Daniel M. Riche

Thiazolidinediones and risk of repeat target vessel revascularization following percutaneous coronary intervention : A meta-analysis

OBJECTIVE—Thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are a class of antidiabetes agents that have a high affinity for peroxisome proliferator–activated receptor-γ. TZDs initiate a multitude of physiologic processes that may elicit benefits as systemic agents for the prevention of restenosis requiring revascularization following percutaneous coronary intervention (PCI). Numerous trials have evaluated the impact of TZDs on repeat target vessel revascularization (TVR) in patients following PCI; however, several limitations (small sample size, inconclusive results, and risk factor stratification) complicate definitive conclusions. A meta-analysis was performed to evaluate the impact of TZDs on repeat TVR following PCI. RESEARCH DESIGN AND METHODS—Included trials met the following criteria: 1) prospective, randomized controlled trials evaluating available TZDs versus standards of care; 2) well-described protocol; 3) minimum of 6 months of follow-up; and 4) data provided on repeat TVR. Data are presented as relative risks (RRs) with 95% CIs. RESULTS—Seven clinical trials (n = 608) met the inclusion criteria. Upon meta-analysis, the risk of repeat TVR was significantly reduced in patients who received TZD therapy compared with standards of care (RR 0.35 [95% CI 0.22–0.57]). In studies using rosiglitazone (0.45 [0.25–0.83]) and pioglitazone (0.24 [0.11–0.51]), risk of repeat TVR was significantly reduced. Risk of repeat TVR was also significantly reduced among patients with (0.34 [0.19–0.63]) and without (0.37 [0.18–0.77]) diabetes. CONCLUSIONS—Results from this meta-analysis suggest that TZDs effectively reduce the risk of repeat TVR following PCI.

Analysis of safety from a human clinical trial with pterostilbene.

Objectives. The purpose of this trial was to evaluate the safety of long-term pterostilbene administration in humans. Methodology. The trial was a prospective, randomized, double-blind placebo-controlled intervention trial enrolling patients with hypercholesterolemia (defined as a baseline total cholesterol ≥200 mg/dL and/or baseline low-density lipoprotein cholesterol ≥100 mg/dL). Eighty subjects were divided equally into one of four groups: (1) pterostilbene 125 mg twice daily, (2) pterostilbene 50 mg twice daily, (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, and (4) matching placebo twice daily for 6–8 weeks. Safety markers included biochemical and subjective measures. Linear mixed models were used to estimate primary safety measure treatment effects. Results. The majority of patients completed the trial (91.3%). The average age was 54 years. The majority of patients were females (71%) and Caucasians (70%). There were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. There were no statistically significant self-reported or major ADRs. Conclusion. Pterostilbene is generally safe for use in humans up to 250 mg/day.

New Obesity Agents: Lorcaserin and Phentermine/Topiramate

OBJECTIVE To evaluate the evidence for lorcaserin and phentermine/topiramate in the treatment of obesity. DATA SOURCES Literature was accessed through PubMed (June 1975-March 2013) using the search terms lorcaserin, phentermine, topiramate, or phentermine/topiramate. Additionally, reference citations from publications identified were reviewed. Additional information was obtained from the Food and Drug Administration (FDA)–approved prescribing information and FDA briefing documents. STUDY SELECTION AND DATA EXTRACTION English-language articles focusing on Phase 3 clinical trials for obesity were critiqued. Data from preclinical and Phase 1 and/or 2 trials are reported when appropriate. Six prospective Phase 3 trials were reviewed. DATA SYNTHESIS Obesity has reached epidemic proportions, affecting more than one third of adults in the US. Two medication products, lorcaserin and phentermine/topiramate, have recently received FDA approval as adjuncts to a reduced-calorie diet and increased physical activity among individuals with a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 27 kg/m2 with an obesity-related comorbidity, such as hypertension, dyslipidemia, or diabetes. Lorcaserin is a selective serotonin 5-HT2C agonist that regulates food intake, while the combination of phentermine/topiramate causes appetite suppression and enhanced satiety. Three Phase 3 randomized, placebo-controlled trials reported approximately 75% and 45% of patients achieved greater than or equal to 5% weight loss with phentermine/topiramate and lorcaserin, respectively. CONCLUSIONS With lifestyle modification, phentermine/topiramate appears most effective in terms of weight loss. Lorcaserin demonstrates moderate efficacy. Long-term cardiovascular outcomes studies are needed to confirm the safety and benefit of these new obesity agents.

