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.

Falls Prevention for Older Adults.

This article summarizes a 2022 clinical practice guideline on falls prevention and management in older adults from the World Falls Guidelines Initiative.

Lower Gastrointestinal Hemorrhage.

This JAMA Clinical Guidelines Synopsis summarizes the 2023 American College of Gastroenterology guidelines on management of patients with acute lower gastrointestinal bleeding.

Diagnosis and Management of Celiac Disease.

This JAMA Clinical Guidelines Synopsis summarizes the American College of Gastroenterology's 2023 guideline update on diagnosis and management of celiac disease.

Topical Therapies for Atopic Dermatitis.

This JAMA Clinical Guidelines Synopsis summarizes the American Academy of Dermatology's 2023 guidelines for topical-therapy management of adults with atopic dermatitis.

Prescribing Opioids for Pain.

This JAMA Clinical Guidelines Synopsis summarizes the Centers for Disease Control and Prevention's 2022 clinical practice guideline for prescribing opioids for pain.

2023 Update in ambulatory general internal medicine.

The practice of outpatient medicine is demanding, encompasses a wide scope of practice, and leaves little time for internists to stay up to date with the current literature. This article reviews 5 studies published in 2022 and 2023 that have the potential to change the practice of outpatient medicine. Topics covered include chronic kidney disease, secondary cardiovascular disease, kidney stones, obesity, and lipid management.

Red blood cells stored for increasing periods produce progressive impairments in nitric oxide-mediated vasodilation.

BACKGROUND: Clinical outcomes in transfused patients may be affected by the duration of blood storage, possibly due to red blood cell (RBC)-mediated disruption of nitric oxide (NO) signaling, a key regulator of vascular tone and blood flow. STUDY DESIGN AND METHODS: AS-1 RBC units stored up to 42 days were sampled at selected storage times. Samples were added to aortic rings ex vivo, a system where NO-mediated vasodilation could be experimentally controlled. RESULTS: RBC units showed storage-dependent changes in plasma hemoglobin (Hb), RBC 2,3-diphosphoglycerate acid, and RBC adenosine triphosphate conforming to expected profiles. When freshly collected (Day 0) blood was added to rat aortic rings, methacholine (MCh) stimulated substantial NO-mediated vasodilation. In contrast, MCh produced no vasodilation in the presence of blood stored for 42 days. Surprisingly, the vasoinhibitory effects of stored RBCs were almost totally mediated by RBCs themselves: removal of the supernatant did not attenuate the inhibitory effects, while addition of supernatant alone to the aortic rings only minimally inhibited MCh-stimulated relaxation. Stored RBCs did not inhibit vasodilation by a direct NO donor, demonstrating that the RBC-mediated vasoinhibitory mechanism did not work by NO scavenging. CONCLUSIONS: These studies have revealed a previously unrecognized vasoinhibitory activity of stored RBCs, which is more potent than the described effects of free Hb and works through a different mechanism that does not involve NO scavenging but may function by reducing endothelial NO production. Through this novel mechanism, transfusion of small volumes of stored blood may be able to disrupt physiologic vasodilatory responses and thereby possibly cause adverse clinical outcomes.

Validity of the Childhood Asthma Control Test in diverse populations: A systematic review.

PURPOSE: We examined the validity of the Childhood Asthma Control Test (C-ACT) and identified recommended thresholds for uncontrolled asthma in children from varying backgrounds. METHODS: A systematic literature review was performed utilizing PubMed, Ovid Medline, SCOPUS, CINAHL, and conference proceedings. Studies were included if they enrolled children, had a primary outcome of asthma control, examined test validity or psychometrics, and utilized the C-ACT. Along with study design and demographic data, we extracted all outcomes and comparisons used to validate the C-ACT. We evaluated risk of bias using the COSMIN Risk of Bias tool. Our protocol was registered with PROSPERO (CRD42020211119). RESULTS: Of 4924 records screened, 28 studies were included. Studies were conducted internationally and published between 2007 and 2018. Average number of enrolled participants was 193 (SD = 155, range = 22-671). Ten studies calculated Cronbach's α (mean [SD] = 0.78(0.05), range = 0.677-0.83). Thirteen studies recommended cut-offs for uncontrolled asthma (≤18-≤24). Nine studies found significant agreement or correlation between C-ACT and Global Initiative for Asthma guidelines/physician assessment of asthma control (correlation coefficients range = 0.219-0.65). Correlation coefficients between C-ACT and spirometry were <0.6 in five of six studies that included spirometry. Kappa values for C-ACT and various spirometry measurements ranged 0.00-0.34. CONCLUSIONS: The C-ACT showed good internal consistency and mixed levels of agreement and correlation with various clinical asthma measures. Recommended cut-offs for asthma control varied and had no consistent relationship with nationality, race, ethnicity, or language. Few studies examined cross-cultural validity and multiple populations remain under-studied.

Endocrine Society Hypercalcemia of Malignancy Guidelines.

This guideline synopsis summarizes the Endocrine Society guidelines for hypercalcemia of malignancy in adults.