A Review of the Safety and Efficacy of Bexagliflozin for the Management of Type 2 Diabetes.

OBJECTIVE: To review the pharmacology of bexagliflozin in addition to its safety and efficacy from available clinical trials used for its approval, as well as available clinical evidence to date. DATA SOURCES: A search of the National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) and PubMed database was performed from inception through June 1, 2023. STUDY SELECTION AND DATA EXTRACTION QUANTIFICATION: The following study designs were included: meta-analyses, systematic review, clinical trial, or observational study design. Abstracts and drug monographs were also reviewed. Narrative or scoping reviews were excluded. Only articles in the English language and those evaluating the pharmacology, pharmacokinetics, safety, or efficacy of bexaglifozin in humans were included. DATA SYNTHESIS: Bexagliflozin reduces hemoglobin A1c ~0.5% with similar reductions in systolic blood pressure and body weight to other SGLT2 inhibitors. No cardiovascular outcomes trial is published, nor ongoing at this time. Adverse effects are similar to other SGLT2 inhibitors (genital mycotic and urinary tract infections, increased urination) including a warning for lower extremity amputation similar to canagliflozin. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Although no cost-effectiveness data are available, statements from the manufacturer suggest a competitive price point. Given limited trial data, lower cost, if chosen, may create a temporary niche for bexagliflozin pending generic availability of other SGLT2 inhibitors. However, given lack of cardiovascular and renal outcome data, empagliflozin, dapagliflozin, or canagliflozin may be preferred. CONCLUSION: Bexagliflozin appears safe and effective as monotherapy and add-on pharmacological therapy for the treatment of T2D.

Discontinuing semaglutide after weight loss: strategy for weight maintenance and a possible new side effect.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) facilitate weight loss. Weight regain off therapy is concerning. We reported the case of a 35-year-old male prescribed oral semaglutide with 22.7 kg weight loss over 120 days. Herein, we describe the clinical course when discontinuing GLP-1 RA therapy, one approach to maintaining weight loss after discontinuation, and a possible new side effect. At day 120, we continued oral semaglutide 7 mg daily, down from 14 mg, for weight maintenance with subsequent weight regain. We re-increased semaglutide to 14 mg/day with weight re-loss within 1 month and weight maintance for a year. We then discontinued semaglutide; weight loss was maintained for 6 months. The patient reported lactose intolerance ∼13 months before starting semaglutide. During semaglutide therapy, the patient reported worsened lactose intolerance and new gluten intolerance. Food allergy/celiac testing were negative. Intolerances did not improve with semaglutide discontinuation. Six months after semaglutide discontinuation, the patient was diagnosed with small intestinal bacterial overgrowth, possibly worsened by semaglutide. Factors potentially supporting weight maintenance were early drug treatment for new-onset obesity, non-geriatric age, strength training, and diet modification. The case highlights tailoring approaches to maintain weight loss without GLP-1 RAs. Trials are needed to optimize weight maintenance strategies.

Pharmacist-driven continuous glucose monitoring in community and ambulatory care pharmacy practice: A scoping review.

BACKGROUND: Continuous glucose monitoring (CGM) devices improve clinical outcomes and facilitate achieving patient-specific goals. However, opportunities and barriers to implementation of pharmacist-driven CGM services are not well-described. OBJECTIVES: This scoping review was conducted to identify opportunities and barriers to implementing pharmacist-driven CGM services in the community and ambulatory care setting. Clinical outcomes resulting from pharmacist-driven CGM were also explored. METHODS: A health librarian searched Ovid MEDLINE, Cochrane CENTRAL, Embase, Web of Science, Scopus, International Pharmaceutical Abstracts using keywords and subject headings from inception through December 2, 2022 to identify studies describing pharmacist or pharmacy-based CGM programs. No publication type, date limits, language restrictions, or other filters were applied. The database search was supplemented by a search of Google Scholar and a citation search of preselected gold standard articles. RESULTS: The scoping review initially identified 942 citations of which 249 passed abstract screening and 11 were included in the review. Among studies, the most common design was retrospective, populations varied, control groups were not consistently used, follow-up was primarily short, and sample sizes were small. One study evaluated pharmacist-driven CGM in a community pharmacy setting. Ten studies took place in the ambulatory care setting. Barriers to initiating pharmacist-driven CGM as a clinical service include educational, logistical, workflow, and financial incentive. Beneficial outcomes from pharmacist-driven CGM include improved quality of life, increased empowerment, and improved glycemic control. CONCLUSION: There is lack of strong evidence to support pharmacist-driven CGM in the community pharmacy setting. However, small studies suggest pharmacist-driven CGM is feasible and beneficial in the ambulatory care setting. Further exploration of how educational, logistical, workflow, and financial barriers can be overcome is warranted, given potential for improved clinical outcomes.

