Use of Low-Density Lipoprotein-Lowering Therapies Before and After PCSK9 Inhibitor Initiation.

Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are used to reduce low-density lipoprotein (LDL) cholesterol. PCSK9i use after initiation, as well as persistence with or alterations to other LDL-lowering therapy after PCSK9i initiation, is not well understood. Methods and Results We conducted a retrospective study of alirocumab or evolocumab (PCSK9i) new users from July 2015 to December 2017 in the MarketScan Early View database of US commercial insurance beneficiaries. We determined the prevalence of PCSK9i interruption (≥30-day gap in supply) and LDL-lowering therapy use in the year after PCSK9i initiation. The average age of 6151 patients initiating PCSK9i therapy was 63 years, 44.4% were women, and 76.8% had atherosclerotic cardiovascular disease. Overall, 52.2% (95% CI, 50.8%-53.7%) of patients had an interruption in PCSK9i therapy in the first year after treatment initiation and 62.5% remained on PCSK9i therapy at 1-year postinitiation. Also, 27.7% of patients were taking a statin at the time of PCSK9i initiation, with only 22.4% on statin therapy at 1 year after PCSK9i initiation. Ezetimibe use decreased from 20.9% at the time of PCSK9i initiation to 12.0% a year later. By 1 year after PCSK9i initiation, 44.0% of patients had experienced an interruption in all LDL-lowering therapies, and 26.6% were no longer on any LDL-lowering therapies. Conclusions After PCSK9i initiation, statins were often discontinued, whereas more than half of patients experienced an interruption in PCSK9i therapy. These results suggest that many new PCSK9i users may remain at high risk for cardiovascular events because of interruptions in LDL-lowering therapy.

Lipid-Lowering Prescription Patterns in Patients With Diabetes Mellitus or Cardiovascular Disease.

The purpose of this study is to describe lipid-lowering therapy (LLT) prescriptions and low-density lipoprotein cholesterol (LDL-C) monitoring in patients with diabetes mellitus (DM) with or without concomitant cardiovascular disease (CVD). Olmsted County, Minnesota residents with a first-ever diagnosis of DM or CVD (ischemic stroke/transient ischemic attack, myocardial infarction, unstable angina pectoris, or revascularization procedure) between 2005 and 2012 were classified as having DM only, CVD only, or CVD + DM. All LLT prescriptions and LDL-C measurements were obtained for 2 years after diagnosis. A total of 4,186, 2,368, and 724 patients had DM, CVD, and CVD + DM, respectively. Rates of LDL-C measurement were 1.31, 1.66, and 1.88 per person-year and 14%, 32%, and 42% of LDL-C measurements were <70 mg/dl in those with DM, CVD, and CVD + DM. Within 3 months after diagnosis, 47%, 71%, and 78% of patients with DM, CVD, and CVD + DM were prescribed LLT. Most prescriptions were for moderate-intensity statins. Under one-fifth of patients with CVD and CVD + DM were prescribed high-intensity statins. Predictors of high-intensity statin prescriptions included male sex, having CVD or CVD + DM, increasing LDL-C, and LDL-C measured more recently (2012 to 2014 vs before 2012). In conclusion, a large proportion of patients at high CVD risk are not adequately treated with LLT. Despite often being considered a risk equivalent, patients with DM have substantially lower rates of LLT prescriptions and lesser controlled LDL-C than those with CVD or CVD + DM.

Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents. OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. METHODS: This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged >or=18 years with type 2 diabetes were randomly assigned to receive exenatide 5 microg, exenatide 10 microg, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA(1c)); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA(1c) values or=1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 microg, 3%; 10 microg, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-microg and placebo groups, respectively (P = NS), with no incidents of severe hypoglycemia reported. CONCLUSIONS: In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA(1c), improved fasting and postprandial glucose control, reduced weight, improved beta-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.

Effect of 2013 ACC/AHA Blood Cholesterol Guidelines on Statin Treatment Patterns and Low-Density Lipoprotein Cholesterol in Atherosclerotic Cardiovascular Disease Patients.

