Altering therapy of type II diabetes mellitus from insulin to tolazamide increases blood pressure in spite of weight loss.

In a retrospective study we investigated the effects of altering treatment of type II diabetes mellitus from insulin to tolazamide on weight and blood pressure. In 17 patients, weight decreased from 136 +/- 6 to 131 +/- 6% of ideal body weight (P = .01). Even though weight loss occurred, mean systolic blood pressure increased from 133 +/- 3 mm Hg to 142 +/- 4 mm Hg (P = .025). There was no difference in diastolic blood pressure on the two treatments (79 +/- 3 v 78 +/- 4 mm Hg). In an additional 10 patients whose treatment was changed from tolazamide to insulin, mean systolic blood pressure decreased from 136 +/- 1 to 124 +/- 2 mm Hg (P < .01). In spite of the potential benefits of reversal of insulin resistance and weight reduction, altering therapy of type II diabetes mellitus from insulin to tolazamide may increase blood pressure, thereby increasing cardiovascular risk.

Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A metaanalysis.

OBJECTIVE: To assess the efficacy of combination therapy with insulin and sulfonylurea in the treatment of NIDDM. RESEARCH DESIGN AND METHODS: Studies published between January 1966 and January 1991 were identified through a computerized Medline search and by hand searching the bibliographies of identified articles. We identified 17 eligible randomized, controlled trials of combination therapy in NIDDM. These trials had a minimum duration of 8 wk and at least one of three outcome measures (fasting glucose, HbA1, or C-peptide) with SD or SE of the mean reported to do metaanalysis. With standardized forms, three independent reviews abstracted measures of study quality and specific descriptive information about population, intervention, and outcome measurements. RESULTS: We calculated effect size and weighted mean changes of the three outcome measures for control and treatment groups. In the treatment group, the fasting plasma glucose decreased from a mean of 11.4 mM (206 mg/dl) at baseline to a mean of 9.16 mM (165 mg/dl) posttreatment, whereas the control group decreased from (11.3 to 10.8 mM) (204 to 194 mg/dl) (effect size 0.39, P less than 0.0001). For HbA1, the treatment group decreased from a baseline of 11.0 to 10.2% compared to 11.0 and 11.2% in the control group (effect size 0.43, P less than 0.0001). For fasting C-peptide, the treatment group increased from 0.49 to 0.58 nM (1.45 to 1.75 ng/ml) compared with 0.47 and 0.43 (1.42 and 1.30) for the control group (effect size 0.26, P less than 0.017). CONCLUSION: Combined insulin-sulfonylurea therapy leads to modest improvement in glycemic control compared with insulin therapy alone. With combined therapy, lower insulin doses may be used to achieve similar control. Obese patients with higher fasting C-peptides may be more likely to respond than others.

Adjunctive use of tolazamide in newly-diagnosed diabetic children.

Recent data suggests that one of the major actions of sulfonylureas is to potentiate the anabolic cellular effects of insulin. This is the first study to examine the use of sulfonylureas as adjunctive therapy in newly-diagnosed type I diabetic children. A random, prospective, double blind study over 15 months, stratified by age at diagnosis, was conducted. The treatment group (n = 13) received daily oral weight-adjusted tolazamide whereas the control group (n = 11) received placebo. Monthly comparison of the HbA1 values between groups revealed no statistical difference; likewise, the fasting serum C-peptide values were not dissimilar. The mean daily insulin dose per kilogram, however, was less in the tolazamide group (P less than 0.001). The data suggests that the addition of tolazamide may not be of therapeutic benefit in newly diagnosed juvenile diabetics, although insulin requirements may be reduced.

Glyburide and glipizide in treatment of diabetic patients with secondary failures to tolazamide or chlorpropamide.

We evaluated therapeutic usefulness of the second-generation sulfonylurea agents glyburide and glipizide in non-insulin-dependent diabetic patients who were secondary failures on chlorpropamide or tolazamide. Twenty patients were treated with glyburide, and 10 of them were subsequently treated with glipizide. Fasting and postprandial serum glucose, insulin, C-peptide, glycosylated hemoglobin, urinary C-peptide, and glucose levels all failed to show significant improvement. We concluded that both glyburide and glipizide proved ineffective in the treatment of secondary failures to first-generation sulfonylureas.

Effects of tolazamide and exogenous insulin on pattern of postprandial carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus. Results of randomized crossover trial.

To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 +/- 0.7 to 7.6 +/- 0.5 and 7.1 +/- 0.2%, respectively, P less than .01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P less than .001). Both agents comparably increased (P less than .01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P less than .05). Tolazamide (P less than .05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P less than .05) lowered postabsorptive hepatic glucose release (from 2.8 +/- 0.3 to 2.3 +/- 0.2 mg . kg-1 . min-1), but not to normal rates (1.8 +/- 0.1 mg . kg-1 . min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Combined therapy of insulin and tolazamide decreases insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus.

