A novel long-acting formulation of oral buprenorphine/naloxone produces prolonged decreases in fentanyl self-administration by rhesus monkeys.

BACKGROUND: Due to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys. METHODS: Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days. RESULTS: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127-265 h*ng/ml. There were no signs of non-specific changes in behavior. CONCLUSIONS: A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).

Randomized trial of transversus abdominis plane block with liposomal bupivacaine after cesarean delivery with or without intrathecal morphine.

STUDY OBJECTIVE: To investigate efficacy and safety of liposomal bupivacaine (LB) transversus abdominis plane (TAP) block with or without intrathecal morphine (ITM) compared with ITM alone for postsurgical analgesia after cesarean delivery (CD). DESIGN: Multicenter, open-label, randomized trial (NCT03853694). SETTING: Operating room. PATIENTS: Women with term pregnancy of 37 to 42 weeks scheduled for elective CD under spinal anesthesia. INTERVENTION: Patients were randomized 1:1:1 to LB 266 mg TAP block alone (LB group), ITM 50 µg followed by LB 266 mg TAP block (LB + ITM group), or ITM 150 µg alone (ITM group). All groups received the same postsurgical multimodal analgesic regimen. MEASUREMENTS: The LB and LB + ITM groups were compared with the ITM group for all efficacy outcomes. Postsurgical opioid consumption in morphine milligram equivalents (MMEs) through 72 h was compared by assessing noninferiority before testing superiority. Postsurgical pruritus severity was assessed on an 11-point numerical rating scale. MAIN RESULTS: Between March 4, 2019, and January 10, 2020, 153 patients (LB, n = 52; LB + ITM, n = 48; ITM, n = 53) were enrolled. Baseline characteristics were comparable across groups. The LB group had statistically noninferior postsurgical opioid consumption through 72 h compared with the ITM group (least squares mean [LSM], 19.2 vs 16.4 MMEs; LSM treatment ratio, 1.17 [95% confidence interval (CI), 0.74-1.86]; noninferiority P < 0.0034) as did the LB + ITM group (LSM, 14.6 vs 16.4 MMEs; LSM treatment ratio, 0.89 [95% CI, 0.55-1.44]; noninferiority P < 0.0001). The LB and LB + ITM groups had significantly reduced pruritus severity scores through 12, 24, 48, and 72 h compared with the ITM group (P ≤ 0.0121). Adverse events occurred in 58%, 85%, and 81% of the LB, LB + ITM, and ITM groups, respectively. CONCLUSIONS: LB TAP block with or without ITM resulted in statistically noninferior postsurgical opioid consumption through 72 h, reduced pruritus, and favorable safety compared with ITM in women undergoing CD.

A multicenter study to evaluate the pharmacokinetics and safety of liposomal bupivacaine for postsurgical analgesia in pediatric patients aged 6 to less than 17 years (PLAY).

STUDY OBJECTIVE: To evaluate the pharmacokinetics and safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery. DESIGN: Multicenter, open-label, phase 3, randomized trial (PLAY; NCT03682302). SETTING: Operating room. PATIENTS: Two separate age groups were evaluated (age group 1: patients 12 to <17 years undergoing spine surgery; age group 2: patients 6 to <12 years undergoing spine or cardiac surgery). INTERVENTION: Randomized allocation of liposomal bupivacaine 4 mg/kg or bupivacaine hydrochloride (HCl) 2 mg/kg via local infiltration at the end of spine surgery (age group 1); liposomal bupivacaine 4 mg/kg via local infiltration at the end of spine or cardiac surgery (age group 2). MEASUREMENTS: The primary and secondary objectives were to evaluate the pharmacokinetics (eg, maximum plasma bupivacaine concentrations [Cmax], time to Cmax) and safety of liposomal bupivacaine, respectively. MAIN RESULTS: Baseline characteristics were comparable across groups. Mean Cmax after liposomal bupivacaine administration was lower versus bupivacaine HCl in age group 1 (357 vs 564 ng/mL); mean Cmax in age group 2 was 320 and 447 ng/mL for spine and cardiac surgery, respectively. Median time to Cmax of liposomal bupivacaine occurred later with cardiac surgery versus spine surgery (22.7 vs 7.4 h). In age group 1, the incidence of adverse events (AEs) was comparable between liposomal bupivacaine (61% [19/31]) and bupivacaine HCl (73% [22/30]). In age group 2, 100% (5/5) and 31% (9/29) of patients undergoing spine and cardiac surgery experienced AEs, respectively. AEs were generally mild or moderate, with no discontinuations due to AEs or deaths. CONCLUSIONS: Plasma bupivacaine levels following local infiltration with liposomal bupivacaine remained below the toxic threshold in adults (~2000-4000 ng/mL) across age groups and procedures. AEs were mild to moderate, supporting the safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery. Clinical trial number and registry URL: ClinicalTrials.gov identifier: NCT03682302.