BACKGROUND: Preceding release of the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines, prescribers aimed for specific low-density lipoprotein cholesterol (LDL-C) goals in patients with atherosclerotic cardiovascular disease (ASCVD). The 2013 guidelines changed this focus to treating patients with appropriate statin intensity given their ASCVD risk. We examined statin use and LDL-C levels before and after the 2013 ACC/AHA guidelines in patients with clinical ASCVD as defined in the guidelines. METHODS AND RESULTS: We conducted a retrospective cohort study of adult commercial and Medicare Advantage health plan enrollees in the Optum Research Database. Patients had ≥1 claim with a diagnosis of clinical ASCVD between November 1, 2012 and December 31, 2014 and were continuously enrolled 6 months before (baseline) and 7 months after (follow-up) the first ASCVD visit. Patients were assigned to monthly cohorts based on ASCVD event month. Statin use and intensity were measured at baseline and first month of follow-up. LDL-C changes were assessed using ordinary least squares regression. For 90 287 patients, mean (SD) age was 68 (12) years; 50% were female; and 30% had commercial insurance. Statin use remained consistent before and after guidelines (32% and 31%, respectively). Of patients receiving statins, high-intensity use increased by 4 percentage points 1 year after guidelines (P<0.001). Mean LDL-C levels were 2.4 mmol/L (94 mg/dL) both pre- and postguidelines. CONCLUSIONS: Statin use and mean monthly LDL-C before and after the guidelines remained largely unchanged; statin intensity increased modestly. More effort may be needed to increase guideline understanding and adherence to improve treatment of high-risk patients.

Weight loss through adjustable gastric banding and improvement in daytime sleepiness: 2 year interim results of APEX study.

OBJECTIVE: Obesity is one factor associated with an increased risk of obstructive sleep apnea (OSA). This study reports the investigator-reported resolution or improvement of OSA and improvements in sleep-related quality of life (QOL) 2 years after surgical placement of the LAP-BAND AP * (LBAP) system. RESEARCH DESIGN AND METHODS: The LBAP Experience (APEX) study is an ongoing 5 year, prospective, observational study assessing change in weight, comorbidities, and QOL after LBAP implantation. This is an interim analysis of patients with evaluable data at 24 months who had OSA at baseline. CLINICAL TRIAL REGISTRATION: NCT00501085. RESULTS: At baseline, 117 of 395 patients (29.6%; mean body mass index [BMI], 45.0 kg/m2) reported OSA; of these, 57 had evaluable patient-reported outcome data at 2 years. Investigator-reported resolution or improvement of OSA was 69% and 86% at post-operative years 1 and 2, respectively. Patients reporting resolution, improvement, or no change in OSA experienced mean changes in BMI and percentage of weight loss of -9.7 kg/m(2)/-21.7%, -8.3 kg/m(2)/-18.7%, and -5.7 kg/m(2)/-13.2%, respectively (n = 54). Mean 2 year BMI was not statistically different between the groups (p = not significant). Mean scores for all Epworth Sleepiness Scale responses for the OSA population improved by -0.43 from baseline (p < 0.0001; n = 78) compared with -0.29 for patients without OSA at baseline (n = 177; p = 0.037 between groups). In addition, the overall study population experienced resolution and/or improvement in other obesity-related comorbidities, such as type 2 diabetes (96%) and hypertension (91%). CONCLUSIONS: These data support that surgically facilitated weight loss can improve sleep-related QOL and may result in resolution or improvement of OSA; the degree of weight loss may be related to these changes.

Efficacy and safety of the adjustable gastric band - pooled interim analysis of the APEX and HERO studies at 48 weeks.

