Inadequate insurance coverage for overweight/obesity management.

OBJECTIVES: To discuss the social, psychological, and access barriers that inhibit weight loss, and to propose steps and initiatives for addressing the growing obesity epidemic. STUDY DESIGN: Narrative review of the obesity epidemic in the US and associated racial/ethnic and socioeconomic disparities. METHODS: An internet search of relevant studies and government reports was conducted. RESULTS: Obesity is a significant health crisis affecting more than 123 million adults and children/adolescents in the US. An estimated 1 in 5 deaths in Black and White individuals aged 40 to 85 years in the US is attributable to obesity. Obesity puts individuals at elevated risk for type 2 diabetes, cardiovascular disease, chronic kidney disease, gastrointestinal disorders, nonalcoholic fatty liver disease, cancer, respiratory ailments, dementia/Alzheimer disease, and other disorders. In the US, significantly more Black (49.9%) and Hispanic (45.6%) individuals are affected by obesity than White (41.4%) and Asian (16.1%) individuals. Health care costs for obesity account for more than $260 billion of annual US health care spending-more than 50% greater in excess annual medical costs per person than individuals with normal weight. CONCLUSIONS: Addressing the obesity epidemic will require a multifaceted approach that focuses on prevention, treatment, and reducing the impact of stigma. Continued advocacy and education efforts are necessary to make progress and improve the health and well-being of individuals affected by obesity.

Managing Patients on SGLT2 Inhibitors in Primary Care.

In this video, Javed Butler, MD, and John E. Anderson, MD, discuss the management of patients on SGLT2 inhibitors in the primary care setting.

Summary and Panel Discussion.

In this video, Javed Butler, MD, Jonathan Rich, MD, Rachel Pessah-Pollack, MD, and John E. Anderson, MD, summarize the key points of the enhanced publication "Role of SGLT2 Inhibitors in the Management of Heart Failure With and Without Type 2 Diabetes." The panel then delves deeper into some of the topics raised.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Patient and physician perspectives and experiences of basal insulin titration in type 2 diabetes in the United States: Cross-sectional surveys.

AIM: Patient- and physician-associated barriers impact the effectiveness of basal insulin (BI) titration in the management of type 2 diabetes (T2D). We evaluated the experiences of patients with T2D and physicians with BI titration education. MATERIALS AND METHODS: In this observational, cross-sectional study, patients with T2D and physicians treating patients with T2D were identified by claims in the Optum Research Database and were invited to complete a survey. Eligible patients had 12 months of continuous health-plan enrolment with medical and pharmacy benefits during the baseline period, and recent initiation of BI therapy. Eligible physicians had initiated BI for ≥1 eligible patient with T2D during the past 6 months. RESULTS: In total, 416 patients and 386 physicians completed the survey. Ninety per cent of physicians reported treating ≥50 patients with T2D; 66% treated ≥25% of patients with BI. Whereas 74% of patients reported that BI titration was explained to them by a physician, 96% of physicians reported doing so. Furthermore, 20% of patients stated they were offered educational materials whereas 56% of physicians reported having provided materials. Physicians had higher expectations of glycaemic target achievement than were seen in the patient survey; their main concern was the patients' ability to titrate accurately (79%). CONCLUSIONS: There is a marked difference in patients' and physicians' experiences of BI titration education. Novel tools and strategies are required to enable effective BI titration, with more educational resources at the outset, and ongoing access to tools that provide clear, simple direction for self-titration with less reliance on physicians/health care providers.

Reducing Ischemic Stroke in Diabetes: The Role of GLP-1 RAs.

KEY TAKEAWAYS: Stroke is a significant cause of mortality worldwide, and diabetes is an independent risk factor for ischemic stroke occurrence and recurrence. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower the risk of ischemic stroke through beneficial effects on traditional stroke risk factors such as hyperglycemia, hypertension, and dyslipidemia. Primary care practitioners (PCPs) can play a substantial role in reducing ischemic stroke; studies have indicated that patients who have a PCP at the time of first stroke have a lower risk of stroke recurrence. Clinical practice guidelines recommend treating type 2 diabetes in patients with or at risk for cardiovascular (CV) disease with glucose-lowering agents with proven CV benefit, such as GLP-1 RAs and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Based on meta-analyses of CV outcomes trials, GLP-1 RAs have a substantial and statistically significant benefit on ischemic stroke risk reduction, whereas SGLT2 inhibitors have a nonsignificant effect. The use of GLP-1 RAs, in addition to non-pharmacologic and pharmacologic management of traditional stroke risk factors, is a key component of complex therapy for ischemic stroke risk reduction.

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers.