Insulin requirements, C-peptide levels, and serum lipids have been assessed in 12 obese, insulin-requiring (greater than 60 U/day) patients with type II diabetes mellitus, in a randomized crossover fashion with two treatment regimens: NPH alone and combined NPH and tolazamide, over a period of 3 months each, with maintenance of weight and glycemic control (HgA1, 2hpp and mean 24h glucose profile) at comparable levels. Serum cholesterol improved in both groups compared to their respective baseline values (p less than 0.05). In addition, serum triglyceride was lower (p less than 0.05) in the combined therapy as compared with NPH alone therapy. Insulin requirements were decreased by 23% (p less than 0.002) in the combined therapy group, without significant change in weight, glycemic control, or C-peptide levels. However, C-peptide increments in the combined therapy group were significantly higher than the baseline by 70% (p less than 0.02). NPH plus tolazamide therapy as compared with NPH alone lowers insulin requirement in obese, type II diabetic women without significant alteration in glycemic control, possibly by an increased tissue sensitivity to insulin, and decreases serum triglyceride levels.

"Alcoholic hepatitis" in a hepatic adenoma.

A unique hepatic adenoma developed in a 26-year-old woman who had used oral contraceptives for 10 years and Tolinase (tolazamide sulfonylurea) for adult-onset diabetes mellitus for five years. Clinically, radiographically, and grossly, the neoplasm showed the usual features of a hepatic adenoma, but microscopically it strongly resembled alcoholic hepatitis with steatonecrosis and Mallory bodies. The surrounding hepatic parenchyma was entirely normal. On transmission electron microscopy these Mallory bodies appeared to be tangles of intermediate filaments. They stained readily with antibodies to cytokeratin but not with antibodies to epidermal keratin or vimentin, just as in "alcoholic" hyalin.

Selective unresponsiveness of pancreatic beta-cells to acute sulfonylurea stimulation during sulfonylurea therapy in NIDDM.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other beta-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess beta-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy. In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 +/- 11 microU/ml when not receiving tolazamide (0.14 +/- 1.3 microU/ml) with tolazamide (P less than .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 +/- 22 microU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5-10 min after intravenous tolbutamide were undetectable (-0.5 microU/ml), yet responses to intravenous glucagon were evident. In these NIDDM patients, exposure of pancreatic beta-cells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic and cellular insulin action in a glucose-intolerant model of type 2 (non-insulin-dependent) diabetes in rats.

A B-cell-deficient model for Type 2 (non-insulin-dependent) diabetes mellitus has been investigated with regard to insulin action at the cellular level. Two-day-old male Sprague Dawley rats were injected with streptozotocin (90 mg/kg) or citrate buffer. At 6 weeks streptozotocin-treated animals were hyperglycaemic and exhibited glucose intolerance, e.g. at 45 min post-glucose (1.5 g/kg) the change in serum glucose level from baseline was 6 +/- 7 mg% in control rats vs. 212 +/- 18 mg% for the streptozotocin-treated rats. Basal activity and insulin action in isolated adipocytes, as estimated by 2-deoxyglucose uptake and glucose metabolism, were not influenced by streptozotocin treatment. For example, uptake of 0.1 mmol/1 2-deoxyglucose at 1000 microU insulin/ml was 58 +/- 8 pmol/10(5) cells min-1 vs 54 +/- 6 pmol for adipocytes isolated from experimental vs. control animals. Although serum insulin levels in streptozotocin-treated rats were significantly decreased (p less than 0.05), there was no difference in insulin receptor number or affinity. Glucose intolerance present in this model is similar to that in Type 2 diabetes. However, concomitant insulin intolerance was not observed. Taken together with our findings of unaltered insulin action at the cellular level, this suggests that the pathogenesis of insulin resistance is not dependent on glucose intolerance. Moreover, this hyperglycaemic model is responsive to oral hypoglycaemic agents and can be used to establish their direct effects on physiologic and cellular insulin action.

Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus.