OBJECTIVE: This 48 week combined analysis reports safety and clinical effectiveness of the LAP-BAND AP * laparoscopic adjustable gastric band (LAGB) in severely obese patients enrolled in the 5 year, prospective, observational, open-label APEX (NCT00501085) and HERO (NCT00953173) studies. METHODS: The studies enrolled 1620 patients (APEX: N = 514; HERO: N = 1106), 1140 patients in the US (including all APEX patients), and 480 patients in the European Union (EU), Canada or Australia. APEX and HERO are non-randomized, non-comparator, open-label studies with differences in study management practices and follow-up. Notably, laboratory data were not collected during the APEX study. RESULTS: After 48 weeks, mean (SD) percentage weight loss (%WL) was for APEX: 18.7% (7.9); HERO-US: 17.9% (8.5); HERO-EU: 16.5% (10.3); HERO-Canada: 13.4% (8.9); and HERO-Australia: 12.3% (6.9). After 48 weeks, there were no significant differences in %WL for APEX vs. HERO-US. After 48 weeks in the combined analysis (APEX + HERO): (1) patients without vs. with type 2 diabetes at baseline had greater %WL (18% [8.7] vs. 16% [8.5], p = 0.002); (2) female patients had greater %WL vs. male patients (17.9% [8.5] vs. 15.9% [9.3], p = 0.003); (3) younger patients had greater %WL vs. older patients (<50 years: 17.8% [8.7] vs. ≥50 years: 16.7% [8.6], p = 0.035); (4) baseline BMI did not affect %WL (≤35 to ≤45 kg/m(2): 17.7% [8.4] vs. >45 kg/m(2): 17.1% [9.1], p = 0.272). Device-related serious adverse events and adverse events were reported in 1.9% and 17.7% of patients, respectively. Revision and explantation surgeries were carried out on 3.4% and 2.3% of patients, respectively during the 48 weeks of follow-up. CONCLUSIONS: This analysis demonstrates the effective weight loss and safety profile of the current LAGB system, with US patients achieving better weight loss than patients from outside the US.

Quality of life after laparoscopic adjustable gastric banding (LAP-BAND): APEX interim 3-year analysis.

BACKGROUND: Obesity is often associated with diminished health-related quality of life (HRQOL), but significant gains in HRQOL have been observed after bariatric surgery. Laparoscopic adjustable gastric banding has been established as a safe, effective treatment to reduce weight in patients with obesity. This report summarizes interim 3-year changes in HRQOL and body weight, as well as safety postimplantation of the LAP-BAND AP (LBAP) system. METHODS: The LAP-BAND AP EXperience (APEX) trial, an ongoing, prospective, 5-year, open-label study, assessed changes in HRQOL (Obesity and Weight-Loss Quality of Life [OWLQOL] questionnaire) and body weight, and safety after placement of LBAP. This interim analysis represents patients with evaluable OWLQOL data at baseline and at 3 years (n = 183). RESULTS: The OWLQOL total score and individual scores significantly improved within 6 months post-LBAP and continued to improve during a 3 year period (P < 0.0001, both). Total score improved from 71.0 to 34.0 (mean improvement from baseline, 52%; range, 18%-65%); mean change in individual scores was -2.2 (range, -0.7 to -3.0). Percent weight loss was maintained through 3 years (19.4%; n = 174). Improvement in OWLQOL was associated with percent weight loss at 3 years (r = -0.5407; P < 0.0001). Revisions and explants were performed in 7 (3.8%) and 20 (10.9%) out of 183 patients, respectively. CONCLUSIONS: Meaningful improvement in quality of life occurred through clinically significant weight loss after LBAP placement, extending throughout the 3 years of this analysis.

Prevalence of comorbidities and baseline characteristics of LAP-BAND AP® subjects in the Helping Evaluate Reduction in Obesity (HERO) study.