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

Characterization of Device-Related Malfunction, Injury, and Death Associated with Using Elastomeric Pumps for Delivery of Local Anesthetics in the US Food and Drug Administration MAUDE Database.

PURPOSE: To characterize medical device reports about elastomeric pumps delivering local anesthesia made to the US Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database. PATIENTS AND METHODS: We conducted a retrospective review of medical device reports submitted to MAUDE from January 2010 to July 2018. A systematic, computerized algorithm was used to identify records pertaining to elastomeric pumps using local anesthesia. Included records indicated the use of local anesthesia or were determined to involve the use of local anesthetics (if they did not contain specific information on drug use). Reports were analyzed within the MAUDE event type categories of malfunction, injury, death, other, and missing. Possible cases of liver injury or surgical site infection were also identified. Manual review of narratives provided in MAUDE was performed by 2 reviewers to identify possible or probable cases of local anesthetic system toxicity (LAST). RESULTS: From a pool of 384,285 reports about elastomeric pumps from the MAUDE database, 4093 met inclusion criteria for involving elastomeric pumps to deliver local anesthetics, with the peak number of reports occurring in 2014. Of these identified reports, 3624 (88.5%) were categorized as malfunctions, 292 (7.1%) as injuries, and 8 (0.2%) as involving death. We identified 13 cases (0.3%) of possible liver injury and 51 cases (1.2%) of possible surgical site infection; 139 reports (3.4%) were determined to be probably (n=53) or possibly (n=86) associated with LAST. CONCLUSION: Malfunction of elastomeric pumps delivering local anesthetics leaves patients vulnerable to injury or death. Our study indicates that reports of malfunction, injury, and death have been reported to the MAUDE database. These reports likely reflect an underrepresentation of cases in the real-world population, emphasizing the need for more comprehensive medical device reporting.

A comparison of approaches to identify possible cases of local anesthetic systemic toxicity in the FDA Adverse Event Reporting System (FAERS) database.

BACKGROUND: Local anesthetic systemic toxicity (LAST) is a rare but potentially serious adverse event . METHODS: Data from the US Food and Drug Administration Adverse Event Reporting System were examined for liposomal bupivacaine (LB), bupivacaine, or other injectable local anesthetics. Possible LAST cases were identified based on MedDRA system organ classes (Approach 1), a recent publication (Approach 2), and a novel approach based on LAST literature (Approach 3). Disproportionality analyses compared possible LAST cases for LB and bupivacaine with other injectable local anesthetics. RESULTS: Approaches 1, 2, and 3 identified 75, 42, and 29 possible LAST cases associated with LB, respectively, compared with 9,595, 3,422, and 549 for other injectable local anesthetics. The proportional reporting ratios (95% CI) for LB versus other injectable local anesthetics for the 3 approaches were 1.9 (1.6-2.3), 2.9 (2.2-3.9), and 1.6 (1.1-2.2), respectively. Based on sales data, the estimated incidence of possible LAST with LB was 0.1 per 10,000 uses; literature estimates for LAST with other injectable local anesthetics were 0 to 18 per 10,000 uses. CONCLUSIONS: Our findings suggest the estimated incidence of possible LAST cases with LB is similar to, or less than, the reported incidence with other injectable local anesthetics.