To determine whether sulfonylureas and exogenous insulin have different effects on insulin action, we studied eight patients with non-insulin-dependent diabetes mellitus before and after three months of treatment with tolazamide and exogenous semisynthetic human insulin, using a randomized crossover design. Therapy with tolazamide and therapy with insulin resulted in similar improvement of glycemic control, as measured by a decrease in mean glycosylated hemoglobin (+/- SEM) from 9.4 +/- 0.7 percent to 7.7 +/- 0.5 percent with tolazamide and to 7.1 +/- 0.2 percent with exogenous insulin (P less than 0.01 for both comparisons). Therapy with either tolazamide or exogenous insulin resulted in a similar lowering (P less than 0.05) of postabsorptive glucose-production rates (from 2.3 +/- 0.1 to 2.0 +/- 0.2 and 1.8 +/- 0.1 mg per kilogram of body weight per minute, respectively) but not to normal (1.5 +/- 0.1 mg per kilogram per minute). Both tolazamide and exogenous insulin increased (P less than 0.05) glucose utilization at supraphysiologic insulin concentrations (from 6.2 +/- 0.7 to 7.7 +/- 0.6 mg per kilogram per minute with tolazamide and to 7.8 +/- 0.6 mg per kilogram per minute with exogenous insulin) to nondiabetic rates (7.9 +/- 0.5 mg per kilogram per minute). Neither agent altered erythrocyte insulin binding at physiologic insulin concentrations. We conclude that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus. Therefore, the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.

Increased resting metabolic rates in obese subjects with non-insulin-dependent diabetes mellitus and the effect of sulfonylurea therapy.

Obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) lose weight soon after diagnosis and tend to gain weight during hypoglycemic therapy. One explanation for these weight shifts is the change in caloric loss from glycosuria. We compared 24 obese Pima Indians with NIDDM to 24 Pima Indians with normal glucose tolerance to determine whether resting metabolic rate changes may be an additional factor influencing the weight shifts. The diabetic and nondiabetic subjects were equally obese, body fat 38 +/- 1% versus 37 +/- 1% (mean +/- SEM), respectively, as determined by densitometry. In the morning after an overnight fast, resting metabolic rate (RMR) was measured by indirect calorimetry. The mean RMR of the diabetic subjects, 32.9 +/- 0.5 kcal/day X kg fat-free mass (FFM), was 5% higher than that of the nondiabetic subjects, 31.4 +/- 0.5 kcal/day X kg FFM (P less than 0.05). In nine of the diabetic subjects, 6 wk of tolazamide therapy was associated with reductions in mean FPG, 253 +/- 16 to 144 +/- 14 mg/dl (P less than 0.01), mean daily urine glucose loss, 128 +/- 26 to 11 +/- 4 g (P less than 0.01), and mean RMR, 31.9 +/- 0.8 to 30.2 +/- 0.6 kcal/day X kg FFM (P less than 0.04). Weight of the subjects was maintained constant from beginning to end of therapy (106.5 +/- 9.6 versus 108.1 +/- 9.9 kg) by decreasing daily calorie intake from 3070 +/- 103 to 2784 +/- 163 kcal (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of sulfonylurea therapy on plasma lipids and high-density lipoprotein composition in non-insulin-dependent diabetes mellitus.

To assess the effects of sulfonylurea therapy on plasma lipids and high-density lipoprotein composition, 11 obese diabetic Pima Indians with type II, or non-insulin-dependent, diabetes mellitus were studied before and after tolazamide therapy for one month. Diet composition and weight were kept constant, and the data were compared with a control group of 18 age-, sex-, and weight-matched non-diabetic subjects. Improvement of glycemic control was accompanied by significant decreases in total and very-low-density lipoprotein triglycerides. Total and low-density lipoprotein cholesterol also declined significantly, and there was an increase in the ratio of high-density lipoprotein to low-density lipoprotein cholesterol. Concentrations of total high-density lipoprotein cholesterol, phospholipid, and apolipoprotein AI were unchanged. An increase in the proportion of the high-density lipoprotein 2 subfraction, however, was suggested by significant increases in the ratios of high-density lipoprotein 2 to high-density lipoprotein 3 cholesterol and apolipoprotein AI. There was also a change in the composition of the high-density lipoprotein 2 particle, as indicated by changes in the molar ratio of cholesterol to apolipoprotein AI. The data suggest that improvement of glycemic control after sulfonylurea therapy, when weight and diet composition remain constant, reverses several of the lipoprotein abnormalities observed in type II diabetic patients. There was no evidence of changes in lipoproteins in directions associated with an increased risk for atherosclerosis.

Dual actions of sulfonylureas and glyburide. Receptor and post-receptor effects.

Glyburide and other sulfonylureas consistently enhance receptor binding in cells from patients with non-insulin-dependent diabetes mellitus, whereas no effects and mixed effects have been demonstrated in cells from patients with insulin-dependent diabetes mellitus and in normal cells, respectively. These findings indicate that the experimental model may be critical in demonstrating sulfonylurea effects on receptor binding. Postbinding function studies have shown a definite enhancement of peripheral glucose metabolism by sulfonylurea drugs; such post-receptor changes have not clearly correlated with receptor binding alterations. Studies using mouse-cultured myocytes indicate that both glyburide and tolazamide have stimulatory effects on glucose uptake, whereas only glyburide caused an increase in receptor binding. The data suggest a major and widespread post-receptor function for the sulfonylurea drugs, particularly glyburide, possibly mediated through pathways similar but not identical to insulin pathways. The direct receptor effects, in contrast, are possibly more tissue-specific and/or disease-dependent. In non-insulin-dependent diabetes mellitus, these drugs exert clinical efficacy by acting through both mechanisms.

