Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.

Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2).

CONTEXT: In previous SURPASS studies tirzepatide reduced HbA1c and body weight and improved markers of insulin sensitivity (IS) and beta-cell function to a greater extent than comparators. OBJECTIVE: Explore changes in biomarkers of beta-cell function and IS and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. DESIGN: Post-hoc analysis of SURPASS-2 Phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). SETTING: Post-hoc analysis of 128 sites in 8 countries. PARTICIPANTS: 1879 participants with T2D. INTERVENTIONS: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. MAIN OUTCOMES MEASURES: Change in HOMA2-B, HOMA2-IR, fasting glucagon, fasting C-peptide, and fasting insulin. RESULTS: At week 40, greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9 to 120.4%) than with semaglutide 1 mg (84.0%) [p<0.05]. There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5 to 24.0%) than with semaglutide 1 mg (5.1%) [p<0.05]. Tirzepatide 10 and 15 mg resulted a significant reduction in both fasting C-peptide (5.2 to 6.0%) and fasting glucagon (53.0 to 55.3%) compared to an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg [p<0.05]. HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. CONCLUSION: In this post-hoc analysis improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, irrespective of baseline beta cell function and insulin resistance, compared to semaglutide.

Obesity and Breast Cancer Risk: The Oncogenic Implications of Metabolic Dysregulation.

CONTEXT: Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. EVIDENCE ACQUISITION: Pubmed literature search using combinations of "obesity," "breast cancer risk," "diet," "exercise," "weight gain," "weight loss," "adipose tissue inflammation," "crown-like structure," "immune markers," "metformin," "gliflozins," "SGLT-2i," "GLP1-RA," and related terms. EVIDENCE SYNTHESIS: Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor-positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk. CONCLUSION: Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

The Longer-Term Benefits and Harms of Glucagon-Like Peptide-1 Receptor Agonists: a Systematic Review and Meta-Analysis.

BACKGROUND: Previous meta-analyses of the benefits and harms of glucagon-like peptide-1 receptor agonists (GLP1RAs) have been limited to specific outcomes and comparisons and often included short-term results. We aimed to estimate the longer-term effects of GLP1RAs on cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events in patients with type 2 diabetes, compared to placebo and other anti-hyperglycemic medications. METHODS: We searched PubMed, Scopus, and clinicaltrials.gov (inception-July 2019) for randomized controlled trials ≥ 52 weeks' duration that compared a GLP1RA to placebo or other anti-hyperglycemic medication and included at least one outcome of interest. Outcomes included cardiovascular risk factors, microvascular and macrovascular complications, all-cause mortality, and treatment-related adverse events. We performed random effects meta-analyses to give summary estimates using weighted mean differences (MD) and pooled relative risks (RR). Risk of bias was assessed using the Cochrane Collaboration risk of bias in randomized trials tool. Quality of evidence was summarized using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The study was registered a priori with PROSPERO (CRD42018090506). RESULTS: Forty-five trials with a mean duration of 1.7 years comprising 71,517 patients were included. Compared to placebo, GLP1RAs reduced cardiovascular risk factors, microvascular complications (including renal events, RR 0.85, 0.80-0.90), macrovascular complications (including stroke, RR 0.86, 0.78-0.95), and mortality (RR 0.89, 0.84-0.94). Compared to other anti-hyperglycemic medications, GLP1RAs only reduced cardiovascular risk factors. Increased gastrointestinal events causing treatment discontinuation were observed in both comparisons. DISCUSSION: GLP1RAs reduced cardiovascular risk factors and increased gastrointestinal events compared to placebo and other anti-hyperglycemic medications. GLP1RAs also reduced MACE, stroke, renal events, and mortality in comparisons with placebo; however, analyses were inconclusive for comparisons with other anti-hyperglycemic medications. Given the high costs of GLP1RAs, the lack of long-term evidence comparing GLP1RAs to other anti-hyperglycemic medications has significant policy and clinical practice implications.

Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are a recent class of medication approved for the treatment of type 2 diabetes (T2D). Previous meta-analyses have quantified the benefits and harms of SGLT2Is; however, these analyses have been limited to specific outcomes and comparisons and included trials of short duration. We comprehensively reviewed the longer-term benefits and harms of SGLT2Is compared to placebo or other anti-hyperglycemic medications. METHODS: We searched PubMed, Scopus, and clinicaltrials.gov from inception to July 2019 for randomized controlled trials of minimum 52 weeks' duration that enrolled adults with T2D, compared an SGLT2I to either placebo or other anti-hyperglycemic medications, and reported at least one outcome of interest including cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events. We conducted random effects meta-analyses to provide summary estimates using weighted mean differences (MD) and pooled relative risks (RR). The study was registered a priori with PROSPERO (CRD42018090506). RESULTS: Fifty articles describing 39 trials (vs. placebo, n = 28; vs. other anti-hyperglycemic medication, n = 12; vs. both, n = 1) and 112,128 patients were included in our analyses. Compared to placebo, SGLT2Is reduced cardiovascular risk factors (e.g., hemoglobin A1c, MD - 0.55%, 95% CI - 0.62, - 0.49), macrovascular outcomes (e.g., hospitalization for heart failure, RR 0.70, 95% CI 0.62, 0.78), and mortality (RR 0.87, 95% CI 0.80, 0.94). Compared to other anti-hyperglycemic medications, SGLT2Is reduced cardiovascular risk factors, but insufficient data existed for other outcomes. About a fourfold increased risk of genital yeast infections for both genders was observed for comparisons vs. placebo and other anti-hyperglycemic medications. DISCUSSION: We found that SGLT2Is led to durable reductions in cardiovascular risk factors compared to both placebo and other anti-hyperglycemic medications. Reductions in macrovascular complications and mortality were only observed in comparisons with placebo, although trials comparing SGLT2Is vs. other anti-hyperglycemic medications were not designed to assess longer-term outcomes.

Denosumab Discontinuation in Patients Treated for Low Bone Density and Osteoporosis.

Denosumab (DMAB) is a potent antiresorptive treatment used for treatment of osteoporosis and low bone mineral density (BMD) in those at high risk for fracture. In postmenopausal women with osteoporosis, DMAB treatment for 10 years has been studied, with results showing continued gains in BMD, sustained fracture risk reduction, and low risk of adverse events. However, upon discontinuation of DMAB, there is a rapid reversal of effect, with increase in bone turnover, loss of BMD, and in a subset of patients, a greater risk for multiple vertebral fractures.

Association of Loneliness With Falls: A Study of Older US Adults Using the National Social Life, Health, and Aging Project.

Objectives: Falls represent a significant cause of morbidity and mortality in older adults, and are more common among those living alone. We aimed to determine if there is an association between loneliness and falls. Methods: Participants were surveyed in three waves separated by 5 years. We used the three-item UCLA Loneliness Scale to measure loneliness. Results: Data from 2337 respondents, with both loneliness and fall data in at least two consecutive waves, were included. Over three waves, 51% respondents reported a fall and 23% reported ≥ two falls. In multivariate analysis, the odds of having ≥ one fall 5 years later increased by a factor of 1.11 per one point increase on the loneliness scale (OR = 1.11, 95% CI 1.04, 1.19; p < .01). Discussion: Lonely older adults have increased odds of future falls. Strategies for combating loneliness in older adults may help reduce fall-related morbidity and mortality.

Vertebral fracture assessment: Enhancing the diagnosis, prevention, and treatment of osteoporosis.

Osteoporosis is a highly prevalent condition, resulting in significant morbidity and mortality. Nevertheless, it is frequently untreated. Vertebral fractures often do not come to clinical attention, yet, their presence is diagnostic of osteoporosis, helps to predict the risk of future fractures, and may alter the choice of pharmacotherapy. The addition of lateral spine imaging technology to the densitometer, for vertebral fracture assessment (VFA), represented a major advancement in the ability to diagnose vertebral fractures and osteoporosis. VFA is an under-utilized and highly effective imaging tool to enhance osteoporosis detection and fracture prevention. Several factors make VFA an ideal technology to evaluate for vertebral fractures. These include: the ability to obtain the image at the same time the bone density is done, with significantly lower radiation exposure than with spine radiography, and at a lower cost. This review provides an overview of the clinical significance of identifying vertebral fractures, the origins of the VFA, its clinical indications, a review of the methods used to diagnose vertebral fracture, an overview on interpreting the VFA, and the strengths and limitations of this technique.

Primary Care Endocrinology in the Adult Woman.