Impact of Overbasalization on Clinical Outcomes in Patients With Type 2 Diabetes: A Post Hoc Analysis of a Large Randomized Controlled Trial.

The American Diabetes Association's Standards of Medical Care in Diabetes emphasize the need for awareness regarding overbasalization (basal insulin doses >0.5 units/kg/day without bolus insulin) in the treatment of type 2 diabetes. However, outcomes data on the impact of overbasalization are limited. This post hoc analysis of a large randomized controlled trial suggests that an insulin therapy regimen involving overbasalization compared with a basal-bolus insulin regimen that avoids overbasalization is less effective at lowering A1C and may be associated with increased cardiovascular risk. Clinicians should consider alternative approaches to glycemic control before increasing basal insulin doses to >0.5 units/kg/day.

Novel biomarkers of inflammation in heart failure with preserved ejection fraction: analysis from a large prospective cohort study.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous cluster of causes, including non-resolving inflammation, endothelial dysfunction, and multi-organ defects. The present study's objective was to identify novel predictors of HFpEF. METHODS: The study analyzed the Multi-Ethnic Study of Atherosclerosis (MESA) to assess the association of specific markers of inflammation with new onset of HFpEF (interleukin-2 [IL-2], matrix metalloproteinase 3 [MMP3], large low-density lipoprotein cholesterol [LDL-C], and medium high-density lipoprotein cholesterol [HDL-C]). The study included men and women 45 to 84 years of age without cardiovascular disease at baseline. The primary outcome was the multivariate association of the hypothesized markers of inflammation with new-onset of HFpEF versus participants without new-onset heart failure. Participants with missing data were excluded. RESULTS: The present analysis included 6814 participants, 53% female, with a mean age of 62 years. Among the entire cohort, HFpEF was diagnosed in 151 (2.2%) participants and heart failure with reduced ejection fraction (HFrEF) was diagnosed in 146 (2.1%) participants. Participants were followed for the outcome of heart failure for a median 13.9 years. Baseline IL-2 was available for 2861 participants. The multivariate analysis included 2792 participants. Of these, 2668 did not develop heart failure, 62 developed HFpEF, 47 developed HFrEF, and 15 developed unclassified heart failure. In the multivariate regression model, IL-2 was associated with new-onset HFpEF (OR, 1.00058; 95% confidence interval, 1.00014 to 1.00102, p = 0.009) but not new-onset HFrEF. In multivariate analysis, MMP3, large LDL-C, and medium HDL-C were not associated with HFpEF or HFrEF. CONCLUSION: These findings portend IL-2 as an important component of suboptimal inflammation in the pathogenesis of HFpEF.

Effect of Antidepressants on Glucagon-Like Peptide-1 Receptor Agonist-Related Weight Loss.