OBJECTIVE: To describe the baseline characteristics in patients who chose placement of a LAP-BAND AP® System (LBAP) and participated in the Helping Evaluate Reduction in Obesity (HERO) Study across regions. PATIENTS AND METHODS: HERO is a five-year, prospective, multicenter, international study of patients with LBAP placement between July 22, 2009 and January 31, 2011. In addition to baseline and peri-surgery clinical data, seven follow up visits are scheduled at 3, 6 and 12 months, and annually through year five. Data collection included family and medical history, clinical outcomes, laboratory data, health-related quality of life (HRQoL), productivity, healthcare resource utilization, and adverse events. RESULTS: LBAP were placed in 1106 enrolled patients; 56.6% from the US, 26.3% from Europe, 7.1% from Canada, and 10.0% from Australia. The majority were female (n = 877 (79.3%)) with a mean age of 43 years (s.d. = 11.4) and mean body mass index of 45.1 kg/m(2) (s.d. = 6.9). The most common comorbidities were hypertension (HTN) (overall  = 42.9%) and diabetes (overall 22.2%, with 27% from the US and 14% from Europe). Overall, less than 5% had a history of cardiovascular disease. The prevalence rates of HTN, diabetes and cardiovascular disease were significantly (p<0.001) higher in men than in women across all regions. Overall HRQoL also worsened with increasing BMI. CONCLUSIONS: The HERO study is the first large, multinational and long-term registry with the LBAP. This study will provide real-world outcomes data on LAGB that will help inform patient choice, clinician treatment strategies, and payer reimbursement decisions.

Reduction in Framingham risk of cardiovascular disease in obese patients undergoing laparoscopic adjustable gastric banding.

BACKGROUND: Obesity is a major risk factor for cardiovascular disease (CVD), with weight loss offering improvement in CVD risk factors. AIMS: To examine whether weight loss in laparoscopic adjustable gastric band (LAGB)-treated obese patients is associated with meaningful reductions in estimated 10- and 30- year Framingham CVD risk 12-15 months post-LAGB. METHODS: Obese adult patients [body mass index (BMI) ≥30 kg/m²] treated with LAGB were identified in a large US healthcare database. Patients without CVD at baseline and with measures of BMI, systolic blood pressure, diabetes, and smoking status at baseline and follow-up were eligible. Non-LAGB patients were propensity score matched to LAGB patients on baseline BMI, age, and gender. Estimated 10- and 30-year risk of developing CVD using office-based data, including BMI, was calculated at baseline and 12-15 months follow-up. RESULTS: Mean BMI in LAGB patients (n = 647, average age 45.66 years, 81.1% female) decreased from 42.7 to 33.4 kg/m² (P < 0.0001), with 35.4% no longer obese; 10- and 30-year estimated CVD risk decreased from 10.8 to 7.6% (P < 0.0001) and 44.34 to 32.30% (P < 0.0001), respectively, 12-15 months post-LAGB. Improvements were significantly greater than in non-LAGB patients (N = 4,295) (P < 0.0001). In the subset with lipid data (n = 74), improvements in total (-20.6 mg/dL; P < 0.05) and high-density lipoprotein (+10.6 mg/dL, P < 0.0001) cholesterol 1 year post-LAGB were also observed. CONCLUSIONS: Data from a US healthcare database show that individuals undergoing LAGB have significant weight loss and reductions in estimated 10- to 30-year CVD risk within 1 year post-LAGB.

Effect of early weight loss on type 2 diabetes mellitus after 2 years of gastric banding.

