of different methods of classifying patients with this condition. The study presented here clearly shows that age and sex have an important influence on plasma renin activity. Women had lower values than age-matched men, and studies in normal volunteers showed that plasma renin activity decreases with age. Other factors also affect renin profiling. Diabetes is associated with renin suppression, and blacks have lower values of plasma renin activity than whites. In addition, use of anti-inflammatory drugs such as aspirin significantly lowers renin levels. Since some of these variables have not been considered in published studies to date, it would seem that the true incidence of low-renin hypertension among hypertensives is lower than the accepted figure of 25%.