Orlistat: current status in clinical therapeutics

Background: Obesity has rapidly become a life-threatening epidemic worldwide. There are a plethora of obesity-related co-morbidities and complications that increase morbidity, mortality and cost of care associated with obesity. Orlistat is approved for the treatment of obesity and has been evaluated both in obesity and in the several obesity-related co-morbidities. Objective: The purpose of this article is to provide detail of the pharmacotherapeutic role of orlistat in obesity, describe orlistat and its pharmacological properties, critique the evidence for orlistats use in obesity and obesity-related co-morbidities, and define the role of orlistat in clinical practice. Methods: A thorough, all-inclusive literature search was conducted to isolate clinical trials, case reports and meta-analyses evaluating the safety and efficacy of orlistat in various patient populations. Results: Orlistats unique mechanism of action, beneficial effects on multiple co-morbidity surrogates and relatively mild adverse effect and drug interaction profile position it favorably as the first option for pharmacotherapy in comprehensive obesity management of adults and children.

Impact of Sitagliptin on Markers of β-cell Function: A Meta-Analysis

Background:Progressive &bgr;-cell dysfunction and &bgr;-cell failure are fundamental pathogenic consequences of type 2 diabetes. Dipeptidyl peptidase-IV inhibitors may exhibit improvement on preclinical measures of both &bgr;-cell function, homeostasis model assessment of &bgr;-cell (HOMA-&bgr;) index, and &bgr;-cell dysfunction, proinsulin/insulin ratio (PI/IR), correlating to &bgr;-cell survival. Research Design and Methods:A systematic literature search through July 2008 was conducted to extract a consensus of randomized, controlled trials of sitagliptin therapy on measures of &bgr;-cell function. A random-effects model meta-analysis evaluated effects on HOMA-&bgr; and PI/IR versus placebo. Several subgroup analyses, including active control, were conducted. Studies were included if they met the following criteria: (1) randomized trials on sitagliptin; (2) placebo or active control; and (3) data reported on HOMA-&bgr; or PI/IR. Results:A total of 11 trials (n = 3039) reported effects on HOMA-&bgr; and 8 trials (n = 2325) on PI/IR versus placebo. Four trials (n = 1425) were included in the active control subgroup analysis. Sitagliptin significantly improved HOMA-&bgr; index by 12.03% [95% confidence interval (CI), 9.45-14.60] versus placebo. Sitagliptin also significantly decreased PI/IR −0.06 (95% CI, −0.08 to −0.04). Sitagliptin was inferior to active control for HOMA-&bgr; index [5.64% (95% CI, 0.38-10.90)], but not different in terms of PI/IR [0.01 (95% CI, −0.04 to 0.06)]. Conclusions:Despite significant improvement in HOMA-&bgr; index and PI/IR from placebo, there does not seem to be a benefit of dipeptidyl peptidase-IV inhibitors over other agents with respect to &bgr;-cell function/activity. Long-term prevention of &bgr;-cell dysfunction cannot be ruled out.

Transdermal testosterone replacement therapy in men.

Androgen deficiency syndrome in men is a frequently diagnosed condition associated with clinical symptoms including fatigue, decreased libido, erectile dysfunction, and metabolic syndrome. Serum testosterone concentrations decline steadily with age. The prevalence of androgen deficiency syndrome in men varies depending on the age group, known and unknown comorbidities, and the respective study group. Reported prevalence rates may be underestimated, as not every man with symptoms of androgen deficiency seeks treatment. Additionally, men reporting symptoms of androgen deficiency may not be correctly diagnosed due to the vagueness of the symptom quality. The treatment of androgen deficiency syndrome or male hypogonadism may sometimes be difficult due to various reasons. There is no consensus as to when to start treating a respective man or with regards to the best treatment option for an individual patient. There is also lack of familiarity with treatment options among general practitioners. The formulations currently available on the market are generally expensive and dose adjustment protocols for each differ. All these factors add to the complexity of testosterone replacement therapy. In this article we will discuss the general indications of transdermal testosterone replacement therapy, available formulations, dosage, application sites, and recommended titration schedule.

Bone Loss and Fracture Risk Associated with Thiazolidinedione Therapy

The increasing use of thiazolidinediones for the treatment of type 2 diabetes mellitus, coupled with the potential for fractures in the aging population, poses a significant concern for health care providers. This concern is based on many reports of postapproval adverse musculoskeletal effects, particularly bone changes and fractures. To better understand the effects of thiazolidinediones on bone health, we conducted a PubMed search of articles published from January 1966‐June 2009. We reviewed the hypothesized mechanisms for thiazolidinedione‐induced adverse effects on bone, studies that evaluated thiazolidinedione use and fracture risk, potential treatment options for fracture minimization, and future directions for research. Thiazolidinedione‐induced bone changes may stem from the ability of these drugs to reduce the activity of osteoblasts without an appreciable effect on osteoclasts, shifting the balance of bone homeostasis to favor bone loss. Clinical data suggest that treating patients who have type 2 diabetes with thiazolidinediones has detrimental effects on bone health, as measured by reduced bone mineral density and increased fracture rates, notably distal extremity fractures in female patients. Thiazolidinediones are selective peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists; thus, continued pursuit of PPAR system selectivity and investigation of other PPAR agonists are crucial to understanding and avoiding these detrimental effects. Clinicians, particularly pharmacists, must take an active role in educating colleagues on the importance of screening thiazolidinedione‐treated patients for fracture risk, counseling patients on adequate calcium and vitamin D intake and fall prevention, and appropriately selecting therapy for secondary prevention of fracture.

