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Biomedical subjects

David S H Bell

Publications and source records attributed to David S H Bell.

At least 19 recordsLinked to original sources
PubMed2006

The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis.

BACKGROUND: Although beta-blocker therapy has been shown to improve survival in patients with chronic heart failure, this class of drugs tends to be underutilized in diabetic patients due to concerns about adverse metabolic effects, especially on glycemic control. No randomized clinical trial has specifically evaluated the effect of beta-blocker therapy on mortality in diabetic patients with heart failure. Previous meta-analyses combining results of heart failure trials with pharmacologically diverse beta-blockers suggest that the survival benefit in diabetic patients may be diminished compared to benefits in non-diabetic patients. However, some trial results indicate that carvedilol, which blocks beta1-, beta2-, and alpha1-receptors and is a potent antioxidant, may produce at least comparable effects in both patient groups. OBJECTIVES: To evaluate the effect of carvedilol in patients with heart failure and diabetes, specifically to determine if the survival benefit of carvedilol demonstrated in heart failure trials was as great in the subgroups of patients with diabetes. METHODS: A meta-analysis was performed that included 5757 patients with heart failure, 25% of whom had diabetes, from seven large placebo-controlled randomized trials with carvedilol. All large (> 100 patients) placebo-controlled, randomized trials with carvedilol in heart failure were included. The endpoint of all-cause mortality was examined in the overall population, patients without diabetes, and patients with diabetes. The number of patients needed to treat (NNT) for 1 year to prevent one death associated with carvedilol use in diabetic versus non-diabetic patients was also calculated. The log-rank test and the Cox proportional hazards regression were used to compare the event time distributions of carvedilol versus placebo with respect to the outcome of mortality. RESULTS: Similar survival benefits were seen with carvedilol use in diabetic and non-diabetic patients (relative risk reductions of 28% [95% confidence interval (CI) 3-46%; p = 0.03] and 37% [95% CI 22-48%; p < 0.001], respectively). There were no significant differences between the relative mortality risk reductions or the NNT with carvedilol use in diabetic versus non-diabetic patients. The NNT for 1 year to prevent one death was 23 for all patients, as well as for non-diabetic patients, and 25 for the diabetic group. CONCLUSIONS: This meta-analysis provides evidence that the same survival benefit may occur with carvedilol in heart failure patients with and without diabetes. The low NNT in the severe heart failure trial, COPERNICUS, and the diabetic subgroup in this meta-analysis suggests that severe heart failure patients and heart failure patients with diabetes may particularly derive benefit from therapy with carvedilol.

Aged↗
PubMed2006

The case for combination therapy as first-line treatment for the type 2 diabetic patient.

The glycosylated hemoglobin (HbA(1c)) goal in patients with type 2 diabetes mellitus should be to achieve as low a value as can be obtained without causing significant or frequent hypoglycemia. This is best achieved by utilizing agents that lower glucose levels without causing hypoglycemia (thiazolidinediones and metformin). To maintain these low HbA(1c) values and avoid the utilization of insulin secretagogues or insulin, which are associated with hypoglycemia and suboptimal dosing leading to higher HbA(1c) values, drugs that maintain or improve pancreatic beta-cell function (thiazolidinediones and possibly incretin-based therapies) should be utilized. Restoration of first-phase insulin release, as has been shown with thiazolidinediones, will not only improve postprandial hyperglycemia but will also improve postprandial hyperlipidemia, both of which will decrease cardiac risk. Utilizing small doses of two drugs will also result in a decreased incidence of adverse effects compared with a large dose of a single drug. The use of fixed-dose combination oral antihyperglycemics will not only improve compliance but will often decrease costs compared with individual component dual therapy.

Diabetes Mellitus, Type 2↗
PubMed2005

Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes.