Timed Bromocriptine-QR Therapy Reduces Progression of Cardiovascular Disease and Dysglycemia in Subjects with Well-Controlled Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD. This study evaluated the impact of bromocriptine-QR, a sympatholytic dopamine D2 receptor agonist, on progression of metabolic disease and CVD in T2DM subjects in good glycemic control (HbA1c ≤ 7.0%). METHODS: 1834 subjects (1219 bromocriptine-QR; 615 placebo) with baseline HbA1c ≤ 7.0% derived from the Cycloset Safety Trial (this trial is registered with ClinicalTrials.gov Identifier: NCT00377676), a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were evaluated. Treatment impact upon a prespecified composite CVD endpoint (first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina/congestive heart failure) and the odds of losing glycemic control (HbA1c >7.0% after 52 weeks of therapy) were determined. RESULTS: Bromocriptine-QR reduced the CVD endpoint by 48% (intention-to-treat; HR: 0.52 [0.28-0.98]) and 52% (on-treatment analysis; HR: 0.48 [0.24-0.95]). Bromocriptine-QR also reduced the odds of both losing glycemic control (OR: 0.63 (0.47-0.85), p = 0.002) and requiring treatment intensification to maintain HbA1c ≤ 7.0% (OR: 0.46 (0.31-0.69), p = 0.0002). CONCLUSIONS: Bromocriptine-QR therapy slowed the progression of CVD and metabolic disease in T2DM subjects in good glycemic control.

Impact of liposome bupivacaine on the adequacy of pain management and patient experiences following aesthetic surgery: Results from an observational study.

BACKGROUND: Despite the efficacy of opioid analgesics for postsurgical pain, they are associated with side effects that may complicate recovery. Liposome bupivacaine is a prolonged-release formulation of bupivacaine approved for intraoperative administration at the surgical site for postsurgical analgesia. OBJECTIVES: To evaluate the effect of a single intraoperative administration of liposome bupivacaine on postsurgical pain, opioid use and opioid-related side effects in subjects undergoing breast surgery and/or abdominoplasty. METHODS: In the present phase IV, multicentre, prospective observational study, subjects received a single intraoperative administration (266 mg) of liposome bupivacaine. Rescue analgesia was available to all subjects as needed. Outcome measures, assessed through postoperative day 3, included postsurgical pain intensity (11-point numerical rating scale), opioid consumption and overall benefit of analgesic score. Results were evaluated comparing investigators' previous experience with similar surgeries. RESULTS: Forty-nine subjects entered the study: 34 underwent breast surgery only and 15 underwent abdominoplasty with or without breast surgery (six underwent breast surgery in addition to abdominoplasty). Mean numerical rating scale pain scores remained ≤4.3 from discharge through postoperative day 3. Median daily oral opioid consumption was approximately 1.0 tablet postoperatively on the day of surgery and was approximately 2.0 tablets by postoperative day 3. Mean overall benefit of analgesic score ranged between 2.8 and 4.9 throughout the study. CONCLUSION: In this particular subject population, liposome bupivacaine was associated with low pain intensity scores and reduced opioid consumption compared with the investigators' previous experiences. Subjects' satisfaction with postsurgical analgesia was high, with a low burden of opioid-related side effects.