This article reviews the efficacy and safety data of tirzepatide, a once-weekly, novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States, the European Union, and other regions for the treatment of type 2 diabetes. All doses of tirzepatide demonstrated superiority in reducing A1C and body weight from baseline versus placebo or active comparators. The safety profile of tirzepatide was consistent with that of the GLP-1 receptor agonist class, with mild to moderate and transient gastrointestinal side effects being the most common adverse events. With clinically and statistically significant reductions in A1C and body weight without increased risk of hypoglycemia in various populations, tirzepatide has demonstrated potential as a first-in-class treatment option for many people with type 2 diabetes.

Recent advances in therapies utilizing superabsorbent hydrogel technology for weight management: A review.

Long-term therapeutic benefit of treatments for weight management in patients with overweight (also termed preobesity) or obesity may be limited by variable safety, tolerability, and efficacy profiles, and patient adherence to treatment regimens. There is a medical need for nonsystemic treatments that promote weight loss in patients with overweight or early obesity. This report reviews four different approaches of utilizing superabsorbent hydrogel technology for weight management at varying stages of preclinical and clinical development. The first is a nonsystemic, oral superabsorbent hydrogel created from naturally derived building blocks used in foods (cellulose-based), designed to mix homogenously with and change the properties of the ingested meal throughout the gastrointestinal tract (stomach and small intestine). This is the first-in-class to be cleared by the Food and Drug Administration (FDA) to aid in weight-management for adults with BMI of 25-40 kg/m2 in conjunction with diet and exercise. In contrast, the other three approaches in development utilize superabsorbent hydrogel technologies to support an intragastric balloon-like structure, solely occupying space in the stomach and displacing the meal: (1) a pufferfish-inspired device; (2) Epitomee, a pH-sensitive self-expanding hydrogel device; and (3) a light-degradable hydrogel used to control balloon deflation. These new approaches that utilize superabsorbent hydrogel technology offer a wide range of clinical applicability and have the potential to broaden the weight management treatment landscape. Over time, increasing the number of patients treated with superabsorbent hydrogel technologies will provide important information on long-term efficacy and safety.

DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.

Continuous Glucose Monitoring (CGM) Is a Tool, Not a Reward: Unjustified Insurance Coverage Criteria Limit Access to CGM.

Recent studies have demonstrated the clinical utility of continuous glucose monitoring (CGM) use in type 2 diabetes (T2D) patients who are treated with intensive insulin management. Large retrospective database analyses of T2D patients treated with less-intensive therapies have also shown that CGM use was associated with significant reductions in hemoglobin A1c levels and health resource utilization, including diabetes-related hospitalizations and emergency room care. Despite the growing body of evidence supporting CGM use in the broader T2D population, current eligibility criteria required by public and many private insurers are denying millions of individuals with T2D access to this valuable technology. In this article, we discuss an evidence-based rationale for modifying current eligibility requirements for CGM coverage.

Synergistic effects of intracoronary infusion of autologous bone marrow-derived mesenchymal stem cells and revascularization procedure on improvement of cardiac function in patients with severe ischemic cardiomyopathy.

BACKGROUND: Ischemic cardiomyopathy (ICM) is a leading cause of cardiovascular mortality worldwide. It is defined as abnormal enlargement of the left ventricular (LV) cavity with poor LV function due to coronary artery disease. Currently available established treatments are palliative whereby blood supply is recovered to ischemic regions but fails to regenerate heart tissues. Mesenchymal stem cells (MSCs) offer a promising treatment for ICM given their regenerative and multipotent characteristics. This study aims to investigate the effect of MSCs infusion with concurrent revascularization in patients with severe ICM compared to receiving only revascularization procedure or MSCs infusion. METHODS: Twenty-seven patients with history of anterior myocardial infarction (MI) and baseline left ventricular ejection fraction (LVEF) of less than 35% were recruited into this study. Patients who are eligible for revascularization were grouped into group A (MSCs infusion with concurrent revascularization) or group B (revascularization only) while patients who were not eligible for revascularization were allocated in group C to receive intracoronary MSCs infusion. LV function was measured using echocardiography. RESULTS: Patients who received MSCs infusion (either with or without revascularization) demonstrated significant LVEF improvements at 3, 6 and 12 months post-infusion when compared to baseline LVEF within its own group. When comparing the groups, the magnitude of change in LVEF from baseline for third visits i.e., 12 months post-infusion was significant for patients who received MSCs infusion plus concurrent revascularization in comparison to patients who only had the revascularization procedure. CONCLUSIONS: MSCs infusion significantly improves LV function in ICM patients. MSCs infusion plus concurrent revascularization procedure worked synergistically to improve cardiac function in patients with severe ICM.

Combining Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors to Target Multiple Organ Defects in Type 2 Diabetes.