A case of chronic liver disease due to tolazamide.

Although chlorpropamide and tolbutamide are well recognized as causes of hepatotoxicity, there are only 3 reported cases of hepatic injury caused by a third oral hypoglycemic agent, tolazamide. In 2 of these cases, the liver-function tests returned to normal when the drug was discontinued. In the third case, the patient had cholestasis from chlorpropamide before administration of tolazamide and developed chronic liver disease. We are reporting the second instance of chronic liver disease induced by tolazamide. Our patient had been taking chlorpropamide, but she had no evidence of liver disease before administration of tolazamide. Tolazamide should be considered as a drug capable of producing hepatotoxicity that on occasion may be chronic.

Lichenoid drug reactions to chlorpropamide and tolazamide.

Many medications, including gold, antimalarials, quinidine, and thiazide diuretics have been implicated in lichenoid drug reactions. Chlorpropamide and tolazamide are sulfonylurea oral hypoglycemic agents, neither of which has previously been implicated in cutaneous lichenoid reactions. We report a case of lichenoid drug reaction related to both chlorpropamide and tolazamide.

Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of glyburide and glipizide, two second-generation oral sulfonylurea hypoglycemic agents, are reviewed. Glyburide and glipizide are well absorbed after oral administration. The absorption of glipizide is delayed by food; in contrast, glyburide absorption does not seem to be affected by administration with meals. Both drugs are extensively metabolized by the liver. A two-compartment open model adequately describes the pharmacokinetics of these drugs. The apparent elimination half-life of glyburide in oral dosage forms available in the United States ranges from 7 to 10 hours. Glipizide has a terminal elimination half-life of 2-7 hours. The effects of renal and hepatic disease on the pharmacokinetics of glyburide and glipizide have not been well studied. Based on controlled, comparative studies in patients with new-onset, diet-failed, Type II diabetes, glyburide appears to be at least as effective as chlorpropamide and tolazamide in controlling blood glucose. Glipizide has shown efficacy comparable to or greater than that of chlorpropamide and tolbutamide. Glyburide and glipizide appear to be comparable in terms of their ability to control fasting blood glucose in Type II diabetics. The recommended initial dosage of glyburide in newly diagnosed Type II diabetics is 2.5-5 mg once daily. For glipizide, the initial dosage should be 5 mg once daily. Elderly or debilitated patients and those with renal or hepatic impairment should be started on lower dosages initially. Glyburide and glipizide have adverse effects that are similar to those observed with the first-generation oral hypoglycemic agents. Glyburide and glipizide do not appear to offer major therapeutic advantages over first-generation oral sulfonylurea hypoglycemic agents. However, they may represent therapeutic alternatives for some patients who do not respond satisfactorily to other sulfonylureas.

Remission of diabetes mellitus in a geriatric patient.

A 67-year-old thin diabetic man went into remission four months after onset of diabetes mellitus and initiation of therapy with an oral hypoglycemic agent. Eighteen months later the patient was still in remission. During this period, he experienced the severe stress of a modified jaw resection for carcinoma.

The effect of chlorpropamide hyponatremia on mental status in a nursing home population.

Fifty-nine nursing home patients (average age, 79.9 +/- .9 years) receiving chlorpropamide were screened with a serum sodium determination. Nine patients (15.3 percent) had a serum sodium concentration less than 135 mEq/L; six of these patients (10.2 percent) had a serum sodium equal to or less than 130 mEq/L; none of the patients had a serum sodium less than 125 mEq/L. Five hyponatremic patients (Na less than or equal to 130 mEq/L) and nine normonatremic patients (Na greater than or equal to 135 mEq/L) were screened with a standardized mental status examination and additional laboratory studies. The hyponatremic patients were switched to tolazamide after a one-week wash-out period, and the mental status examination and laboratory studies were repeated in both groups four weeks later. One patient in the hyponatremic group died during the course of the study; the other four became normonatremic on tolazamide. Mental status scores increased significantly in the hyponatremic group, 16.0 +/- 3.6 to 20 +/- 4.6 (a 37.3 +/- 21.5 percent increase), compared with the normonatremic group, 14.5 +/- 2.6 to 15.8 +/- 2.9 (a 7.8 +/- 3.2 percent increase). There were no significant differences in serum glucose, creatinine, chlorpropamide, or antidiuretic hormone concentrations between the two groups. It is recommended that periodic serum sodium determinations be obtained in geriatric patients receiving chlorpropamide.