OBJECTIVE: Laparoscopic adjustable gastric banding (LAGB) is an established bariatric surgical procedure that produces meaningful weight loss and improvements in patients with type 2 diabetes mellitus (T2DM) and a body mass index (BMI) ≥ 30 kg/m2. This study examined the effect of LAGB on T2DM status in severely obese patients with T2DM. METHODS: This was a 2-year interim analysis of patients with T2DM who required daily hypoglycemic medication at baseline (N = 89) in the 5-year, open-label, prospective, observational LAP-BAND AP® EXperience (APEX) trial. Type 2 diabetes mellitus status was classified as "remission," "improved," "stable," or "worse" based on physician- and patient-reported changes in T2DM control and changes in hypoglycemic medication use. RESULTS: At baseline, 89 (22.5%) of 395 patients required daily hypoglycemic medication; 66 patients had data available after 2 years. Remission of T2DM occurred in 32 (48.5%) patients, improvement occurred in 31 (47.0%) patients, and no change occurred in 3 (4.5%) patients. Overall, 95.5% of patients experienced remission or improvement in T2DM status. Duration of T2DM in patients with remission or improvement after 2 years was 4.0 and 6.7 years, respectively (P = 0.082 between groups), and was associated with change in T2DM status (logistic regression, P = 0.069). Baseline BMI, change in BMI, and percent weight loss were not significantly different between the T2DM response groups. Percent excess weight loss was numerically, but not statistically significantly, greater in remitted (-56.1%) compared with the improved response (-42.9%) group (P = 0.134), and was correlated with change in T2DM status (logistic regression, P = 0.052). After 2 years, patients experienced remission or improvement of other obesity comorbidities. The rate of revisional surgery or explantation was 3.4%, and it was not significantly different between patients with and without T2DM (P = 0.687). CONCLUSION: Shorter duration of T2DM and greater percent excess weight loss were associated with an increased likelihood of remission or improvement in T2DM status through LAGB after 2 years. Laparoscopic adjustable gastric banding is a potential adjunctive treatment for obese patients with T2DM.

Safety and efficacy of the LAP-BAND AP® adjustable gastric band in the treatment of obesity: results at 2 years.

BACKGROUND: The objective of this analysis is to report interim, 2-year results for morbidly obese patients who have undergone laparoscopic adjustable gastric banding in the LAP-BAND AP® EXperience (APEX) trial. METHODS: The APEX trial is an ongoing, multicenter, prospective, open-label, 5-year study of the LAP-BAND AP® System (LBAP) in 517 morbidly obese patients at 50 clinical centers in the United States. Last observation carried forward was used in the analyses of change in body weight and comorbid conditions, and observed data were analyzed for the Obesity and Weight-Loss Quality of Life (OWLQOL) questionnaire. Changes in body weight, percent weight loss, percent excess weight loss, body mass index (BMI), OWLQOL score, remission or improvement in obesity-related comorbid conditions, and adverse events were reported. RESULTS: At baseline, 81.5% of patients were female, and 85.8% were white. The mean age was 42.5 years, and the mean BMI was 44.0 kg/m(2). More than 85% of patients had ≥ 1 obesity-related comorbidity. At 2 years, the mean BMI change was -8.5 kg/m(2), and the mean percent weight loss was -19.3%. Responses to all questions on the OWLQOL questionnaire had a mean improvement of 54% (range, 26%-67%) at 2 years. Obesity-related comorbid conditions were remitted or improved in the majority of patients at 2 years, including type 2 diabetes mellitus (96%), hypertension (91%), gastroesophageal reflux disease (91%), hyperlipidemia (77%), obstructive sleep apnea (86%), depression (75%), and osteoarthritis (93%). The LBAP and its implantation were well tolerated, with 19.1% and 6.0% of patients reporting device-related adverse events or serious device-related adverse events, respectively. CONCLUSION: The LBAP safely and effectively facilitated weight loss in morbidly obese patients, with clinically meaningful improvements in quality of life and obesity-related comorbidities. The durability of these results will be further described with additional follow-up through 5 years. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT00501085.

Interim results at 48 weeks of LAP-BAND AP experience (APEX) study: prospective, multicenter, open-label longitudinal patient observational study.

BACKGROUND: The development of laparoscopic adjustable gastric banding marked a breakthrough in minimally invasive bariatric surgery. The unique features of gastric banding, including device adjustability, lack of malabsorption, and easy reversibility, have contributed to its widespread use. Since Food and Drug Administration approval of the first laparoscopic adjustable gastric band, the device design has undergone engineering improvements. The LAP-BAND AP (LBAP) system received Food and Drug Administration approval in 2006. Little is known about the safety and efficacy of this new system. Our objective was to prospectively assess the efficacy and safety of the LBAP system in real-world clinical settings at 50 clinical centers throughout the United States. METHODS: In an open-label 5-year evaluation, 508 severely or morbidly obese patients from 50 centers in the United States underwent surgery using the LBAP system. The present interim report describes the results from 323 patients after ≥ 48 weeks of follow-up. RESULTS: By week 48, the patients had experienced a mean percentage of excess weight loss of 46% and a mean ± standard deviation reduction in the body mass index of 8.4 ± 3.69 kg/m(2). Sixteen patients (3.1%) experienced a severe device- or procedure-related adverse event. There were no deaths. CONCLUSION: These 48-week interim data demonstrate that the LBAP system offers a safe and effective therapy to reduce weight in severely obese patients.

