Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians.

BACKGROUND: Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. PURPOSE: To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). DATA SOURCES: MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. STUDY SELECTION: RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. DATA EXTRACTION: Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. DATA SYNTHESIS: A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). LIMITATIONS: Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. CONCLUSION: In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42022322129).

Cost-Effectiveness of Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review of Cost-Effectiveness Studies for the American College of Physicians.

BACKGROUND: In the United States, costs of antidiabetes medications exceed $327 billion. PURPOSE: To systematically review cost-effectiveness analyses (CEAs) of newer antidiabetes medications for type 2 diabetes. DATA SOURCES: Bibliographic databases from 1 January 2010 through 13 July 2023, limited to English. STUDY SELECTION: Nonindustry-funded CEAs, done from a U.S. perspective that estimated cost per quality-adjusted life-year (QALY) gained for newer antidiabetic medications. Two reviewers screened the literature; disagreements were resolved with a third reviewer. DATA EXTRACTION: Cost-effectiveness analyses were reviewed for treatment comparisons, model inputs, and outcomes. Risk of bias (RoB) of the CEAs was assessed using Drummond criteria and certainty of evidence (CoE) was assessed using GRADE (Grading of Recommendations Assessment, Development, and Evaluations). Certainty of evidence was determined using cost per QALY thresholds predetermined by the American College of Physicians Clinical Guidelines Committee; low (>$150 000), intermediate ($50 to $150 000), or high (<$50 000) value per QALY compared with the alternative. DATA SYNTHESIS: Nine CEAs were eligible (2 low, 1 high, and 6 some concerns RoB), evaluating glucagon-like peptide-1 agonists (GLP1a), dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucose-dependent insulinotropic peptide agonist (GIP/GLP1a), and insulin. Comparators were metformin, sulfonylureas, neutral protamine Hagedorn (NPH) insulin, and others. Compared with metformin, GLP1a and SGLT2i are low value as first-line therapy (high CoE) but may be of intermediate value when added to metformin or background therapy compared with adding nothing (low CoE). Insulin analogues may be similarly effective but more expensive than NPH insulin (low CoE). The GIP/GLP1a value is uncertain (insufficient CoE). LIMITATIONS: Cost-effectiveness analyses varied in methodological approach, assumptions, and drug comparisons. Risk of bias and GRADE method for CEAs are not well established. CONCLUSION: Glucagon-like peptide-1 agonists and SGLT2i are of low value as first-line therapy but may be of intermediate value when added to metformin or other background therapy compared with adding nothing. Other drugs and comparisons are of low or uncertain value. Results are sensitive to drug effectiveness and cost assumptions. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42022382315).

Reimagining How We Synthesize Information to Impact Clinical Care, Policy, and Research Priorities in Real Time: Examples and Lessons Learned from COVID-19.

Real-time clinical care, policy, and research decisions need real-time evidence synthesis. However, as we found during the COVID-19 pandemic, it is challenging to rapidly address key clinical and policy questions through rigorous, relevant, and usable evidence. Our objective is to present three exemplar cases of rapid evidence synthesis products from the Veterans Healthcare Administration Evidence Synthesis Program (ESP) and, in the context of these examples, outline ESP products, challenges, and lessons learned. We faced challenges in (1) balancing scientific rigor with the speed in which evidence synthesis was needed, (2) sorting through rapidly evolving large bodies of evidence, and (3) assessing the impact of evidence synthesis products on clinical care, policy, and research. We found solutions in (1) engaging stakeholders early, (2) utilizing artificial intelligence capabilities, (3) building infrastructure to establish living reviews, and (4) planning for dissemination to maximize impact.

Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

BACKGROUND: Remdesivir is approved for the treatment of adults hospitalized with COVID-19. PURPOSE: To update a living review of remdesivir for adults with COVID-19. DATA SOURCES: Several electronic U.S. Food and Drug Administration, company, and journal websites from 1 January 2020 through 19 October 2021. STUDY SELECTION: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. DATA EXTRACTION: One reviewer abstracted, and a second reviewer verified data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. DATA SYNTHESIS: Since the last update (search date 9 August 2021), 1 new RCT and 1 new subtrial comparing a 10-day course of remdesivir with control (placebo or standard care) were identified. This review summarizes and updates the evidence on the cumulative 5 RCTs and 2 subtrials for this comparison. Our updated results confirm a 10-day course of remdesivir, compared with control, probably results in little to no mortality reduction (5 RCTs). Updated results also confirm that remdesivir probably results in a moderate increase in the proportion of patients recovered by day 29 (4 RCTs) and may reduce time to clinical improvement (2 RCTs) and hospital length of stay (4 RCTs). New RCTs, by increasing the strength of evidence, lead to an updated conclusion that remdesivir probably results in a small reduction in the proportion of patients receiving ventilation or extracorporeal membrane oxygenation at specific follow-up times (4 RCTs). New RCTs also alter the conclusions for harms-remdesivir, compared with control, may lead to a small reduction in serious adverse events but may lead to a small increase in any adverse event. LIMITATION: The RCTs differed in definitions of COVID-19 severity and outcomes reported. CONCLUSION: In hospitalized adults with COVID-19, the findings confirm that remdesivir probably results in little to no difference in mortality and increases the proportion of patients recovered. Remdesivir may reduce time to clinical improvement and may lead to small reductions in serious adverse events but may result in a small increase in any adverse event. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Major Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

BACKGROUND: Remdesivir is being studied and used for treatment of coronavirus disease 2019 (COVID-19). PURPOSE: To update a previous review of remdesivir for adults with COVID-19, including new meta-analyses of patients with COVID-19 of any severity compared with control. DATA SOURCES: Several sources from 1 January 2020 through 7 December 2020. STUDY SELECTION: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. New evidence is incorporated by using living review methods. DATA EXTRACTION: 1 reviewer abstracted data; a second reviewer verified the data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. DATA SYNTHESIS: The update includes 5 RCTs, incorporating data from a new large RCT and the final results of a previous RCT. Compared with control, a 10-day course of remdesivir probably results in little to no reduction in mortality (risk ratio [RR], 0.93 [95% CI, 0.82 to 1.06]; 4 RCTs) but may result in a small reduction in the proportion of patients receiving mechanical ventilation (RR, 0.71 [CI, 0.56 to 0.90]; 3 RCTs). Remdesivir probably results in a moderate increase in the percentage of patients who recovered and a moderate decrease in serious adverse events and may result in a large reduction in time to recovery. Effect on hospital length of stay or percentage remaining hospitalized is mixed. Compared with a 10-day course for those not requiring ventilation at baseline, a 5-day course may reduce mortality, the need for ventilation, and serious adverse events while increasing the percentage of patients who recovered or clinically improved. LIMITATION: Summarizing findings was challenging because of varying disease severity definitions and outcomes. CONCLUSION: In hospitalized adults with COVID-19, remdesivir probably results in little to no mortality difference but probably improves the percentage recovered and reduces serious harms and may result in a small reduction in the proportion receiving ventilation. For patients not receiving ventilation, a 5-day course may provide greater benefits and fewer harms with lower drug costs than a 10-day course. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Remdesivir for Adults With COVID-19 : A Living Systematic Review for American College of Physicians Practice Points.