Long-term risks of macro- and microvascular complications may be reduced in people with type 2 diabetes who achieve early and sustained glycemic control. Delays in attaining A1C goals are associated with poor long-term cardiovascular (CV) outcomes. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are glucose-lowering therapies that act through complementary mechanisms of action with regard to the pathophysiologic defects of type 2 diabetes. Trials of agents in both drug classes have demonstrated improvements in CV and renal outcomes. This review discusses the rationale for combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor, including early initiation of this combination in newly diagnosed patients. This combination may lead to timely glycemic control and potentially additive CV and renal benefits. Clinical studies of the combination have shown partially additive effects on A1C reduction, additive effects on weight reduction, and potentially synergistic effects on blood pressure reduction. Long-term studies are needed to determine whether the combination provides an additional effect on CV and renal outcomes compared with agents from either drug class when used alone.

Practical guidance for using the FreeStyle Libre flash continuous glucose monitoring in primary care.

Use of continuous glucose monitoring (CGM) improves clinical outcomes in type 1 diabetes, and significant benefits been demonstrated in patients with type 2 diabetes, including improved glycemic control, better treatment adherence, and an increased understanding of their treatment regimens. Currently, there are two types of CGM systems: real-time CGM (rtCGM) and flash CGM (FCGM). Retrospective analysis of CGM data allows patients and their clinicians to identify glycemic patterns that support and facilitate informed therapy decisions. With the increasing prevalence of diabetes, primary care physicians will be compelled to take on more responsibility for managing patients with diabetes. This article focuses on practical approaches and decision-making strategies for utilizing FCGM in primary care settings.

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood. Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery. Design, Setting, and Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019. Main Outcomes and Measures: Overall survival. Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Conclusions and Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.

Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes.

OBJECTIVE: Achieving and maintaining recommended glycemic targets, including those for glycated hemoglobin A1c (A1C), is key to improving outcomes in patients with type 2 diabetes (T2D). As fasting plasma glucose and postprandial glucose contribute to overall A1C, targeting both is essential for sustaining glycemic control. METHODS: This review examines the complementary mechanisms of action of glucagon-like peptide 1 (GLP-1) receptor agonists and basal insulin; they both enhance glucose-stimulated insulin release and suppress glucagon secretion. GLP-1 receptor agonists also slow gastric emptying and increase satiety. RESULTS: Adding a GLP-1 receptor agonist to therapy with a basal insulin analog has been associated with improved overall glycemic control, with comparable risk of hypoglycemia and no weight gain. Titratable fixed-ratio co-formulations of basal insulin and a GLP-1 receptor agonist have been shown to improve glycemic control, with less complex dosing schedules, possibly increasing treatment adherence. The slow titration of fixed-ratio co-formulations has been shown to reduce the occurrence and severity of gastrointestinal adverse events associated with the use of a separate GLP-1 receptor agonist. Titratable fixed-ratio co-formulations also mitigate insulin-associated weight gain, and show a comparable risk of hypoglycemia to basal insulin use alone. CONCLUSIONS: The efficacy and safety of titratable fixed-ratio co-formulations have been demonstrated for insulin degludec/liraglutide and insulin glargine/lixisenatide in the DUAL and LixiLan trials, respectively, in both insulin-naive and -experienced patients. Titratable fixed-ratio co-formulations represent an attractive treatment option for many patients with T2D.

CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling.

Members of the family of nuclear factor κB (NF-κB) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-κB complexes are retained in the cytoplasm by the inhibitory protein IκBα, whereas noncanonical NF-κB complexes are retained by p100. Although activation of canonical NF-κB signaling through the IκBα kinase complex is well studied, few regulators of the NF-κB-inducing kinase (NIK)-dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have been identified. We discovered a role for cyclin-dependent kinase 12 (CDK12) in transcriptionally regulating the noncanonical NF-κB pathway. High-content phenotypic screening identified the compound 919278 as a specific inhibitor of the lymphotoxin ß receptor (LTßR), and tumor necrosis factor (TNF) receptor superfamily member 12A (FN14)-dependent nuclear translocation of p52, but not of the TNF-α receptor-mediated nuclear translocation of p65. Chemoproteomics identified CDK12 as the target of 919278. CDK12 inhibition by 919278, the CDK inhibitor THZ1, or siRNA-mediated knockdown resulted in similar global transcriptional changes and prevented the LTßR- and FN14-dependent expression of MAP3K14 (which encodes NIK) as well as NIK accumulation by reducing phosphorylation of the carboxyl-terminal domain of RNA polymerase II. By coupling a phenotypic screen with chemoproteomics, we identified a pathway for the activation of the noncanonical NF-κB pathway that could serve as a therapeutic target in autoimmunity and cancer.