Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder.

BACKGROUND: Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD: This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION: This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION: 10 May 2023.

Recruitment and Retention Strategies for the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: Recruitment and retention of patients with acute pancreatitis (AP) in clinical studies can be challenging. While some obstacles are similar to other clinical conditions, some are unique to AP. Identifying potential barriers early and developing targeted solutions can help optimize recruitment and retention in AP studies. Such pre-emptive and detailed planning can help prospective, longitudinal studies focus on exocrine and endocrine complications of AP in accurately measuring outcomes. This article highlights the challenges in recruitment and retention strategies in AP studies and reviews available resources to create opportunities to address them. We describe the multifaceted approach used by the Recruitment and Retention Committee of the Type 1 Diabetes in Acute Pancreatitis Consortium, which builds upon earlier experiences to develop a recruitment and retention plan for the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) study.

Do Mindfulness Interventions Improve Obesity Rates in Children and Adolescents: A Review of the Evidence.

Mindfulness interventions have shown promise in improving self-regulation, depression, anxiety, and stress levels across all ages. Obesity rates in children are rising worldwide. It has been postulated that through improvements in self-regulation with mindfulness interventions, obesity rates can be improved in children and adolescents. In this review, we attempt to explain how mindfulness interventions may impact obesity rates and obesity-related complications and give the current state of evidence for the following mindfulness interventions: Mindful Eating, Mindfulness-Based Stress Reduction, Yoga, Spirituality, and Dialectical Behavior Therapy.

Diabetes, Drug Treatment, and Mortality in COVID-19: A Multinational Retrospective Cohort Study.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes possibly because of dysregulated inflammatory responses. Glucose-regulating medications, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone, are known to have anti-inflammatory effects that may improve outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a multinational retrospective cohort study, we used the TriNetX COVID-19 Research Network of 56 large health care organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days after a COVID-19 diagnosis. After matching for age, sex, race, ethnicity, BMI, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs. 23.5%, risk ratio [RR] 0.67 [95% CI 0.57-0.79; P < 0.001]; pioglitazone: 20.0% vs. 28.2%; RR 0.71 [95% CI 0.54-0.93; P = 0.01]). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs. 24.9%, RR 0.62 [95% CI 0.52-0.73]; P < 0.001) and incidence of mortality (1.9% vs. 3.3%, RR 0.58 [95% CI 0.35-0.97]; P = 0.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs. 29.2%, RR 0.82 [95% CI 0.74-0.90]; P < 0.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs. 19%, RR 0.45 [95% CI 0.28-0.72]; P < 0.001). In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility.

Mindfulness-Based Stress Reduction in Women with Overweight or Obesity: A Randomized Clinical Trial.

OBJECTIVE: To evaluate the feasibility and cardiometabolic effects of mindfulness-based stress reduction (MBSR) in women with overweight or obesity. METHODS: Eighty-six women with BMI ≥ 25 kg/m2 were randomized to 8 weeks of MBSR or health education and followed for 16 weeks. The primary outcome was the Toronto Mindfulness Scale. Secondary outcomes included the Perceived Stress Scale-10, fasting glucose, and blood pressure. RESULTS: Compared to health education, the MBSR group demonstrated significantly improved mindfulness at 8 weeks (mean change from baseline, 4.5 vs. -1.0; P = 0.03) and significantly decreased perceived stress at 16 weeks (-3.6 vs. -1.3, P = 0.01). In the MBSR group, there were significant reductions in fasting glucose at 8 weeks (-8.9 mg/dL, P = 0.02) and at 16 weeks (-9.3 mg/dL, P = 0.02) compared to baseline. Fasting glucose did not significantly improve in the health education group. There were no significant changes in blood pressure, weight, or insulin resistance in the MBSR group. CONCLUSIONS: In women with overweight or obesity, MBSR significantly reduces stress and may have beneficial effects on glucose. Future studies demonstrating long-term cardiometabolic benefits of MBSR will be key for establishing MBSR as an effective tool in the management of obesity.

Exclusion of Women of Childbearing Potential in Clinical Trials of Type 2 Diabetes Medications: A Review of Protocol-Based Barriers to Enrollment.