BACKGROUND: Few treatments exist for coronavirus disease 2019 (COVID-19). PURPOSE: To evaluate the effectiveness and harms of remdesivir for COVID-19. DATA SOURCES: Several databases, tables of contents of journals, and U.S. Food and Drug Administration and company websites were searched from 1 January through 31 August 2020. STUDY SELECTION: English-language, randomized trials of remdesivir treatments for adults with suspected or confirmed COVID-19. New evidence will be incorporated using living review methods. DATA EXTRACTION: Single-reviewer abstraction and risk-of-bias assessment verified by a second reviewer; GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods used for certainty-of-evidence assessments. DATA SYNTHESIS: Four randomized trials were included. In adults with severe COVID-19, remdesivir compared with placebo probably improves recovery by a large amount (absolute risk difference [ARD] range, 7% to 10%) and may result in a small reduction in mortality (ARD range, -4% to 1%) and a shorter time to recovery or clinical improvement. Remdesivir may have little to no effect on hospital length of stay. Remdesivir probably reduces serious adverse events by a moderate amount (ARD range, -6% to -8%). Compared with a 10-day remdesivir course, a 5-day course may reduce mortality, increase recovery or clinical improvement by small to moderate amounts, reduce time to recovery, and reduce serious adverse events among hospitalized patients not requiring mechanical ventilation. Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity. LIMITATIONS: Low-certainty evidence with few published trials, including 1 preliminary report and 2 open-label trials. Trials excluded pregnant women and adults with severe kidney or liver disease. CONCLUSION: In hospitalized adults with COVID-19, remdesivir probably improves recovery and reduces serious adverse events and may reduce mortality and time to clinical improvement. For adults not receiving mechanical ventilation or extracorporeal membrane oxygenation, a 5-day course of remdesivir may provide similar benefits to and fewer harms than a 10-day course. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs, Veterans Health Administration Office of Research and Development, Health Services Research and Development Service, and Evidence Synthesis Program.

Risk prediction models for diabetic foot ulcer development or amputation: a review of reviews.

BACKGROUND: In adults with diabetes, diabetic foot ulcer (DFU) and amputation are common and associated with significant morbidity and mortality. PURPOSE: Identify tools predicting risk of DFU or amputation that are prognostically accurate and clinically feasible. METHODS: We searched for systematic reviews (SRs) of tools predicting DFU or amputation published in multiple databases from initiation to January, 2023. We assessed risk of bias (ROB) and provided a narrative review of reviews describing performance characteristics (calibration and discrimination) of prognostically accurate tools. For such tools, we additionally reviewed original studies to ascertain clinical applicability and usability (variables included, score calculation, and risk categorization). RESULTS: We identified 3 eligible SRs predicting DFU or amputation risk. Two recent SRs (2020 and 2021) were rated as moderate and low ROB respectively. Four risk prediction models - Boyko, Martins-Mendes (simplified), Martins-Mendes (original), and PODUS 2020 had good prognostic accuracy for predicting DFU or amputation over time horizons ranging from 1- to 5-years. PODUS 2020 predicts absolute average risk (e.g., 6% risk of DFU at 2 years) and consists of 3-binary variables with a simple, summative scoring (0-4) making it feasible for clinic use. The other 3 models categorize risk subjectively (e.g., high-risk for DFU at 3 years), include 2-7 variables, and require a calculation device. No data exist to inform rescreening intervals. Furthermore, the effectiveness of targeted interventions in decreasing incidence of DFU or amputation in response to prediction scores is unknown. CONCLUSIONS: In this review of reviews, we identified 4 prognostically accurate models that predict DFU or amputation in persons with diabetes. The PODUS 2020 model, predicting absolute average DFU risk at 2 years, has the most favorable prognostic accuracy and is clinically feasible. Rescreening intervals and effectiveness of intervention based on prediction score are uncertain.

Angioinvasive Trichophyton rubrum associated necrotizing fasciitis in an immunocompromised patient.

Angioinvasive dermatophytosis with necrotizing fasciitis can be a rare complication in immunocompromised patients with early surgical debridement, 12 weeks of oral terbinafine, and reduction in immunosuppression being a viable management strategy.

Pneumococcal pyomyositis: report of 2 cases and review of the literature.