HISTORIQUE: Malgré l'efficacité des opioïdes pour soulager la douleur postchirurgicale, des effets secondaires peuvent compliquer le rétablissement. La bupivacaïne liposomique est une formulation à libération prolongée approuvée pour l'administration peropératoire d'une analgésie postchirurgicale au site opératoire. OBJECTIFS: Évaluer l'effet de l'administration peropératoire d'une seule dose de bupivacaïne liposomique sur la douleur postchirurgicale, ainsi que sur l'utilisation d'opioïdes et leurs effets secondaires chez des sujets subissant une chirurgie mammaire, une abdominoplastie ou les deux interventions. MÉTHODOLOGIE: Dans le cadre de la présente étude d'observation prospective et multicentrique de phase IV, les sujets se sont fait administrer une seule dose peropératoire de bupivacaïne liposomique (266 mg). Tous les sujets pouvaient recevoir une analgésie de secours, au besoin. Les mesures des résultats, évaluées jusqu'au troisième jour postopératoire, incluaient l'intensité de la douleur postchirurgicale (sur une échelle numérique de onze points), la consommation d'opioïdes et les bienfaits globaux du score analgésique. Les chercheurs ont évalué les résultats en les comparant à leur expérience de chirurgies similaires. RÉSULTATS: Quarante-neuf sujets ont participé à l'étude : 34 ont subi seulement une chirurgie mammaire et 15, une abdominoplastie accompagnée ou non d'une chirurgie mammaire (six ont subi une chirurgie mammaire en plus de l'abdominoplastie). Les scores de douleur moyens sur l'échelle numérique ne dépassaient pas 4,3 entre le congé et le troisième jour postopératoire. La consommation quotidienne médiane d'opioïdes par voie orale après l'opération était d'environ 1,0 comprimé le jour de la chirurgie et d'environ 2,0 comprimés le troisième jour postopératoire. Les avantages globaux moyens du score analgésique se situaient entre 2,8 et 4,9 tout au long de l'étude. CONCLUSION: Au sein de cette population de sujets, la bupivacaïne liposomique s'associait à de faibles scores d'intensité de la douleur et à une consommation réduite d'opioïdes par rapport aux expériences passées des chercheurs. Les sujets étaient très satisfaits de l'analgésie postchirurgicale et présentaient un faible fardeau d'effets secondaires liés aux opioïdes.

Impact of postsurgical opioid use and ileus on economic outcomes in gastrointestinal surgeries.

OBJECTIVES: To assess the incidence and economic impact of postoperative ileus (POI) following laparotomy (open) and laparoscopic procedures for colectomies and cholecystectomies in patients receiving postoperative pain management with opioids. METHODS: Using the Premier research database, we retrospectively identified adult inpatients discharged between 2008 and 2010 receiving postsurgical opioids following laparotomy and laparoscopic colectomy and cholecystectomy. POI was identified through ICD-9 diagnosis codes and postsurgical morphine equivalent dose (MED) determined. RESULTS: A total of 138,068 patients met criteria, and 10.3% had an ileus. Ileus occurred more frequently in colectomy than cholecystectomy and more often when performed by laparotomy. Ileus patients receiving opioids had an increased length of stay (LOS) ranging from 4.8 to 5.7 days, total cost from $9945 to $13,055 and 30 day all-cause readmission rate of 2.3 to 5.3% higher compared to patients without ileus. Patients with ileus received significantly greater MED than those without (median: 285 vs. 95 mg, p < 0.0001) and were twice as likely to have POI. MED above the median in ileus patients was associated with an increase in LOS (3.8 to 7.1 days), total cost ($8458 to $19,562), and readmission in laparoscopic surgeries (4.8 to 5.2%). Readmission rates were similar in ileus patients undergoing open procedures regardless of MED. CONCLUSIONS: Use of opioids in patients who develop ileus following abdominal surgeries is associated with prolonged hospitalization, greater costs, and increased readmissions. Furthermore, higher doses of opioids are associated with higher incidence of POI. Limitations are related to the retrospective design and the use of administrative data (including reliance on ICD-9 coding). Yet POI may not be coded and therefore underestimated in our study. Assessment of pre-existing disease and preoperative pain management was not assessed. Despite these limitations, strategies to reduce opioid consumption may improve healthcare outcomes and reduce the associated economic impact.

Development and validation of a risk score to identify patients at high risk for opioid-related adverse drug events.