Increases in the cardiovascular risk marker microalbuminuria are attenuated by blood pressure reduction using blockers of the renin-angiotensin system. Such changes in microalbuminuria have not been observed when beta-blockers are used. A prespecified secondary end point of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was to examine the effects of different beta-blockers on changes in albuminuria in the presence of renin-angiotensin system blockade. Participants with hypertension and type 2 diabetes were randomized to either metoprolol tartrate (n=737) or carvedilol (n=498) in blinded fashion after a washout period of all antihypertensive agents except for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Blinded medication was titrated to achieve target blood pressure, with a-5 month follow-up period. The current analysis examined microalbuminuria, using spot urine albumin:creatinine, in participants who had values at screening and trial end. A greater reduction in microalbuminuria was observed for those randomized to carvedilol (-16.2%Delta; 95% confidence interval, -25.3, -5.9; P=0.003). Of those with normoalbuminuria at baseline, fewer progressed to microalbuminuria on carvedilol versus metoprolol (20 of 302 [6.6%] versus 48 of 431 [11.1%], respectively; P=0.03). Microalbuminuria development was not related to differences in blood pressure or achievement of blood pressure goal (68% carvedilol versus 67%, metoprolol). Presence of metabolic syndrome at baseline was the only independent predictor of worsening albuminuria throughout the study (P=0.004). Beta-blockers have differential effects on microalbuminuria in the presence of renin-angiotensin system blockade. These differences cannot be explained by effects on blood pressure or alpha1-antagonism but may relate to antioxidant properties of carvedilol.

Adrenergic beta-Antagonists↗
PubMed2005

Hyperinsulinemic hypoglycemia precipitated by weight loss.

OBJECTIVE: To describe a case of hyperinsulinemic hypoglycemia precipitated by weight loss. METHODS: We present a detailed case report and results of a related literature search on hyperinsulinemic hypoglycemia precipitated by weight loss. RESULTS: The presence of an insulinoma was unveiled by voluntary weight loss and reduction of insulin resistance. Hypoglycemia occurred during the postprandial period and not at night. The diagnostic workup was accomplished without hospital admission. CONCLUSION: Classically, insulinomas present with weight gain and fasting hypoglycemia but may present with postprandial hypoglycemia and weight loss. Voluntary weight loss, by lowering insulin resistance, accelerates the time to clinical presentation of an asymptomatic insulinoma.

Blood Glucose↗
PubMed2005

Optimizing treatment of diabetes and cardiovascular disease with combined alpha,beta-blockade.

BACKGROUND: Cardiovascular risk factors of the diabetic patient should be treated as aggressively as those of the nondiabetic patient who has had a myocardial infarction. beta-Blockers are established to reduce cardiovascular risk in patients with hypertension, coronary heart disease, and heart failure. Despite this benefit of beta-blockers, physicians have been reluctant to use them in patients with diabetes, in whom they are even more effective, because of the negative effects on carbohydrate and lipid metabolism. OBJECTIVE: This paper reviews (based on a Medline literature search to December 2004) the relationship between diabetes and cardiovascular risk factors, describes the metabolic consequences of insulin resistance, and discusses the impact of different beta-blockers on the treatment of cardiovascular disease in patients with diabetes. RESULTS: There is a large cardioprotective benefit with the use of beta-blockers in patients with diabetes; however, metabolic risks are associated with some beta-blockers. Newer, vasodilating, nonselective beta-blockers do not have the same adverse metabolic consequences observed with earlier beta-blockers. Recent evidence has shown that they have a neutral effect on metabolic parameters and lipid profile. They do not promote insulin resistance and can be used safely in heart failure patients with diabetes. CONCLUSIONS: Nonselective vasodilating beta-blockers, such as carvedilol, may be used in patients with cardiovascular disease and diabetes without the same negative metabolic consequences seen with the use of earlier generation beta-blockers.

Adrenergic alpha-Antagonists↗
PubMed2004

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial.

CONTEXT: Beta-blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM); however, some components of the metabolic syndrome are worsened by some beta-blockers. OBJECTIVE: To compare the effects of beta-blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks. INTERVENTIONS: Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target. MAIN OUTCOME MEASURES: Difference between groups in mean change from baseline HbA1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria. RESULTS: The 2 groups differed in mean change in HbA1c from baseline (0.13%; 95% confidence interval [CI], -0.22% to -0.04%; P = .004; modified intention-to-treat analysis). The mean (SD) HbA1c increased with metoprolol (0.15% [0.04%]; P<.001) but not carvedilol (0.02% [0.04%]; P = .65). Insulin sensitivity improved with carvedilol (-9.1%; P = .004) but not metoprolol (-2.0%; P = .48); the between-group difference was -7.2% (95% CI, -13.8% to -0.2%; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs 10.3%; odds ratio, 0.60; 95% CI, 0.36-0.97; P = .04). CONCLUSIONS: Both beta-blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 beta-blockers on clinical outcomes need to be compared in long-term clinical trials.