OBJECTIVE: Women of childbearing potential are often excluded from participating in clinical trials owing to concerns about adverse fetal effects of treatment. This study aims to determine the prevalence of fertility-related exclusion criteria in clinical trials of type 2 diabetes medications and to determine whether these criteria are commensurate with drug risk. RESEARCH DESIGN AND METHODS: ClinicalTrials.gov was queried for trials of type 2 diabetes medications that were phase 2 or 3, were based in the U.S., and enrolled participants 18-40 years old. Six hundred eighty-eight trials met criteria. Information collected about each trial included enrollment, trial length, exclusion and inclusion criteria, trial sponsor, and pregnancy category of drug(s) administered. RESULTS: Most studies (59%) included one or more fertility-related exclusion criteria, most often excluding current pregnancy (55%) and breast-feeding (44%). Trials of medications with increased fetal risk were not more restrictive: trials of category C drugs (evidence of fetal risks in animals) were less likely to exclude pregnancy compared with trials of category B drugs (no known human or animal fetal risks) (45.6% vs. 69.8%, odds ratio [OR] 0.37 [95% CI 0.20, 0.65], P = 0.0005) or to require contraceptive use (29.9% vs. 57.1%, OR 0.32 [95% CI 0.18, 0.56], P = 0.001). CONCLUSIONS: In clinical trials of type 2 diabetes medications, exclusion criteria affecting women of childbearing potential are often disproportionate to risk to the participant and fetus. These criteria have the potential to impede young women's access to clinical trials and may hinder the acquisition of clinical knowledge critical for improving the care of women with diabetes.

Mindfulness-based stress reduction for overweight/obese women with and without polycystic ovary syndrome: design and methods of a pilot randomized controlled trial.

INTRODUCTION: Mindfulness-based stress reduction (MBSR) may be beneficial for overweight/obese women, including women with polycystic ovary syndrome (PCOS), as it has been shown to reduce psychological distress and improve quality of life in other patient populations. Preliminary studies suggest that MBSR may also have salutary effects on blood pressure and blood glucose. This paper describes the design and methods of an ongoing pilot randomized controlled trial evaluating the feasibility and effects of MBSR in PCOS and non-PCOS women who are overweight or obese (NCT01464398). METHODS AND DESIGN: Eighty six (86) women with body mass index ≥ 25 kg/m(2), including 31 women with PCOS, have been randomized to 8 weeks of MBSR or health education control, and followed for 16 weeks. The primary outcome is mindfulness assessed with the Toronto Mindfulness Scale. Secondary outcomes include measures of blood pressure, blood glucose, quality of life, anxiety and depression. DISCUSSION: Our overall hypothesis is that MBSR will increase mindfulness and ultimately lead to favorable changes in blood pressure, blood glucose, psychological distress and quality of life in PCOS and non-PCOS women. This would support the integration of MBSR with conventional medical treatments to reduce psychological distress, cardiovascular disease and diabetes in PCOS and non-PCOS women who are overweight or obese.

High-dose vitamin D supplementation and measures of insulin sensitivity in polycystic ovary syndrome: a randomized, controlled pilot trial.

OBJECTIVE: To determine the effects of high-dose vitamin D on insulin sensitivity in polycystic ovary syndrome (PCOS). DESIGN: Randomized, placebo-controlled trial. SETTING: Academic medical center. PATIENT(S): Twenty-eight women with PCOS. INTERVENTION(S): Vitamin D3, 12,000 IU, or placebo daily for 12 weeks. MAIN OUTCOME MEASURE(S): The primary outcome was quantitative insulin sensitivity check index. Secondary outcomes included glucose and insulin levels during a 75-g oral glucose tolerance test and blood pressure. RESULT(S): Twenty-two women completed the study. Compared with placebo, vitamin D significantly increased 25-hydroxyvitamin D (mean [95% confidence interval] in vitamin D group 20.1 [15.7 to 24.5] ng/mL at baseline and 65.7 [52.3 to 79.2] ng/mL at 12 weeks; placebo 22.5 [18.1 to 26.8] ng/mL at baseline and 23.8 [10.4 to 37.2] ng/mL at 12 weeks). There were no significant differences in quantitative insulin sensitivity check index and other measures of insulin sensitivity; however, we observed trends toward lower 2-hour insulin and lower 2-hour glucose. We also observed a protective effect of vitamin D on blood pressure. CONCLUSION(S): In women with PCOS, insulin sensitivity was unchanged with high-dose vitamin D, but there was a trend toward decreased 2-hour insulin and a protective effect on blood pressure. CLINICAL TRIAL REGISTRATION NUMBER: NCT00907153.