BACKGROUND: Opioid-related adverse drug events (ORADEs) are common causes of hospitalization and increased health care costs. OBJECTIVES: To (a) estimate rates of specific adverse drug events (ADEs) among gastrointestinal (GI) surgery patients receiving postoperative opioids; (b) examine the utility of a risk-scoring model in categorizing patients at high risk of experiencing ORADEs; and (c) quantify potential clinical/economic benefits of targeting high-risk GI surgical patients for opioid-sparing regimens in terms of hospitalization cost, length of stay (LOS), and 30-day readmission rates. METHODS: Using a retrospective design based on an administrative database, patients with an inpatient surgical procedure between January 1, 2010, and December 31, 2010, were included. GI surgical patients aged greater than 18 years followed from admission through 30 days postdischarge were characterized as high or low risk using clinical/demographic characteristics and were evaluated for several outcomes. Using multivariate logistic regression, the ORADE incidence, total hospitalization cost, LOS, and 30-day readmissions were compared for high-risk and low-risk patients. RESULTS: In 87.8% (n = 3,235) of the surgical population, there was a strong concordance between risk assignment and ORADE incidence. Among the remaining 12.2% (n = 449) of patients, 5.5% (n = 202) were low risk with an ORADE, and 6.7% (n = 247) were high risk without an ORADE. Overall, 20.6% (n = 344) of high-risk patients experienced ≥1 ORADE (mean cost: $31,988; LOS: 12.1 days) compared with only 5.3% (n = 107) of low-risk patients (mean cost: $25,216; LOS: 8.0 days). High-risk patients had higher hospitalization costs and longer LOS than low-risk patients, respectively (mean cost: $19,234 vs. $13,036; mean LOS: 6.8 days vs. 3.3 days). These differences correspond to 47.0% higher costs for high-risk patients and an LOS approximately twice as long compared with low-risk patients. CONCLUSIONS: Patient clinical/demographic characteristics influence the risk of developing ORADEs. Risk assessment tools can effectively identify high-risk patients, thereby enabling interventions that can reduce ORADEs, decrease hospital costs, and improve postsurgical experiences for patients.

Erectile dysfunction diagnosis and treatment as a means to improve medication adherence and optimize comorbidity management.

INTRODUCTION: Optimal pharmacologic management of diseases comorbid with erectile dysfunction (ED), such as cardiovascular disease, depression, diabetes, dyslipidemia, hypertension, and benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), is dependent upon long-term treatment compliance and may be complicated by poor adherence to medication use. ED may contribute to poor adherence to medication use because poor quality erectile function may be an unwanted adverse effect of antihypertensives, antidepressants, and 5-α reductase inhibitors for treatment of BPH/LUTS. Diminished erectile spontaneity, rigidity, and/or sustaining capability also negatively affects mood, self-esteem, and confidence, which compromise motivation to be compliant with medications that treat diseases comorbid with ED. AIM: Literature review was performed to explore the role of ED diagnosis and effective treatment in enhancing overall management of selected ED comorbidities, highlighting the role of medication adherence. METHODS: Several PubMed searches were performed. RESULTS: Diagnosis and successful treatment of concomitant ED may promote improved adherence and management of comorbid diseases. Concomitant ED management may improve treatment outcome, decrease healthcare costs, and possibly prevent or even improve deterioration in medical conditions comorbid with ED. Because ED is a silent marker and predictor of comorbidities, especially cardiovascular disease, earlier diagnosis of ED may provide an opportunity to prevent future cardiovascular events. In men presenting with complaints of ED, screening for, monitoring, and appropriately treating diseases that are comorbid with ED is essential. Screening for and appropriately treating ED is important for enhanced life quality and improved motivation in men with existing ED comorbidities or risk factors. CONCLUSIONS: Appropriate management of ED and its risk factors may have beneficial effects on diseases that are comorbid with ED, and vice versa, most likely via shared pathophysiological pathways. Clinicians may need to consider men's health overall, of which sexual health is a central component, in order to provide optimal disease management.

Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents.