Adrenergic beta-Antagonists↗
PubMed2004

Advances in diabetes for the millennium: the heart and diabetes.

The risk of ischemic heart disease is 2-4 times greater in diabetes, occurs at a younger age, and is much higher in women with diabetes. The risk of coronary disease is increased in patients with poor glycemic control, but studies have not shown a major impact of improved glucose management on cardiovascular mortality. This apparent contradiction may be due to the many potential mechanisms of increased cardiovascular damage in diabetes, including hypertension; abnormal clotting function due to changes in fibrinolysis, platelet adherence, and plasminogen activity; abnormal vascular reactivity; and abnormal lipid patterns and particles. Some, but not all, of these issues are related to lifestyle factors, including diet, exercise, and cigarette smoking. The treatment of hypertension and hypercholesterolemia has been more successful in reducing cardiovascular mortality than reducing HbA1c levels. One of the major, unresolved questions is whether insulin resistance rather than hyperglycemia is the primary risk factor for cardiovascular disease (CVD). Antidiabetic agents that target insulin resistance may be more cardioprotective than those that primarily augment insulin secretion.

Cardiovascular Diseases↗
PubMed2004

Advantages of a third-generation beta-blocker in patients with diabetes mellitus.

beta-Blocker use improves outcomes even more for the patient with diabetes mellitus than for the patient without diabetes with a history of acute myocardial infarction or coronary artery disease. beta-Blockers facilitate shifting the metabolism of the myocardium away from free fatty acid toward glucose utilization, thereby reducing the cardiac workload and myocardial ischemia. beta-Blockers are also able to reverse the fetal gene induction program to reverse myocardial remodeling and improve ventricular function. Side effects of beta-blockers in the patient with diabetes include increased insulin resistance with worsening glycemic control, elevated triglyceride levels, and lowered levels of high-density lipoprotein cholesterol. Increased frequency of hypoglycemia and its lack of recognition can also be a problem in the insulin-deficient patient but is a minimal problem with the patient with type 2 diabetes. In addition, vasoconstriction, caused by unopposed alpha-activity, can worsen peripheral vascular disease. However, carvedilol, a nonselective beta-blocker with vasodilating and insulin-sensitizing properties, can largely circumvent these problems and is the ideal beta-blocker for the patient with diabetes.

Adrenergic beta-Antagonists↗
PubMed2004

Type 2 diabetes mellitus: what is the optimal treatment regimen?

Treatment options for type 2 diabetes mellitus currently consist of insulin sensitizers, alpha-glucosidase inhibitors, secretagogues, and insulin. However, the emphasis on initial therapy has been shifting from secretagogues and alpha-glucosidase inhibitors to insulin sensitizers such as metformin and the thiazolidinediones (TZDs). This article outlines the benefits of treatment with sensitizers vis à vis alpha-glucosidase inhibitors and secretagogues as part of a comprehensive treatment algorithm for type 2 diabetes. Secretagogues and alpha-glucosidase inhibitors effectively lower plasma glucose levels only, whereas insulin sensitizers reduce several important cardiac risk factors in addition to reducing plasma glucose levels. TZDs, in particular, are also beneficial for their ability to preserve or even rejuvenate pancreatic beta-cell function. The treatment algorithm has a layered approach, beginning with a combination of insulin-sensitizer therapy and incrementally progressing to triple oral therapy with the addition of secretagogues and, if necessary, the addition of subcutaneous insulin to maintain glycemic control.

Administration, Oral↗
PubMed2004

Practical considerations and guidelines for dosing sulfonylureas as monotherapy or combination therapy.

BACKGROUND: Oral antidiabetic agents are the initial and most commonly used therapy for type 2 diabetes mellitus. To effectively utilize the oral antidiabetic agents, familiarity with the efficacy and side effects of each agent is essential so that strategies for effective therapy with 1 or more agents can be developed when transitioning is needed either with monotherapy or to combination therapy with another antidiabetic agent. OBJECTIVES: The purposes of this article were to review the efficacy and adverse-event profile of sulfonylureas, the most widely used class of oral antidiabetic agents in the United States, and to provide a simple set of guidelines for use in transitioning patients between sulfonylureas or to combination therapy. METHODS: A comprehensive search of the MEDLINE and PubMed databases for the years 1966 to present and a thorough review of abstracts of recently presented clinical trials were used to identify relevant literature on dosing conversion and equivalence between sulfonylureas. Search terms used were as follows: sulfonylureas, dosing conversion, equivalence, glyburide, glipizide, glimepiride, and combination therapy. Strategies are provided for switching patients between sulfonylureas so that switching within the sulfonylurea class or to a combination tablet can be accomplished efficaciously and safely. Recommendations for dosing conversion were based on the results of the literature and abstract search, manufacturer recommendations for each available agent, and the author's clinical experience. RESULTS: When switching between agents or starting combination therapy, it is important to monitor for hypoglycemia. Fasting serum glucose levels and glycosylated hemoglobin should also be monitored to determine the optimal dose of sulfonylurea for each patient Patients not achieving adequate control on a single agent should be transferred to combination therapy. CONCLUSION: When transferring a diabetic patient to a combination tablet, improved compliance, cost savings, and better glycemic control may be achieved.

