Alan G. Meehan

Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo.

PURPOSE We analyzed data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression. MATERIALS AND METHODS A total of 3,047 patients with LUTS were randomized to either placebo, doxazosin (4 to 8 mg), finasteride (5 mg), or a combination of doxazosin and finasteride. Average length of followup was 4.5 years. The primary outcome was time to overall clinical progression of BPH, defined as either a confirmed 4-point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. We analyzed BPH progression event data from the 737 men who were randomized to placebo. RESULTS The rate of overall clinical progression of BPH events in the placebo group was 4.5 per 100 person-years, for a cumulative incidence (among men who had at least 4 years of followup data) of 17%. The risk of BPH progression was significantly greater in patients on placebo with a baseline TPV of 31 ml or greater vs less than 31 ml (p <0.0001), a baseline PSA of 1.6 ng/dl or greater vs PSA less than 1.6 ng/dl (p = 0.0009), a baseline Qmax of less than 10.6 ml per second vs 10.6 ml per second or greater (p = 0.011), a baseline PVR of 39 ml or greater vs less than 39 ml (p = 0.0008) and baseline age 62 years or older vs younger than 62 years (p = 0.0002). CONCLUSIONS Among men in the placebo arm, baseline TPV, PSA, Qmax, PVR and age were important predictors of the risk of clinical progression of BPH.

Effects of Laropiprant on Nicotinic Acid-Induced Flushing in Patients With Dyslipidemia

Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

Pharmacokinetics and Pharmacodynamic Effects of the Oral DPP-4 Inhibitor Sitagliptin in Middle-Aged Obese Subjects

Sitagliptin (MK‐0431) is an oral, potent, and selective dipeptidyl peptidase‐IV (DPP‐4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double‐blind, placebo‐controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle‐aged (45–63 years), nondiabetic, obese (body mass index: 30–40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady‐state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to ∼90% inhibition of plasma DPP‐4 activity, increased active glucagon‐like peptide‐1 (GLP‐1) levels by 2.7‐fold (P < .001), and decreased post—oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP‐4 activity, increased active GLP‐1, and reduced glycemic excursion.

Combination Therapy With Doxazosin and Finasteride for Benign Prostatic Hyperplasia in Patients With Lower Urinary Tract Symptoms and a Baseline Total Prostate Volume of 25 Ml or Greater

Purpose: We examined data from the Medical Therapy of Prostatic Symptoms trial to determine the relationship between baseline TPV and the effect of medical therapy in men with LUTS secondary to BPH.Materials and Methods: A total of 3,047 patients with LUTS were randomized to placebo, 4 to 8 mg doxazosin, 5 mg finasteride or the combination of doxazosin and finasteride. Average treatment duration was 4.5 years The primary outcome was time to overall clinical progression of BPH, defined as a confirmed 4 point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency or recurrent urinary tract infection. Secondary outcomes were the need for invasive therapy for BPH, and changes in AUA SS and the maximum urinary flow rate with time. TPV was measured by transrectal ultrasound at baseline and study end.Results: In patients with a small prostate (baseline TPV less than 25 ml) combination therapy was no better than doxazosin alone for decreasing the risk of clinical progression of ...

Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia

OBJECTIVES To evaluate the effects of finasteride, a specific type II 5-alpha-reductase inhibitor, on symptoms of benign prostatic hyperplasia, prostate volume, and urinary flow during a 7 to 8-year period. METHODS A total of 190 men with symptomatic benign prostatic hyperplasia and enlarged prostates entered one of two Phase II double-blind 3 to 6-month studies. Of these, 156 patients continued taking open-label finasteride, and more than 70 patients completed 7 to 8 years of treatment. The symptoms were scored using a patient self-administered modified Boyarsky symptom questionnaire. Prostate volume was measured by magnetic resonance imaging or ultrasonography, and the maximal urinary flow rate was assessed noninvasively. RESULTS Treatment with finasteride for 7 to 8 years led to sustained improvement in symptoms, reduction in prostate volume (28% from baseline), and increased urinary flow (median 2.5 mL/s from baseline). Decreases in dihydrotestosterone (86%) and prostate-specific antigen (54%) levels were also maintained. Long-term finasteride treatment was safe and generally well tolerated. CONCLUSIONS Long-term treatment with finasteride was well tolerated and resulted in durable symptom relief and improvement in prostate volume and urinary flow.

PCPT: Evidence that finasteride reduces risk of most frequently detected intermediate- and high-grade (Gleason score 6 and 7) cancer.

OBJECTIVES To determine the effect of finasteride relative to placebo on prostate cancer (PCa) risk at each individual Gleason score in the Prostate Cancer Prevention Trial using a post hoc generalization of a prespecified, exploratory, biopsy sampling density-adjusted analysis. METHODS The Prostate Cancer Prevention Trial enrolled 18 882 men aged >or=55 years with a prostate-specific antigen level of <3.0 ng/mL and normal digital rectal examination findings, and randomized them to finasteride 5 mg daily or placebo. PCa data from evaluable biopsies obtained within 7 years plus <or=90 days of randomization were examined. Polytomous logistic regression analysis of PCa risk was performed across individual Gleason scores using no PCa as the reference group, with no adjustment for multiplicity. The analysis model included treatment, age, race, first-degree family history of PCa, baseline prostate-specific antigen level, and the postrandomization variables of prostate volume and the number of biopsy cores at biopsy as covariates. RESULTS Finasteride significantly reduced the PCa risk relative to placebo across multiple Gleason scores (4 through 7), including a 58% reduction in Gleason score 5 PCa risk (P < .0001), a 52% reduction in Gleason score 6 PCa risk (P < .0001), and a 22% reduction in Gleason score 7 PCa risk (P = .0368). Finasteride had no significant effect on the risk of Gleason score 2, 3, or 8-10 cancer. CONCLUSIONS After adjusting for biopsy sampling density, finasteride significantly reduced the PCa risk relative to placebo across multiple Gleason scores in the Prostate Cancer Prevention Trial, including the most frequently detected intermediate- and high-grade cancers (Gleason scores 6 and 7).