OBJECTIVE: To investigate the effect of Bromocriptine-QR on glycemic control in patients with type 2 diabetes whose glycemia is poorly controlled on one or two oral anti-diabetes agents. METHODS: Five hundred fifteen Type 2 Diabetes Mellitus (T2DM) subjects (ages 18 to 80 and average body mass index [BMI] of 32.7) with baseline HbA1c ≥ 7.5 and on one or two oral anti-diabetes (OAD) medications (metformin, sulfonylurea, and/or thiazolidinediones) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 24 week treatment period. Study investigators were allowed to adjust, if necessary, subject anti-diabetes medications during the study to attempt to achieve glycemic control in case of glycemic deterioration. The impact of bromocriptine-QR treatment intervention on glycemic control was assessed in subjects on any one or two OADs (ALL treatment category) (N = 515), or on metformin with or without another OAD (Met/OAD treatment category) (N = 356), or on metformin plus a sulfonylurea (Met/SU treatment category) (N = 245) 1) by examining the between group difference in change from baseline a) concomitant OAD medication changes during the study, and b) HbA1c and 2) by determining the odds of reaching HbA1c of ≤ 7.0% on bromocriptine-QR versus placebo. RESULTS: Significantly more patients (approximately 1.5 to 2-fold more; P<.05) intensified concomitant anti-diabetes medication therapy during the study in the placebo versus the bromocriptine-QR arm. In subjects that did not change the intensity of the baseline diabetes therapy (72%), and that were on any one or two OADs (ALL), or on metformin with or without another OAD (Met/OAD), or on metformin plus sulfonylurea (Met/SU), the HbA1c change for bromocriptine-QR versus placebo was -0.47 versus +0.22 (between group delta of -0.69, P<.0001), -0.55 versus +0.26 (between group delta of -0.81, P<.0001) and -0.63 versus +0.20 (between group delta of -0.83, P<.0001) respectively, after 24 weeks on therapy. The odds ratio of reaching HbA1c of ≤ 7.0% was 6.50, 12.03 and 11.45 (P<.0002) for these three groups, respectively. CONCLUSION: In T2DM subjects whose hyperglycemia is poorly controlled on one or two oral agents, bromocriptine-QR therapy for 24 weeks can provide significant added improvement in glycemic control relative to adding placebo.

Effect of bromocriptine-QR (a quick-release formulation of bromocriptine mesylate) on major adverse cardiovascular events in type 2 diabetes subjects.

BACKGROUND: Bromocriptine-QR (a quick-release formulation of bromocriptine mesylate), a dopamine D2 receptor agonist, is a US Food and Drug Administrration-approved treatment for type 2 diabetes mellitus (T2DM). A 3070-subject randomized trial demonstrated a significant, 40% reduction in relative risk among bromocriptine-QR-treated subjects in a prespecified composite cardiovascular (CV) end point that included ischemic-related (myocardial infarction and stroke) and nonischemic-related (hospitalization for unstable angina, congestive heart failure [CHF], or revascularization surgery) end points, but did not include cardiovascular death as a component of this composite. The present investigation was undertaken to more critically evaluate the impact of bromocriptine-QR on cardiovascular outcomes in this study subject population by (1) including CV death in the above-described original composite analysis and then stratifying this new analysis on the basis of multiple demographic subgroups and (2) analyzing the influence of this intervention on only the "hard" CV end points of myocardial infarction, stroke, and CV death (major adverse cardiovascular events [MACEs]). METHODS AND RESULTS: Three thousand seventy T2DM subjects on stable doses of ≤2 antidiabetes medications (including insulin) with HbA1c ≤10.0 (average baseline HbA1c=7.0) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 52-week treatment period. Subjects with heart failure (New York Heart Classes I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. Study outcomes included time to first event for each of the 2 CV composite end points described above. The relative risk comparing bromocriptine-QR with the control for the cardiovascular outcomes was estimated as a hazard ratio with 95% confidence interval on the basis of Cox proportional hazards regression. The statistical significance of any between-group difference in the cumulative percentage of CV events over time (derived from a Kaplan-Meier curve) was determined by a log-rank test on the intention-to-treat population. Study subjects were in reasonable metabolic control, with an average baseline HbA1c of 7.0±1.1, blood pressure of 128/76±14/9, and total and LDL cholesterol of 179±42 and 98±32, respectively, with 88%, 77%, and 69% of subjects being treated with antidiabetic, antihypertensive, and antihyperlipidemic agents, respectively. Ninety-one percent of the expected person-year outcome ascertainment was obtained in this study. Respecting the CV-inclusive composite cardiovascular end point, there were 39 events (1.9%) among 2054 bromocriptine-QR-treated subjects versus 33 events (3.2%) among 1016 placebo subjects, yielding a significant, 39% reduction in relative risk in this end point with bromocriptine-QR exposure (P=0.0346; log-rank test) that was not influenced by age, sex, race, body mass index, duration of diabetes, or preexisting cardiovascular disease. In addition, regarding the MACE end point, there were 14 events (0.7%) among 2054 bromocriptine-QR-treated subjects and 15 events (1.5%) among 1016 placebo-treated subjects, yielding a significant, 52% reduction in relative risk in this end point with bromocriptine-QR exposure (P<0.05; log-rank test). CONCLUSIONS: These findings reaffirm and extend the original observation of relative risk reduction in cardiovascular adverse events among type 2 diabetes subjects treated with bromocriptine-QR and suggest that further investigation into this impact of bromocriptine-QR is warranted. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique Identifier: NCT00377676.