The role of TGF-ß in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic oligoanovulation and hyperandrogenism and associated with insulin resistance, type 2 diabetes, and cardiovascular risk. In recent years, genetic studies have linked PCOS to a dinucleotide marker D19S884 in the fibrillin 3 gene. Fibrillins make up the major component of microfibrils in the extracellular matrix (ECM) and interact with molecules in the ECM to regulate transforming growth factor ß (TGF-ß) signaling. Therefore, variations in fibrillin 3 and subsequent dysregulation of TGF-ß may contribute to the pathogenesis of PCOS. Here, we review the evidence from genetic studies supporting the role of TGF-ß in PCOS and describe how TGF-ß dysregulation may contribute to (1) the fetal origins of PCOS, (2) reproductive abnormalities in PCOS, and (3) cardiovascular and metabolic abnormalities in PCOS.

Familial aggregation of circulating C-reactive protein in polycystic ovary syndrome.

STUDY QUESTION: What is the heritability of C-reactive protein (CRP) levels in women with polycystic ovary syndrome (PCOS) and their first-degree relatives? SUMMARY ANSWER: Women with PCOS and their siblings are more likely to have elevated CRP levels when both of their parents have elevated CRP. This PCOS family-based study indicates that CRP levels are likely a heritable trait. WHAT IS KNOWN ALREADY: Previous studies have established that an elevated blood level of CRP is variably present in women with PCOS, and may be present independent of metabolic status. STUDY DESIGN, SIZE AND DURATION: A familial based phenotyping study consisting of 81 families comprised of PCOS patients and their first-degree relatives for 305 subjects. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Study conducted at an academic health center. An elevated CRP level was defined as >28.6 nmol/l. To account for familial clustering, generalized estimating equations with a logit link were used to model the association between elevated CRP levels in patients with PCOS and their siblings with their parental group (A = neither parent with elevated CRP; B = one parent with elevated CRP; C= both parents with elevated CRP), adjusting for gender, age and BMI of the offspring. We did additional heritability analyses by using a variance component estimation method for CRP levels, adjusting for sex, age and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: We observed elevated CRP levels in 94% of the offspring in group C, 45% in group B and 10% in group A after adjusting for age, gender and BMI of the offspring. The median BMI of the offspring in group A, B and C were 30.0, 28.7 and 31.2 kg/m², respectively. Heritability estimates of CRP levels ranged from 0.75 to 0.83 and remained significant after excluding for type 2 diabetes mellitus. Our small sample size increases the possibility of a type 1 error. LIMITATIONS, REASONS FOR CAUTION: This is a single report in an adequately powered but limited sample size study identifying the strong heritability of CRP levels. Replication in other large family cohorts is necessary. WIDER IMPLICATION OF THE FINDINGS: These findings support the concept that there is an increased cardiovascular disease risk profile in families of women with PCOS. STUDY FUNDING/COMPETING INTEREST: This research was supported by National Institutes of Health grants U54HD-034449 and P50 HD044405 (A.D.). Priyathama Vellanki is supported in part by NIH/NIDDK Training Grant T32 DK007169.

The physiological basis of complementary and alternative medicines for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. This article describes how the physiological effects of major complementary and alternative medicine (CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduces hyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects are mediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulation of the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolic functions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficial physiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe and effective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychological distress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. In conclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects in PCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled. Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms of CAM treatments for PCOS.

Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial.

To determine the effects of statins on vascular function, inflammation, and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had low-density lipoprotein cholesterol levels >100 mg/dL to atorvastatin (40 mg/day) or placebo for 6 weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure; increased insulin levels and brachial artery conductance during reactive hyperemia; and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment.

Brachial artery conductance during reactive hyperemia is increased in women with polycystic ovary syndrome.

OBJECTIVE: To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls. STUDY DESIGN: This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia. RESULTS: Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P<0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P=0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P<0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels. CONCLUSIONS: Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.

A variant in the fibrillin-3 gene is associated with TGF-ß and inhibin B levels in women with polycystic ovary syndrome.

In an attempt to evaluate the association between allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating transforming growth factor (TGF) ß and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8- PCOS) with 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8- Non-PCOS). A8- PCOS is associated with higher levels of TGF-ß1 compared with A8+ PCOS or A8- Non-PCOS, similar levels of TGF-ß2 compared with A8+ PCOS but lower levels of TGF-ß2 compared with A8- Non-PCOS, and lower levels of inhibin B and aldosterone compared with A8+ PCOS.

Review of biphasic insulin aspart in the treatment of type 1 and 2 diabetes.