Effect of adjustable gastric banding on changes in gastroesophageal reflux disease (GERD) and quality of life.

OBJECTIVE: Bariatric surgery is an effective treatment for the reduction of weight in obese patients (BMI ≥ 40 kg/m(2) or 30 kg/m(2) with ≥1 comorbidities), who are refractory to behavioral and medical therapies. This study examined the effect of the adjustable gastric band (AGB) system on changes in gastroesophageal reflux disease (GERD) and patient-reported outcomes, including measures of quality of life. METHODS: Two-year interim analysis of patients (N = 171) in the 5 year, prospective APEX study who reported GERD prior to the AGB procedure. An unrecorded number of hiatal hernia repairs were conducted during the APEX study. RESULTS: At baseline, 171 of 395 patients (43%) reported GERD requiring daily medical therapy. After 2 years, 122 patients had sufficient data to assess outcome (71%). Complete resolution of GERD was reported in 98 patients (80%), improvement in 13 (11%), no change in 9 (7%), and worsening in 2 (2%). Overall, 91% of GERD patients experienced resolution and/or improvement of GERD. Baseline BMI was not significantly different among the GERD response categories (resolved, improved, and stable/worse), p = 0.4581. Mean ΔBMI and percentage excess weight loss (%EWL) were: -8.8 kg/m(2)/-0.9%, -11.4 kg/m(2)/-53.9%, -6.4 kg/m(2)/-36.1%, and -7.1 kg/m(2)/-31.2%, respectively. There were no significant differences in reductions in BMI or %EWL between responder groups (resolved versus stable/worse ΔBMI p = 0.1031, %EWL p = 0.0667 OR resolved/improved versus stable/worse ΔBMI p = 0.0918, %EWL p = 0.0552). After 2 years, resolution or improvement occurred in pre-existing comorbidities: type 2 diabetes (96%), hypertension (91%), hyperlipidemia (77%), obstructive sleep apnea (86%), osteoarthritis (93%), and depression (75%). Patient satisfaction with AGB was assessed as: very satisfied/satisfied (87%), very satisfied (50%), dissatisfied (5.0%). Quality of life measured by the Obesity and Weight-Loss Quality of Life Instrument (GERD patients) significantly improved from baseline. CONCLUSION: Obese patients with GERD had meaningful improvement in patient-reported outcomes with the AGB system. In addition, other obesity-related comorbidities and measures of quality of life improved.

Risk of lymphoma in women with breast implants: analysis of clinical studies.

Large studies suggest that the overall rate of lymphoma in women with breast implants is no greater than in the general population; clinical reports suggest an association between breast implants and the rare non-Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL). Observed cases of lymphoma reported in Allergan-sponsored breast implant clinical studies were compared with expected cases on the basis of the incidence of lymphoma among women in the National Cancer Institute's Surveillance Epidemiology and End Results program, using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). In clinical studies, there were 28 observed cases of lymphoma among 89 382 patients and 204 682 person-years of follow-up compared with 43 expected cases [SIR: 28/43=0.65 (95% CI: 0.43-0.94), P=0.02]. SIRs were calculated stratifying by baseline cancer history: women without prior cancer [SIR: 17/24=0.70 (95% CI: 0.41-1.13), P=0.17] and women with prior cancer [SIR: 11/14=0.79 (95% CI: 0.39-1.41), P=0.52]. SIRs were calculated by implant shell type: textured shell implants [SIR: 16/23=0.70 (95% CI: 0.40-1.13), P=0.16] and smooth shell implants [SIR: 12/19=0.63 (95% CI: 0.33-1.10), P=0.12]. Surveillance Epidemiology and End Results reported 12 cases of primary breast ALCL in women between 1996 and 2007 without a history of cancer, for an average annual incidence of 4.28 (95% CI: 3.51-5.05)/100 million women in the US - these women may or may not have breast implants. In clinical studies, three ALCL cases were reported in women with breast implants and a history of breast cancer, yielding a crude incidence rate of 1.46 (95% CI: 0.30-4.3)/100 000 person-years. Large clinical studies, based on over 200 000 person-years of follow-up, suggest no evidence of an increased risk of lymphoma among women who have received breast implants.

Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes.

BACKGROUND: The majority of patients with type 2 diabetes mellitus have blood pressure (BP) exceeding the recommended value of <130/80 mm Hg. Optimal control of hyperglycemia and hypertension has been shown to reduce the incidence of macrovascular and microvascular complications due to diabetes. Treatment with the GLP-1 receptor agonist exenatide, previously demonstrated to reduce hemoglobin A(1C) and weight in subjects with type 2 diabetes, was associated with BP reduction in several studies. METHODS: This analysis explored the effects of exenatide vs. placebo or insulin on BP measurements in pooled data from six trials including 2,171 subjects studied for at least 6 months. RESULTS: Overall, 6 months of exenatide treatment was associated with a significantly greater reduction in systolic BP (SBP) compared with placebo (least squares mean (s.e.): difference of -2.8 mm Hg (0.75); P = 0.0002) or insulin (difference of -3.7 mm Hg (0.85); P < 0.0001). No significant intergroup differences in diastolic BP (DBP) were observed. The majority of the intergroup difference was observed in subjects with SBP > or = 130 mm Hg (difference of -3.8 mm Hg (1.08) from placebo: P = 0.0004; difference of -4.0 mm Hg (1.01) from insulin; P < 0.0001). The largest intertreatment differences between exenatide and comparators were observed in subjects with SBP >/=150 mm Hg. Similar responses were observed in African-American subjects. A weak correlation between the amount of weight lost and reduction in SBP was found (r = 0.09, P = 0.002) for exenatide-treated subjects. CONCLUSIONS: These results support the need for a prospective, randomized, controlled study of BP changes during exenatide treatment in patients with hypertension and type 2 diabetes.

Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors.

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Effects of exenatide on diabetes, obesity, cardiovascular risk factors, and hepatic biomarkers in patients with type 2 diabetes.

Obesity increases the risk of diabetes up to 90-fold and worsens hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. For patients with type 2 diabetes, weight loss can trigger improvements in all these conditions and decrease the need for glucose-lowering agents. The incretin mimetic exenatide shares many glucoregulatory properties with native glucagon-like peptide-1, including enhancement of glucose-dependent insulin secretion, glucose-dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, and reduction of food intake in patients with type 2 diabetes. Exenatide treatment was associated with progressive weight loss in the majority of patients in clinical trials. In addition, patients with elevated markers of liver injury at baseline showed improvements. Therefore, exenatide represents a unique option for adjunctive therapy for patients with type 2 diabetes not achieving adequate glycemic control on oral antidiabetic agents, especially in patients for whom weight gain would be an additional contraindication.

Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study.

BACKGROUND: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients. METHODS: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 +/- 5 kg/m(2); HbA(1c): 8.5 +/- 1.2%; 2-h PPG: 245 +/- 65 mg/dL. Patients received exenatide (5 microg BID for 1 week, then 10 microg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581). RESULTS: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 +/- 6 mg/dL versus 208 +/- 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 +/- 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by -76 +/- 10 mg/dL. Postprandial glucose parameters (AUC, C(ave), C(max)) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (-15 +/- 4 mg/dL vs. -19 +/- 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 +/- 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 +/- 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 +/- 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 +/- 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (-134 +/- 97 kcal vs. +130 +/- 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature. CONCLUSIONS: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.