Insulin—Carcinogen or Mitogen? Preclinical and Clinical Evidence from Prostate, Breast, Pancreatic, and Colorectal Cancer Research

Abstract Diabetes mellitus is a chronic disease that affects > 23.6 million Americans, and occurs when the body is unable to produce or becomes resistant to endogenous insulin. This alteration of insulins action reduces adequate utilization of glucose transporter type 4 (GLUT4) receptors, which are responsible for cellular glucose uptake. Thus, exogenous administration of human insulin and insulin analogs is an important modality used to reduce morbidity and mortality in both type 1 and type 2 diabetes. According to 2007 estimates, 27% of all patients with diabetes use some form of insulin therapy. The increasing utilization of insulin has become a cause for concern because findings from several observational trials have suggested an association with an increased risk of developing cancer. To help elucidate the potential interplay between insulin use and cancer, we searched PubMed and MEDLINE to identify articles that assessed the carcinogenic and/or mitogenic potential of diabetes treatments, focusing on insulin specifically. Data from our review suggest that insulin analogs, particularly insulin glargine, may play more of a mitogenic than a carcinogenic role in association with different types of cancer, suggesting an amplified rate of existing tumor growth in the presence of insulin analogs. Evidence for insulin-induced mitogenicity appears to be most prevalent in prostate, breast, pancreatic, and colorectal cancers. In conclusion, the positive effects of insulin therapy on reducing morbidity and mortality in diabetes greatly outweigh the risks at this time. However, clinicians must be diligent in both screening for new cancers in patients receiving insulin and in monitoring for tumor growth or maintenance of remission in patients with existing cancers.

Denosumab, a RANK Ligand Inhibitor, for Postmenopausal Women with Osteoporosis

OBJECTIVE: To review the evidence for use of denosumab for the treatment of postmenopausal osteoporosis. DATA SOURCES: A search of MEDLINE and EMBASE databases was conducted during January 2012, using the terms denosumab and osteoporosis, with index dates of 2000 to 2011. Additional information was gathered from Amgen and references cited in articles retrieved. STUDY SELECTION AND DATA EXTRACTION: English-language articles including clinical trials involving denosumab for treatment of osteoporosis and review articles were reviewed. Articles using denosumab in males or as treatment for conditions other than osteoporosis or osteopenia were excluded. DATA SYNTHESIS: Many clinical trials have supported the safety and efficacy of denosumab in postmenopausal women with bone loss. It has been shown to improve bone mineral density, decrease markers of bone turnover, and prevent new vertebral fractures. It shows improvement over placebo in studies and has at least similar efficacy to alendronate in measurements of bone mineral density, with less risk for osteonecrosis of the jaw and atypical fracture, but with an increased risk of infections and neoplasms. European cost-effectiveness studies have also demonstrated that denosumab is a cost-effective choice compared to risedronate and no treatment for fracture prevention for postmenopausal women with osteoporosis. CONCLUSIONS: Denosumab has demonstrated efficacy and safety as a first-line treatment for postmenopausal osteoporosis in multiple clinical trials over at least 6 years. It may be most cost-effective for women who are unable or refuse to take bisphosphonate drugs.

Pterostilbene on Metabolic Parameters: A Randomized, Double-Blind, and Placebo-Controlled Trial

Introduction. The purpose of this trial was to evaluate the effect of pterostilbene on metabolic parameters. Methods. A prospective, randomized, double-blind, and placebo-controlled study that enrolled 80 patients with a total cholesterol ≥200 mg/dL and/or LDL ≥ 100 mg/dL. Subjects were divided into four groups: (1) pterostilbene 125 mg twice daily; (2) pterostilbene 50 mg twice daily; (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily; (4) matching placebo twice daily for 6–8 weeks. Endpoints included lipids, blood pressure, and weight. Linear mixed models were used to examine and compare changes in parameters over time. Models were adjusted for age, gender, and race. Results. LDL increased with pterostilbene monotherapy (17.1 mg/dL; P = 0.001) which was not seen with GE combination (P = 0.47). Presence of a baseline cholesterol medication appeared to attenuate LDL effects. Both systolic (−7.8 mmHg; P < 0.01) and diastolic blood pressure (−7.3 mmHg; P < 0.001) were reduced with high dose pterostilbene. Patients not on cholesterol medication (n = 51) exhibited minor weight loss with pterostilbene (−0.62 kg/m2; P = 0.012). Conclusion. Pterostilbene increases LDL and reduces blood pressure in adults. This trial is registered with Clinicaltrials.gov NCT01267227.