Background: Depression and obesity have a bidirectional relationship making the management of one, without the other, problematic. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a preferred medication class for diabetes and obesity treatment given their weight loss effect; however, it is not known how antidepressants impact this effect. Objective: To assess the impact of antidepressant use on GLP-1 RA-associated weight loss in patients with or without type 2 diabetes mellitus. Methods: This was a retrospective, propensity matched, cohort study conducted using TriNetX. The study identified patients initiating a GLP-1 RA being treated with citalopram/escitalopram, bupropion, or no antidepressant. Cohorts were propensity score matched to analyze the primary outcome of mean end-of-study (77-371 days) body weight. Results: An initial query identified 31 273 patients eligible for analysis (30 160 receiving no antidepressant, 311 receiving bupropion, and 802 receiving citalopram/escitalopram). After propensity score matching, the study found patients receiving citalopram/escitalopram were taking more antidiabetic therapies at baseline compared with patients not treated with an antidepressant. Patients in the antidepressant cohorts experienced less weight loss compared with their respective matched cohorts not receiving antidepressants (citalopram/escitalopram -0.73 kg versus -1.74 kg; bupropion -0.84 kg versus -3.46 kg). Only the bupropion cohort was significantly heavier at end-of-study versus the non-antidepressant cohort (108 kg versus 103 kg, P = 0.018). Conclusion and Relevance: Antidepressants may diminish the weight loss effect of GLP-1 RAs. Additional research is needed to assess whether all GLP-1 RAs are affected similarly and the optimal weight loss strategies in patients receiving antidiabetic therapy with comorbid depression.

Review of Prediabetes and Hypertensive Disorders of Pregnancy.

Obesity and diabetes increase hypertensive disorders of pregnancy (HDP) risk, thus preventive interventions are heavily studied. How pregestational prediabetes and related interventions impact HDP risk is less characterized. Therefore, we searched and reviewed the literature to assess the impact on HDP risk of prediabetes and varied interventions. We identified 297 citations related to pregnancy, prediabetes, and early pregnancy interventions. We also reviewed the references and citations of included articles. We included five studies assessing HDP outcomes in women with first trimester hemoglobin A1c in the prediabetes range (5.7-6.4%). One prospective observational study demonstrated first trimester hemoglobin A1c (5.9-6.4%) is associated with increased HDP risk, while another prospective observational study and one retrospective observational study had similar trends without statistical significance. A small and underpowered randomized controlled trial demonstrated initiating gestational diabetes mellitus treatment (i.e., diet, monitoring, ± insulin) in response to first trimester hemoglobin A1c (5.7-6.4%) did not statistically reduce HDP compared with standard care. One retrospective observational study suggested metformin, when started early, may reduce HDP risk in patients with prediabetes. Pregestational prediabetes appears to increase HDP risk. Interventions (i.e., metformin, diet/glucose monitoring, and/or exercise) to reduce HDP risk require additional study with long-term follow-up.

Open data, trials and new ethics of using others' work.

Data and ideas are the capital of research productivity. Is it ethical to preempt the publication of another researcher's unpublished data or preliminary analysis, perhaps without citation? The long-established answer is 'certainly not'-but recent 'open data' use suggests otherwise. A research competition was held using data from The Systolic Blood Pressure Intervention Trial (SPRINT). This SPRINT Data Analysis Challenge created a novel environment for using open data as data became open early. This allowed third-party researchers the opportunity to assess some of the trial's outcomes before trialists. Could this infringe on trialists' right to analyse their data? Simultaneously, trialists had access to analyses from submissions to the competition that were not formally 'published' with a typical author credit or citation. Therefore, trialists had the opportunity to view the competition submissions and published on those ideas first without a typical way to cite the source of that idea. Could this infringe on researchers' right to be credited for their ideas? This is not intended as a criticism of open data, the SPRINT Data Analysis Challenge, or similar systems/ventures, but is an effort to objectively note what may be remediable flaws in the worthwhile, growing and dynamic uses of open data. We offer preliminary analytics to shed more light and provide fodder for additional discussion.

Metformin's impact on statin-associated muscle symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center.