Effects of finasteride on serum testosterone and body mass index in men with benign prostatic hyperplasia

OBJECTIVES To examine the effect of finasteride on serum testosterone in men with benign prostatic hyperplasia (BPH). METHODS The Proscar Long-Term Efficacy and Safety Study (PLESS) was a 4-year trial comparing the safety and efficacy of finasteride 5 mg with placebo in 3040 men with moderate to severe symptomatic BPH and enlarged prostates. PLESS included the prospective measurement of annual serum testosterone in a randomly selected subset of patients comprising approximately 10% of the randomized population (n = 301). RESULTS Finasteride treatment led to a modest, but significant (P <0.001), increase relative to placebo in serum testosterone, with this increase greatest in patients who had low baseline testosterone levels. The larger testosterone increases seen in finasteride-treated patients in the lower baseline testosterone tertiles were associated with significant mean reductions relative to placebo at year 4 in body mass index (BMI), ranging from 0.6 to 0.8 kg/m2. No statistically significant between-group difference was found in BMI in the upper testosterone tertile. The sexual adverse experience profiles for finasteride and placebo were similar across the baseline testosterone cohorts examined. CONCLUSIONS Finasteride treatment led to a generally modest increase relative to placebo in serum testosterone, with the greatest increases occurring in men with low baseline testosterone levels. The physiologic significance of these changes in men with low baseline testosterone levels is unclear, but the associated reduction in BMI is intriguing and may be related, because BMI is known to be negatively correlated with serum testosterone levels in men.

Long-Term Treatment With Finasteride Results in a Clinically Significant Reduction in Total Prostate Volume Compared to Placebo Over the Full Range of Baseline Prostate Sizes in Men Enrolled in the MTOPS Trial

PURPOSE In the present analysis we examined data from the MTOPS (Medical Therapy of Prostatic Symptoms) trial to determine the effect of long-term finasteride treatment, either alone or in combination with doxazosin, on total prostate volume across the full range of baseline total prostate volume values in men enrolled in this study. MATERIALS AND METHODS In this trial a total of 3,047 patients with lower urinary tract symptoms were randomized to placebo, doxazosin (4 to 8 mg), finasteride (5 mg) or the combination of doxazosin and finasteride (average length of treatment 4.5 years). Total prostate volume was measured by transrectal ultrasound in all patients at baseline, yearly and at study end or at termination of participation. RESULTS Long-term treatment with finasteride led to a consistent reduction of approximately 25% in total prostate volume compared to placebo in men with a relatively small prostate (less than 25 to 30 ml), as well as in those with a moderate size (30 to less than 40 ml) or enlarged prostate (40 ml or greater) at baseline. CONCLUSIONS In this MTOPS data analysis long-term (more than 4 years) treatment with finasteride, either alone or in combination with doxazosin, led to a consistent, clinically significant reduction in total prostate volume compared to placebo in patients with lower urinary tract symptoms and benign prostatic hyperplasia whose baseline prostate size ranged from relatively small (less than 25 to 30 ml) to enlarged (40 ml or greater).

Long-term treatment with finasteride 1 mg decreases the likelihood of developing further visible hair loss in men with androgenetic alopecia (male pattern hair loss)

There are no reports on the effects of pharmacologic treatment on the likelihood of developing further visible hair loss in men with androgenetic alopecia (AGA). Our objectives were to examine whether finasteride 1 mg treatment decreases the likelihood of developing further visible hair loss in men with AGA. We conducted an analysis of global photographic assessment data from two Phase III trials in which 1553 men with AGA received finasteride 1 mg/day or placebo for up to 5 years. Finasteride 1 mg treatment led to a 93% decrease relative to placebo in the 5-year likelihood of developing further visible hair loss (95% CI: 89-97%; p < 0.001). We conclude that, in men with AGA, treatment with finasteride 1 mg/day over 5 years led to a marked and sustained decrease in the likelihood of developing further visible hair loss.

Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia.

OBJECTIVES To compare the efficacy and safety of finasteride 5 mg in older (65 years old or older) versus younger (45 to younger than 65 years old) men with benign prostatic hyperplasia (BPH). METHODS The Proscar Long-Term Efficacy and Safety Study (PLESS) was a 4-year, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of finasteride 5 mg in 3040 men 45 to 78 years old with symptomatic BPH, enlarged prostates, and no evidence of prostate cancer. The endpoints included urinary symptoms, prostate volume, occurrence of acute urinary retention and/or BPH-related surgery, and safety. RESULTS In both age cohorts, finasteride treatment led to a 51% reduction (P <0.001) in the relative risk for acute urinary retention and/or BPH-related surgery, a significant (P <0.001) and durable improvement in symptom score, and a significant (P <0.001) and sustained reduction in prostate volume. Within each age cohort, no significant differences were found between the placebo and finasteride-treated patients in the incidence of cardiovascular adverse events. Significant differences were evident between the placebo and finasteride groups in the incidence of the typical, known, drug-related adverse events, but no specific differences were associated with age. No drug interactions of clinical importance were observed in the finasteride-treated patients. CONCLUSIONS The present analysis from PLESS demonstrates that in both older (65 years old or older) and younger men with symptomatic BPH and enlarged prostates, finasteride is highly effective in improving symptoms and reducing prostate volume in many men and in reducing the risk of acute urinary retention and BPH-related surgery. In addition, the safety profile of finasteride in both older and younger men is similar and no drug interactions of clinical importance were observed.