Statins and prostate cancer diagnosis and grade in a veterans population.

BACKGROUND: Although prostate cancer is commonly diagnosed, few risk factors for high-grade prostate cancer are known and few prevention strategies exist. Statins have been proposed as a possible treatment to prevent prostate cancer. METHODS: Using electronic and administrative files from the Veterans Affairs New England Healthcare System, we identified 55,875 men taking either a statin or antihypertensive medication. We used age- and multivariable-adjusted Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer incidence among patients taking statins (n = 41,078) compared with patients taking antihypertensive medications (n = 14,797). We performed similar analyses for all lipid parameters including total cholesterol examining each lipid parameter as a continuous variable and by quartiles. All statistical tests were two-sided. RESULTS: Compared with men taking an antihypertensive medication, statin users were 31% less likely (HR = 0.69, 95% CI = 0.52 to 0.90) to be diagnosed with prostate cancer. Furthermore, statin users were 14% less likely (HR = 0.86, 95% CI = 0.62 to 1.20) to be diagnosed with low-grade prostate cancer and 60% less likely (HR = 0.40, 95% CI = 0.24 to 0.65) to be diagnosed with high-grade prostate cancer compared with antihypertensive medication users. Increased levels of total cholesterol were also associated with both total (HR = 1.02, 95% CI = 1.00 to 1.05) and high-grade (HR = 1.06, 95% CI = 1.02 to 1.10) prostate cancer incidence but not with low-grade prostate cancer incidence (HR = 1.01, 95% CI = 0.98 to 1.04). CONCLUSIONS: Statin use is associated with statistically significantly reduced risk for total and high-grade prostate cancer, and increased levels of serum cholesterol are associated with higher risk for total and high-grade prostate cancer. These findings indicate that clinical trials of statins for prostate cancer prevention are warranted.

Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes.

OBJECTIVE: Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patient's usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin). The all-cause-safety end point was the occurrence of any serious adverse event (SAE), with a hazard ratio (HR) noninferiority margin of 1.5. In a prespecified analysis, the frequency of cardiovascular disease (CVD) events defined as a composite of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure was evaluated using modified intent-to-treat analysis (clinicaltrials.gov, NCT00377676). RESULTS: In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98 (9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respecively) (HR 0.60 [95% two-sided CI 0.35-0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group. CONCLUSIONS: The frequency of SAEs was comparable between the treatment arms. Compared with patients in the placebo arm, fewer patients taking bromocriptine-QR experienced a cardiovascular end point.