David Q. Pham

Vitamin E Supplementation in Cardiovascular Disease and Cancer Prevention: Part 1

OBJECTIVE To review clinical trials evaluating the safety and efficacy of vitamin E supplementation in cardiovascular disease and cancer prevention. DATA SOURCES Using the MeSH search terms alpha-tocopherol, tocopherols, vitamin E, cardiovascular diseases, cancer, malignancy, and clinical trials, a literature review was conducted to identify peer-reviewed articles in MEDLINE (1966–July 2005). STUDY SELECTION AND DATA EXTRACTION Published materials including original research, and previous meta-analyses were included. Only English-language articles and trials on vitamin E alone or in combination with other vitamins or minerals were reviewed. Emphasis was placed on prospective, randomized, double-blind, placebo-controlled clinical trials. DATA SYNTHESIS Eight clinical studies demonstrated contradicting results regarding the benefits of vitamin E in the prevention of cardiovascular disease and cancer. There is enough evidence from large, well-designed studies to discourage the use of vitamin E in the primary prevention of cardiovascular disease. Secondary prevention requires more adequate clinical trials with selected populations to examine protective effects of vitamin E in cardiovascular disease. The findings of the studies reviewed do not provide evidence that vitamin E may reduce the risk of cancer; thus, at the present time, we do not recommend daily vitamin E intake for cancer prevention is not recommended. CONCLUSIONS Available data do not support the supplementation of vitamin E in cardiovascular disease and cancer prevention.

Vitamin E Supplementation in Alzheimer's Disease, Parkinson's Disease, Tardive Dyskinesia, and Cataract: Part 2

OBJECTIVE To review clinical trials evaluating the safety and efficacy of vitamin E supplementation in Alzheimers disease, Parkinsons disease, tardive dyskinesia, and cataract. DATA SOURCES Using the MeSH terms alpha-tocopherol, tocopherols, vitamin E, Parkinson disease, tardive dyskinesia, Alzheimer disease, cataract, and clinical trials, a literature review was conducted to identify peer-reviewed articles in MEDLINE (1966–July 2005). STUDY SELECTION AND DATA EXTRACTION Published materials including original research, review articles, and meta-analyses were reviewed. Only English-language articles and trials that included vitamin E alone or in combination with other vitamins or minerals were reviewed. Emphasis was placed on prospective, randomized, double-blind, placebo-controlled clinical trials. DATA SYNTHESIS The clinical studies demonstrated contradicting results regarding the benefits of vitamin E in Parkinsons disease, tardive dyskinesia, and cataract. The study reviewed for Alzheimers disease seemed to show benefit when vitamin E was used; however, the statistical methods employed are questionable. There is enough evidence from large, well-designed studies to discourage the use of vitamin E in Parkinsons disease, cataract, and Alzheimers disease. We recommend that vitamin E be considered a treatment option in patients with tardive dyskinesia only if they are newly diagnosed. CONCLUSIONS We encourage patients to supplement with vitamin E–rich foods. The use of a daily multivitamin, which usually contains 30 IU of alpha-tocopherol, may be beneficial; however, we discourage individual vitamin E supplements that usually contain 400 IU of alpha-tocopherol.

Evaluating the Impact of Clinical Interventions by PharmD Students on Internal Medicine Clerkships: The Results of a 3 Year Study:

Background: As the practice of pharmacy evolves, requiring more clinically oriented healthcare providers, PharmD programs expand their training to more hospital sites to expose students to management of a variety of disease states. These hospital sites often require proof of the impact of PharmD students on patient care over an extended period. This is the first long-term (3 year) study reported. Objective: To evaluate the impact of clinical interventions by PharmD students on internal medicine clerkships over a 3 year period at a 627 bed county hospital with 165 general medical/surgical beds and 10 internal medicine teams. Methods: Between January 1, 2003, and December 31, 2005, all pharmacy interventions at Kings County Hospital Center in Brooklyn, NY, were recorded and analyzed for percentage of contribution, acceptance rate, type, frequency, and impact level. Results: PharmD students contributed to 28.8% of all pharmacy interventions made, with an acceptance rate for interventions of 92%. The most frequent types of interventions performed by PharmD students involved providing drug information (46.8%), recommending alternative agents (10.8%), and providing drug indications (10.6%). Overall, 49.5% of PharmD student interventions were categorized as having moderate to high level impact. Conclusions: This study demonstrates that the impact of PharmD students on clinical interventions is significant and improves overall patient care over a long-term period.