Statins are widely prescribed, yet statin muscle pain limits their use, leading to increased cardiovascular risk. No validated therapy for statin muscle pain exists. The goal of the study was to assess whether metformin was associated with reduced muscle pain. A secondary analysis of data from the ACCORD trial was performed. An ACCORD sub-study assessed patients for muscle cramps and leg/calve pain while walking, typical non-severe statin muscle pain symptoms. We compared muscle pain between patients using a statin (n = 445) or both a statin and metformin (n = 869) at baseline. Overall patient characteristics were balanced between groups. Unadjusted analysis showed fewer reports of muscle cramps (35%) and leg/calve pain while walking (40%) with statins and metformin compared to statin only (muscle cramps, 42%; leg/calve pain while walking, 47%). Multivariable regression demonstrated a 22% odds reduction for muscle cramps (P = 0.049) and a 29% odds reduction for leg/calve pain while walking (P = 0.01). Metformin appears to reduce the risk of non-severe statin muscle pain and additional research is needed to confirm the findings and assess metformin's impact on statin adherence and related cardiovascular outcomes.

Evaluation of SAMe-TT2R2 Score on Predicting Success With Extended-Interval Warfarin Monitoring.

BACKGROUND: In patients with stable international normalized ratios, 12-week extended-interval warfarin monitoring can be considered; however, predictors of success with this strategy are unknown. The previously validated SAMe-TT2R2 score (considering sex, age, medical history, treatment, tobacco, and race) predicts anticoagulation control during standard follow-up (every 4 weeks), with lower scores associated with greater time in therapeutic range. OBJECTIVE: To evaluate the ability of the SAMe-TT2R2 score in predicting success with extended-interval warfarin follow-up in patients with previously stable warfarin doses. METHODS: In this post hoc analysis of a single-arm feasibility study, baseline SAMe-TT2R2 scores were calculated for patients with ≥1 extended-interval follow-up visit. The primary analysis assessed achieved weeks of extended-interval follow-up according to baseline SAMe-TT2R2 scores. RESULTS: A total of 47 patients receiving chronic anticoagulation completed a median of 36 weeks of extended-interval follow-up. The median baseline SAMe-TT2R2 score was 1 (range 0-5). Lower SAMe-TT2R2 scores appeared to be associated with greater duration of extended-interval follow-up achieved, though the differences between scores were not statistically significant. No individual variable of the SAMe-TT2R2 score was associated with achieved weeks of extended-interval follow-up. Analysis of additional patient factors found that longer duration (≥24 weeks) of prior stable treatment was significantly associated with greater weeks of extended-interval follow-up completed ( P = 0.04). Conclusion and Relevance: This pilot study provides limited evidence that the SAMe-TT2R2 score predicts success with extended-interval warfarin follow-up but requires confirmation in a larger study. Further research is also necessary to establish additional predictors of successful extended-interval warfarin follow-up.

The changing cost to prevent diabetes: A retrospective analysis of the Diabetes Prevention Program.

OBJECTIVES: Diabetes prevention interventions are poorly implemented. While health care costs generally increase, 2 factors affect the relative cost of diabetes prevention interventions: the declining cost of metformin (even without insurance) and the new recommendation for vitamin B12 monitoring during metformin treatment. The study's objective was to update the relative health system cost estimate of metformin for diabetes prevention by incorporating the current health system cost of metformin and the cost of addressing potential metformin-associated vitamin B12 deficiency. The study was designed to assess whether metformin with vitamin B12 supplementation is a cost-saving measure for diabetes prevention and for the updated cost estimate to be useful in assessing future implementation studies. METHODS: In 2012, the Diabetes Prevention Program Research Group published detailed per capita total direct health system costs for the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). The present analysis incorporated the declining cost of metformin and the increasing cost of metformin monitoring into the detailed per capita health system costs found in the DPP and DPPOS. The updated costs were used to assess the total cost of metformin use for diabetes prevention relative to placebo and lifestyle intervention. RESULTS: The current health system cost to acquire metformin ranges from $0 to $72 per year. The estimated health system cost to address potential metformin-associated vitamin B12 deficiency is $28 per metformin-treated patient per year. The 10-year total health system cost for metformin in diabetes prevention can decrease by $329 or increase by $21 depending on the cost to acquire metformin. Compared with placebo, the unadjusted cost savings of metformin is generally maintained, although it may double or quadruple depending on how metformin is acquired by patients. Metformin with vitamin B12 supplementation remained less costly and less effective than lifestyle intervention. CONCLUSION: Metformin is generally more cost-saving for diabetes prevention than previously reported because of decreasing costs for patients to acquire metformin. The cost savings was increased despite increased management cost associated with addressing metformin-associated vitamin B12 deficiency.