BACKGROUND: Insulin is an effective treatment for achieving glycemic control and preventing complications in patients with diabetes. In order to make insulin therapy more acceptable to patients, newer formulations of insulin have been developed, such as biphasic insulins. Biphasic insulins conveniently provide both prandial and basal insulin in a single injection. One of the most well-studied biphasic insulins is biphasic insulin aspart 70/30. OBJECTIVE: Our goal was to review the current literature on the safety and efficacy of biphasic insulin aspart in type 1 and type 2 diabetes. METHODS: A MEDLINE search was conducted using the terms "biphasic insulin aspart" to identify clinical studies and reviews. RESULTS: Biphasic insulin aspart more effectively reduces post-prandial glucose compared to other biphasic insulins and basal insulins. Compared to biphasic insulin aspart, fasting glucose levels are lower with NPH, similar with glargine, and similar or lower with biphasic human insulin. Treat-to-target trials have shown that a goal HbA1c below 6.5 or 7% can be achieved with biphasic insulin aspart. The risk of hypoglycemia is similar to or less than that seen with other biphasic insulins or NPH insulin. CONCLUSION: Biphasic insulin aspart 70/30 is a safe and effective treatment option for patients with diabetes.

Independent association of insulin resistance with larger amounts of intermuscular adipose tissue and a greater acute insulin response to glucose in African American than in white nondiabetic women.

BACKGROUND: African Americans (AAs) have a higher prevalence of obesity and type 2 diabetes than do whites. Higher insulin resistance and hyperinsulinemia have been reported in adult AAs than in whites. Differences in adipose tissue and its distribution may account for these findings. OBJECTIVE: The objective was to ascertain whether differences between AA and white women in adipose tissue (AT) and skeletal muscle (SM) volumes account for ethnic differences in insulin resistance. DESIGN: We used whole-body magnetic resonance imaging to measure AT and SM volumes and used the intravenous-glucose-tolerance test to measure insulin resistance. RESULTS: AAs (n = 32) were 29-42% more insulin resistant than were whites (n = 28) after adjustment for weight and height or any AT volumes (P < 0.05). After adjustment for SM volume, the difference decreased to 19% and became nonsignificant. AAs had a 163% greater acute insulin response to glucose than did whites; this difference was significant even after adjustment for insulin sensivitity index, weight, height, and any magnetic resonance imaging measures. With respect to regional AT volumes, an association independent of race, weight, height, and SM volume was found only between increased intermuscular AT and lower insulin sensitivity index. CONCLUSIONS: Premenopausal AA women had significantly higher insulin resistance and acute insulin response to glucose than did their white counterparts. Whereas the difference in insulin resistance was partially accounted for by a greater SM volume in the AAs than in the whites, the difference in the acute insulin response to glucose was independent of any AT and SM measures and was disproportionately larger than expected according to the difference in insulin resistance. In addition, whole-body intermuscular AT was an important independent correlate of insulin resistance.

The management of the obese diabetic patient.

The prevalence of obesity and diabetes is increasing in the United States and worldwide. These diseases are predicted to explode to epidemic proportions, unless appropriate counteractive measures are taken. Several large studies (DCCT, UKPDS, Kumamoto) clearly showed that intensive glycemic control in the diabetic patient reduced microvascular complications and improved mortality. Despite this, the NHANES III showed that only 50% of diabetics have been able to achieve a HgbAic level that is less than 7%; this suggests the need for a re-evaluation of our approach to these patients. The management of the obese diabetic patient involves glycemic control and weight reduction. These goals are particularly difficult to achieve in the obese diabetic patient because progressive beta-cell dysfunction and increasing insulin resistance necessitates the administration of increasingly higher dosages of insulin, which, in turn, promotes weight gain. A vicious cycle may ensue. Lifestyle modifications with diet and exercise are an essential part of the management of the obese diabetic patient. These measures alone are often insufficient and concomitant pharmacologic therapy is usually required to achieve glycemic and weight control. Oral agents that improve glycemia, decrease insulin resistance, and limit weight gain are desirable. Because of the progressive nature of diabetes, glycemic control with monotherapy often deteriorates over time, which necessitates the addition of other pharmacologic agents, including insulin. When insulin therapy is required in the treatment of the obese diabetic patient, combinations with oral agents that have been shown to minimize the amount of exogenous insulin that is required, may minimize weight gain. In addition, the obese diabetic patient who is poorly controlled with maximum oral hypoglycemic therapy may benefit from weight-reducing agents, such as sibutramine or orlistat. The introduction of these agents at other points in the management of the obese diabetic patients have been successful. Finally, for the severely obese diabetic patient, bariatric surgery may be the only effective treatment. Gastric bypass has been unequivocally shown to produce significant weight loss and improve glycemic control on a long-term basis in the obese diabetic patient. It is recommended that physicians avail themselves of all of these strategies in the management of the obese patient who has type 2 diabetes.