Cinnamon Supplementation in Patients with Type 2 Diabetes Mellitus

Diabetes mellitus is the sixth leading cause of death in the United States, and most patients with the disease have type 2 diabetes. The effectiveness of cinnamon supplementation in patients with type 2 diabetes has received a great deal of media attention after a study was published in 2003. Although the efficacy of cinnamon in patients with diabetes has not been established, many patients seek other therapies and supplement their prescribed pharmacologic therapy with cinnamon. We conducted a literature search, limited to English‐language human studies, using MEDLINE (1966–August 2006), EMBASE (1980–August 2006), International Pharmaceutical Abstracts (1970–August 2006), and Iowa Drug Information Service (1966–August 2006). References from articles and clinical trials were reviewed for additional sources; no abstracts were reviewed. We found two prospective, randomized, double‐blind, placebo‐controlled, peer‐reviewed clinical trials and one prospective, placebo‐controlled, peer‐reviewed clinical trial that evaluated the efficacy of cinnamon supplementation in patients with type 2 diabetes; a total of 164 patients were involved in these trials. Two of the studies reported modest improvements in lowering blood glucose levels with cinnamon supplementation in small patient samples. One trial showed no significant difference between cinnamon and placebo in lowering blood glucose levels. Overall, cinnamon was well tolerated. These data suggest that cinnamon has a possible modest effect in lowering plasma glucose levels in patients with poorly controlled type 2 diabetes. However, clinicians are strongly urged to refrain from recommending cinnamon supplementation in place of the proven standard of care, which includes lifestyle modifications, oral antidiabetic agents, and insulin therapy.

Sitagliptin: a novel agent for the management of type 2 diabetes mellitus.

PURPOSE The pharmacologic, pharmacokinetic, safety, clinical efficacy, and role of sitagliptin in the management of type 2 diabetes mellitus are reviewed. SUMMARY Sitagliptin is a dipeptidyl-peptidase IV (DPP4) inhibitor that increases insulin release and decreases glucagon levels by preventing the activation of incretin hormones--glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The clinical trials reviewed provide evidence that sitagliptin, either alone or in combination with metformin or thiazolidinediones, is effective in reducing glycosylated hemoglobin (HbA(1c)), fasting plasma glucose, and two-hour postprandial glucose levels in patients with type 2 diabetes. Specifically, sitagliptin has a role in patients who have been compliant with their oral hypoglycemic agents but unable to attain target HbA(1c) values with monotherapy and lifestyle modifications. Sitagliptin is generally well tolerated, with the frequency of adverse events being similar to placebo and a low frequency of hypoglycemia. Sitagliptin does not appear to alter the pharmacokinetics of metformin, rosiglitazone, glyburide, simvastatin, warfarin, or oral contraceptives. The addition of sitagliptin to a patients oral antidiabetic regimen would necessitate close monitoring for adverse events and possible drug interactions. The sitagliptin dosage recommended by the manufacturer is 100 mg once daily as monotherapy or in combination with metformin or a thiazolidinedione. No formal pharmacoeconomic evaluations of sitagliptin therapy have been conducted. CONCLUSION Sitagliptin, a DPP4 inhibitor, offers a novel treatment option for patients with type 2 diabetes mellitus.

Clevidipine for the treatment of severe hypertension in adults.

BACKGROUND Intravenous antihypertensive agents are used when immediate control of blood pressure (BP) is required, including during the perioperative cardiac surgery period. Controlling postoperative BP is challenging because of the need to adequately reduce BP while maintaining appropriate end-organ perfusion. Clevidipine is an intravenous, ultra-short-acting, third-generation dihydropyridine calcium channel antagonist with selectivity for arteriolar vasodilatation. It is approved by the US Food and Drug Administration for the treatment of severe hypertension. OBJECTIVE This paper reviews the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and clinical efficacy of clevidipine. METHODS To minimize selection bias, each author conducted an independent search for English-language publications indexed on MEDLINE and International Pharmaceutical Abstracts through January 2010 using the term clevidipine. All identified prospective, randomized and nonrandomized Phase III trials were included in the review. RESULTS Seven Phase III trials were identified in which clevidipine was compared with baseline, placebo, or other intravenous antihypertensive agents in the settings of severe hypertension (1 study), preoperative cardiac surgery (1), perioperative cardiac surgery (1), and postoperative cardiac surgery (4). In a multicenter, randomized, double-blind, placebo-controlled study of the efficacy of clevidipine in treating preoperative hypertension, the mean reduction from baseline in mean arterial pressure was 31.2% with clevidipine and 11.2% with placebo (P < 0.001). In a randomized, open-label, prospective study involving separate comparisons of clevidipine with nitroglycerin, sodium nitroprusside, and nicardipine, the median total AUC for digression in systolic BP from the predetermined target range differed significantly between clevidipine and nitroglycerin (4.14 vs 8.87 mm Hg . min/h; respectively, P < 0.001) and between clevidipine and sodium nitroprusside (4.37 vs 10.5 mm Hg . min/h; P = 0.003), but not between clevidipine and nicardipine (1.76 and 1.69 mm Hg . min/h). Another study found no significant difference in efficacy in controlling BP during the 3-hour study period between clevidipine and sodium nitroprusside (AUC for mean [SD] arterial pressure, 106 [25] and 101 [28] mm Hg . min/h, respectively). Adverse events in these studies included atrial fibrillation (13.0%-36.1% clevidipine vs 12.0% placebo), nausea (5.0%-21.0% vs 12.0%, respectively), fever (19.0% vs 13.7%), insomnia (12.0% vs 6.1%), and acute renal failure (9.0% vs 2.0%). In the studies reviewed, only 1 case of chest discomfort in the setting of severe hypertension was considered a serious adverse event related to clevidipine therapy. CONCLUSION In the Phase III trials reviewed, clevidipine was effective in controlling BP in the settings of perioperative cardiac surgery and severe hypertension and was associated with minimal adverse effects.