Diabetes mellitus, thyroid disorders, and osteoporosis are endocrine conditions affecting a significant proportion of women presenting to the obstetrician-gynecologist. Obstetrician-gynecologists are often the first health-care providers that young women see in adulthood, and thus, have a critical opportunity to identify women at risk for gestational and overt diabetes and manage the condition in those who have developed it. The obstetrician-gynecologist should be aware of the appropriate therapeutic options and treatment goals (eg, hemoglobin A1c) for women with diabetes. Thyroid disorders often present with menstrual irregularities or infertility, can affect pregnancy outcomes, and contribute to cardiovascular and bone disorders as women age. Finally, osteoporosis and low bone mineral density affect a substantial proportion of older women and some younger women with risk factors for secondary osteoporosis. The morbidity and mortality of osteoporotic fractures is substantial. There are many lifestyle interventions and therapeutic options available for these conditions, and the gynecologist plays a key role in optimizing risk factor assessment, screening, and providing treatment when appropriate.

Diabetes and Aging: Meeting the Needs of a Burgeoning Epidemic in the United States.

Abstract-In the United States, one out of every four adults over the age of 65 has diabetes and one half of all adults in this age group are prediabetic, placing them at high risk for developing the disease. Beyond the United States, many other countries are also facing aging populations and high obesity rates that contribute to a staggering global diabetes epidemic. The care of the older patient with diabetes is frequently challenging, due to the accumulation of diabetic complications, extensive comorbidities, and functional impairments. Compounding this challenge is the lack of directly available evidence to guide management and care in this population. Though the global community shares in the epidemiologic burden of diabetes, there are large disparities across health systems and nations in the allocation of resources to the prevention, diagnosis, and treatment of the disease. Yet there is a consistency across many countries in the sub-optimal glycemic control and health outcomes for a majority of diabetics. This article reviews the context in which health systems provide diabetes care for the elderly and provides a framework for policy makers to support comprehensive diabetes care in the older adult. Nearly half of global diabetes expenditures occur in the United States, where only 6% of the world's diabetics reside. This article focuses on how to improve diabetes care in the United States, given its disproportionate contribution to global diabetes expenditures. Many of the recommendations presented, however, may be adapted and applied to other health systems.

Clinical, endoscopic, and histologic features of eosinophilic inflammation of the gastrointestinal tract in pediatric liver transplant patients.

Immunosuppression during the post-transplantation period has led to dramatic outcome improvements in PLTR patients. There have been reports describing the development of food allergies and an increased predilection for development of EGI in PLTR. We aimed to identify the clinical, endoscopic and histologic features of EGI in PLTR patients. In this retrospective case series we analyzed medical record of all PLTR who underwent EGD and/or colonoscopy at our institution from 2000 to 2006. From 2000 to 2006, 32 PLTR patients underwent endoscopic evaluation. Seventeen (53%) of 32 patients were diagnosed with EGI. Endoscopic abnormalities were seen in the esophagus, stomach, and small intestine in 11 (65%), 11 (65%), and four (24%) patients, respectively. Eosinophilic inflammation was seen in the esophagus, stomach, and small intestine in 13 (76%), 10 (59%), and five (29%) patients, respectively. Nine of 17 patients underwent colonoscopy and endoscopic abnormalities were seen in four (44%) patients. Five patients (56%) had eosinophilic inflammation. In conclusion, we have characterized the clinical, endoscopic, and histologic features of EGI. Histologic and endoscopic examination reveals that, when present, EGI is often found at multiple segments along the gastrointestinal tract.

Talking it out: helping our patients live better while dying.

Although dying is an inevitable part of the life cycle, there has been extensive political debate over end-of-life care. Participating in end-of-life care conversations can be emotionally challenging for everyone involved. Messages about serious or terminal illnesses can be very hard for patients and their families to hear, and physicians frequently struggle with the burden of delivering these messages. Still, evidence shows that conversations about end-of-life care options between physicians and patients can improve the quality of life of dying patients and help to relieve the emotional burden on surviving loved ones. Legislation to support these discussions by consistently reimbursing physicians for their time spent performing this service has been blocked on multiple occasions. More research on how to improve end-of-life care will enable health care providers to optimize treatment of their patients. Overcoming political divides to support end-of-life care conversations is needed to promote care that is consistent with patients' values and needs and is a key step in encouraging better quality of life for dying patients.