Streptococcus pneumoniae is an uncommon cause of pyomyositis. It is unclear whether the clinical presentation and outcome of pneumococcal pyomyositis differ depending on the host's underlying immune status. We describe 2 patients with pneumococcal pyomyositis, review all published cases, and compare characteristics between apparently healthy hosts and at-risk hosts. A total of 35 cases of pneumococcal pyomyositis were identified, 11 in apparently healthy hosts and 24 in at-risk hosts. Two-thirds of the patients had an antecedent respiratory illness or meningitis. At-risk hosts tended to have a longer interval between the development of symptomatic muscle infection and the diagnosis of pyomyositis and a significantly higher risk of disseminated disease at presentation, as manifested by involvement of multiple noncontiguous muscles or presence of meningitis. Overall, other than 1 death, all patients recovered with antibiotics and surgical drainage, but as might be expected there was a significantly higher rate of complications among at-risk hosts.

COVID-19 postacute care major organ damage: a systematic review.

BACKGROUND: Major organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls. OBJECTIVE: Examine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls. DATA SOURCES: MEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021. STUDY ELIGIBILITY CRITERIA: English language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text. STUDY APPRAISAL AND SYNTHESIS METHODS: Study quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised. RESULTS: Of 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%-94% male and 48%-78% White race; 10%-40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls. LIMITATIONS: Applicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Postacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps. PROSPERO REGISTRATION NUMBER: CRD42020204788.

Aspergillus Osteomyelitis Secondary to Chronic Necrotizing Pulmonary Aspergillosis in a Patient With Rheumatoid Arthritis.

Aspergillus spp. are ubiquitous molds that cause a wide range of clinical syndromes depending on the immune status of the host. Herein, we present a case of a patient with rheumatoid arthritis on long-term immunosuppressive medications, with a persistent dry cough and left-sided chest pain for over a year, who presented with acute sternal drainage. Computed tomography of the chest showed chronic pulmonary abnormalities, parasternal fluid, and bone destruction of the distal sternum and left sixth rib. The patient underwent debridement; sternal biopsy tissue showed septate hyphae with acute-angled branching, and Aspergillus fumigatus grew in culture. We suspected that the patient developed chronic necrotizing pulmonary aspergillosis (CNPA) that traversed tissue planes and caused chest wall osteomyelitis. The patient received voriconazole and surgical debridement, with clinical and radiological improvement. This case demonstrates the importance of considering CNPA as a diagnosis in patients with moderate degrees of immunosuppression and chronic respiratory symptoms, and Aspergillus spp. as an etiology of osteomyelitis in such patients.

Diagnosis and Management of Osteomyelitis Associated With Stage 4 Pressure Ulcers: Report of a Query to the Emerging Infections Network of the Infectious Diseases Society of America.

BACKGROUND: Few studies exist to guide the management of patients with stage 4 pressure ulcers with possible underlying osteomyelitis. We hypothesized that infectious disease (ID) physicians would vary widely in their approach to such patients. METHODS: The Emerging Infections Network distributed a 10-question electronic survey in 2018 to 1332 adult ID physicians in different practice settings to determine their approach to such patients. RESULTS: Of the 558 respondents (response rate: 42%), 17% had managed no such patient in the past year. Of the remaining 464 respondents, 60% usually felt confident in diagnosing osteomyelitis; the strongest clinical indicator of osteomyelitis reported was palpable or visible bone at the ulcer base. Approaches to diagnosing osteomyelitis in patients with visible and palpable bone varied: 41% of respondents would assume osteomyelitis, 27% would attempt pressure off-loading first, and 22% would perform diagnostic testing immediately. Preferred tests for osteomyelitis were bone biopsy (for culture and histopathology) and magnetic resonance imaging. Respondents differed widely on favored route(s) (intravenous, oral, or both) and duration of antimicrobial therapy but would treat longer in the absence, vs presence, of full surgical debridement (P < .001). Overall, 62% of respondents opined that osteomyelitis under stage 4 pressure ulcers is usually or almost always treated excessively, and most (59%) suggested multiple topics for future research. CONCLUSIONS: Regarding osteomyelitis underlying stage 4 pressure ulcers, ID physicians reported widely divergent diagnostic and treatment approaches. Most of the reported practice is not supported by the available evidence, which is quite limited and of low quality.