Adjunctive therapy with pramlintide in patients with type 1 or type 2 diabetes mellitus.

Uncontrolled diabetes mellitus is associated with both microvascular and macrovascular complications. Despite an array of treatment options available, achievement of euglycemia in most patients with diabetes is still lacking. Pramlintide acetate, a synthetic analog of the human hormone amylin and belonging to a new class of agents, was approved in March 2005 as adjunctive treatment in patients with type 1 or 2 diabetes mellitus. To evaluate the data available on the efficacy and safety of pramlintide, we conducted a search of MEDLINE (January 1966–May 2006) and International Pharmaceutical Abstracts (January 1970–May 2006). Bibliographies of clinical trials were reviewed for additional references. The literature reviewed demonstrated that pramlintide is effective in reducing levels of glycosylated hemoglobin and potentially preventing weight gain. The most commonly reported adverse effects associated with pramlintide were nausea, anorexia, and hypoglycemia. These adverse effects occurred more often during the initiation of therapy and were usually mild to moderate in nature. Whether this therapy is a cost‐effective option for patients with type 1 or type 2 diabetes mellitus is yet to be determined.

Inhaled Technosphere Insulin: A Novel Delivery System and Formulation for the Treatment of Types 1 and 2 Diabetes Mellitus

Complications from uncontrolled diabetes mellitus were reduced significantly with the introduction of insulin more than 90 years ago. Despite the proven benefits of normal glycemic levels, patients are deterred by the inconvenience and perceived pain related to multiple daily subcutaneous insulin injections. Inhaled insulin was first approved by the U.S. Food and Drug Administration (FDA) in 2006, but because profit margins did not achieve expectations, the drug manufacturer discontinued sales 2 years later. The second‐generation inhaled insulin, developed with Technosphere technology, received FDA approval in 2014. The pharmacology, pharmacokinetics, drug interactions, clinical safety and efficacy, patient satisfaction, dosage and administration, warnings, precautions, contraindications, adverse effects, and place in therapy of inhaled Technosphere insulin are reviewed in this article.

GLP1-RA Add-on Therapy in Patients with Type 2 Diabetes Currently on a Bolus Containing Insulin Regimen.

Adding glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) to basal insulin regimens has become a guideline‐recommended treatment option for uncontrolled type 2 diabetes. However, limited data exist to support the use of GLP‐1 RAs with insulin regimens, including bolus insulin in patients with type 2 diabetes. The primary objectives of this review were to identify if the combination of a GLP‐1 RA and an insulin regimen containing bolus insulin resulted in improvements in HbA1c, weight loss, reduction in insulin doses, and to evaluate the side effect profile of this combination in terms of nausea and hypoglycemia risk. Eight studies using exenatide twice/day, liraglutide, and dulaglutide were reviewed ranging in average duration of follow‐up from 3 to 15 months. Seven studies showed that addition of a GLP‐1 RA was associated with significant HbA1c reductions ranging from 0.4% to 1.64% from baseline to follow‐up. Patients in all eight studies had significant weight loss in the GLP‐1 RA arm from baseline to follow‐up ranging from 0.87 to 10.2 kg. In all the studies, total daily bolus insulin doses decreased 25–67% from baseline to follow‐up. In some studies, a portion of patients were able to discontinue bolus insulin all together after initiation of a GLP‐1 RA. In addition, in two randomized trials included in the review, the GLP‐1 RA arm showed significant improvement in HbA1c and weight compared with the control group who received basal/bolus regimens. Nausea was identified in 7–42% of participants using GLP‐1 RAs with insulin. Data support the use of GLP‐1 RAs added to insulin regimens already containing bolus insulin for glycemic control, weight loss, and reduction or discontinuation of bolus insulin.

Inhaled human [rDNA origin] insulin, a novel formulation for diabetes mellitus.

Diabetic complications have been reduced significantly with the introduction of insulin more than 8 decades prior. Despite the proven benefits of normal glycemic levels, patients are deterred by the inconvenience and expect worse pain than there is on average with multiple daily insulin injections. Inhaled insulin was approved by the Food and Drug Administration in early 2006 and is a novel product that introduces inhaled insulin as an alternate to the traditional subcutaneous delivery system, and hence could potentially improve patient compliance. The objective of this article is to review the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and tolerability of inhaled insulin.