Administration, Oral↗
PubMed2004

A comparison of agents used to manage type 2 diabetes mellitus: need for reappraisal of traditional approaches.

In patients with type 2 diabetes mellitus, the traditional method of initiating therapy with a sulfonylurea and increasing the dosage until maximum levels are reached before adding an insulin-sensitizing agent has persisted and should be re-evaluated. Similarly, the current practice of starting therapy with one agent and increasing to maximum dosage before adding a second agent, rather than starting with combination therapy, also needs to be addressed. There is much evidence to suggest that initiating therapy with lower doses of two agents that have complementary effects can increase the overall efficacy and decrease the incidence of adverse effects. Clearly, there is a need for a paradigm shift away from the traditional approach of therapy using insulin secretagogues to a more pathophysiologic approach using an insulin-sensitizing agent, such as the thiazolidinediones. The thiazolidinediones have been shown to reduce insulin resistance, improve the ability of beta-cells to produce insulin, and decrease cardiac risk factors. By reducing insulin resistance, improving glycemic control, and preserving beta-cell function with a thiazolidinedione early in the course of therapy, it is likely that durable glycemic control will be achieved and both microvascular and macrovascular complications may be reduced. Furthermore, early use of an insulin-sensitizing agent either alone or incombination is expected to improve both acute and long-term outcomes in patients with type 2 diabetes.

Animals↗
PubMed2004

Effect of rosiglitazone versus insulin on the pancreatic beta-cell function of subjects with type 2 diabetes.

OBJECTIVE: In a previous study, we found observational evidence of improvement in beta-cell function when rosiglitazone was added to a failing oral antihyperglycemic regimen consisting of sulfonylureas and metformin. To confirm our previous observations, we designed and performed a prospective, randomized, and controlled study. RESEARCH DESIGN AND METHODS: A total of 17 subjects with type 2 diabetes, inadequately controlled on a maximized oral antihyperglycemic double regimen of glimepiride and metformin, were randomized to the addition of rosiglitazone or insulin to their treatment regimens for a period of 6 months. At baseline and at 6 months, the following were performed: measurement of fasting plasma glucose, fasting proinsulin, and insulin levels; frequently sampled intravenous glucose tolerance test; and glucagon stimulation test for C-peptide. RESULTS: Nine subjects were randomized to the addition of 8 mg rosiglitazone, and eight subjects were randomized to the addition of one injection of insulin (premixed 70/30) before their evening meal. The treatment groups were well matched for age, duration of diabetes, and BMI. Most important, the HbA(1c) was well matched between groups before treatment (8.7 +/- 0.3 and 9.0 +/- 0.3%; NS) and at the end of the 6 months (7.8 +/- 0.5 and 7.8 +/- 0.3%; NS). After 6 months, at the end of the study, there was a significant improvement in acute insulin response to glucose in the rosiglitazone group (+15.3 microIU x ml(-1) x 10 min(-1); P < 0.001) that led to an increase in the disposition index from 0.18 at baseline to 4.18 at 6 months (P = 0.02). Furthermore, at the end of the study, the proinsulin-to-insulin ratio had decreased in the rosiglitazone group by 36% (P = 0.03) but did not change significantly in the insulin treatment group. CONCLUSIONS: Rosiglitazone, but not insulin, induced a recovery of pancreatic beta-cell function, as evidenced by the restoration of the first-phase insulin response to glucose, improvement in the disposition index, and a decrease in the proinsulin-to-insulin ratio in subjects with type 2 diabetes in whom oral antihyperglycemic therapy failed. This improvement was independent of the correction of glucotoxicity.

Diabetes Mellitus, Type 2↗