First Pharmacological Therapy for Hypoactive Sexual Desire Disorder in Premenopausal Women: Flibanserin.

OBJECTIVE: To review data regarding flibanserin, a recently approved therapy for hypoactive sexual desire disorder (HSDD). DATA SOURCES: Literature search of MEDLINE (September 1995 to November 2015) was performed using the search term flibanserin. Reference lists from included articles were reviewed for pertinent citations. STUDY SELECTION AND DATA EXTRACTION: We included phase-3 trials of flibanserin as a treatment for HSDD. Four reports of phase-3 trials were included. One extension study of four phase-3 trials and one phase-2 pharmacokinetic trial were also included. DATA SYNTHESIS: Though a strong placebo response was demonstrated, flibanserin consistently, yet marginally, showed improvement (compared with placebo) in the number of satisfying sexual events per month. The most common adverse events were dizziness (11.4%), somnolence (11.2%), nausea (10.4%), fatigue (9.2%), insomnia (4.9%), and dry mouth (2.4%). CONCLUSIONS: Flibanserin is effective in the treatment of HSDD. Flibanserin should be administered at bedtime to limit the risk for hypotension/syncope, accidental injury, and central nervous system (CNS) depression. Concomitant alcohol use contributes to significant CNS depression and hypotension/syncope with flibanserin and should be avoided according to the boxed warning. Careful patient assessment prior to the diagnosis of HSDD and the use of flibanserin is needed for safe use. Prescribing guidelines recommend discontinuing flibanserin at 8 weeks in the absence of benefit. Sexual dysfunction should be addressed in a patient-specific manner. Providers should exercise shared decision making in prescribing flibanserin for HSDD and discuss flibanserin's benefits and alternative options.

Patient satisfaction with extended-interval warfarin monitoring.

Extended-interval monitoring of warfarin has been proposed to reduce follow-up burden and improve patient satisfaction. We aimed to make an initial assessment of anticoagulation satisfaction before and after an extended-interval warfarin monitoring intervention. We conducted a translational prospective single-arm pilot study of extended-interval warfarin monitoring in five pharmacist-managed anticoagulation clinics. Patients meeting CHEST guideline criteria for extended-interval warfarin monitoring began progressive extended-interval follow-up (6, 8, and 12 weeks thereafter). The Duke Anticoagulation Satisfaction Scale (DASS) was administered at baseline and at end-of-study or study removal (in patients no longer appropriate for extended interval follow-up). Forty-six patients had evaluable pre- and post-intervention DASS survey data. Mean age of patients was 66.5 years, 74 % were non-Hispanic whites, and 48 % were men. Patients completed a mean ± SD of 34 ± 22 weeks of follow-up. Mean ± SD total DASS score at baseline was 45.2 ± 14.2 versus 49.1 ± 14.9 at end-of-study (mean change, +3.9 [95 % CI -0.6-8.4; p = 0.09]), indicating no benefit-and trending toward decrement-to anticoagulation satisfaction. Change in anticoagulation satisfaction varied substantially following extended-interval monitoring, with no evidence of improved satisfaction. Plausible reasons for patients not preferring extended-interval monitoring include increased anxiety and disengagement from self-management activities, both potentially related to less frequent feedback and reassurance during extended interval-monitoring. Additional research is needed to identify who is likely to benefit most from extended-interval monitoring. Anticoagulation satisfaction should be considered with clinical factors and shared-decision making when implementing extended-interval warfarin monitoring.