Rodríguez‐Gutiérrez, René

Abstract Clinical question What are the benefits and harms of medications for adults with type 2 diabetes at varied risks of cardiovascular and kidney related complications? Context Emerging clinical trials of novel medications have demonstrated benefits on cardiovascular, kidney, and weight related outcomes in people with type 2 diabetes. Dynamically updated practice guidelines adhering to standards of trustworthiness are necessary in response to a rapidly evolving evidence base and the availability of multiple medication alternatives. This living practice guideline incorporates the latest available medications and evidence and provides recommendations stratified by risks of cardiovascular and kidney complications to inform diabetes management. Recommendations The panel issued risk-stratified recommendations regarding four prioritised medications for adults with type 2 diabetes (SGLT-2 inhibitors, GLP-1 receptor agonists, finerenone and tirzepatide): • Lower risk (three or fewer cardiovascular risk factors without established cardiovascular disease (CVD) or chronic kidney disease (CKD)): weak recommendation against SGLT-2 inhibitors or GLP-1 receptor agonists. • Moderate risk (more than three cardiovascular risk factors without established CVD or CKD; or established CVD and/or CKD at lower risk of complications): weak recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation against finerenone in adults with CKD. • Higher risk (established CVD and/or CKD at higher risk of complications, or established heart failure): strong recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation in favour of finerenone in adults with CKD. • Across risk strata: weak recommendation in favour of tirzepatide in adults with obesity. About this guideline and how it was created An international panel including two patient partners, clinicians, and methodologists produced these recommendations. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits, harms and burdens of treatment from an individual patient perspective. Recommendations were informed by a linked living systematic review and network meta-analysis evaluating relative benefits and harms updated to 31 July 2024; and by linked systematic reviews addressing risk prediction models and values and preferences of adults with type 2 diabetes. Candidate therapeutics are prioritised based on availability of sufficient randomised trial data, relevance to a global audience and likelihood of changing practice. This is the first version of the living guideline. The guideline is part of the BMJ Rapid Recommendations series. MAGICapp displays the most recent version of the guideline and full content including evidence summaries and decision aids; major updates will be published in The BMJ . We encourage re-use, adaptation and translation of these living guidelines, and recognise that the lack of availability or high costs of some medications may be prohibitive and will impact on how these recommendations are implemented across different health care systems.

Aim. To evaluate retinal vascular perfusion and density by optical coherence tomography angiography (OCTA) before, during, and after hypoglycemia in individuals with diabetes mellitus with or without diabetic retinopathy (DR). Methods. A focused clinical history was performed, followed by an ophthalmological examination to document retinopathy status. OCTA was performed at baseline, at hypoglycemia, and at glucose normalization. Eye tracking and eye alignment devices on the platform were used to obtain a macular thickness cube (512 × 128) and vascular perfusion and density protocols of 3 × 3 mm. Retinal vascular reactivity was analyzed with superficial plexus vascular perfusion and density protocols on OCTA. Results. Fifty-two participants encompassing 97 eyes fulfilled the eligibility criteria. Their mean age was 42.9 ± 15.1 years (range, 22 to 65), and 20 (38.2%) were men. We found a statistically significant difference in vascular perfusion and density when comparing all groups at baseline. The controls had higher vascular perfusion and density values than the cases. Vascular perfusion and density were significantly reduced in all groups during the hypoglycemia episode, except for vascular density in DR cases. Conclusion. Acute hypoglycemia significantly alters the retinal vascularity in DM patients with and without DR, suggesting that repeated episodes of acute hypoglycemia could exacerbate retinopathy in the long term.

We assessed the available evidence regarding adverse effects on surrogate and patient-important health outcomes of third- and fourth-generation combined oral contraceptives among premenopausal women. We performed a systematic review and meta-analysis including randomized controlled trials and observational studies comparing third- and fourth-generation combined oral contraceptives with other generation contraceptives or placebo. Studies that enrolled women aged 15 to 50 years, with at least three cycles of intervention and 6 months of follow-up were included. A total of 33 studies comprising 629,783 women were included. Low-density lipoprotein cholesterol levels were significantly lower in fourth-generation oral contraceptives (mean differences (MD): −0.24 mmol/L; [95% CI −0.39 to −0.08]), while total cholesterol was significantly increased in levonorgestrel users when compared to third-generation oral contraceptives (MD: 0.27 mmol/L; [95% CI 0.04 to 0.50]). A decreased arterial thrombosis incidence was shown in fourth-generation oral contraceptive users, as compared to levonorgestrel (incidence rate ratio (IRR): 0.41; [95% CI 0.19 to 0.86]). No difference was found in the occurrence of deep venous thrombosis between fourth-generation oral contraceptives and levonorgestrel users (IRR: 0.91; [95% CI 0.66 to 1.27]; p = 0.60; I 2 = 0%). Regarding the remaining outcomes, data were heterogeneous and showed no clear difference. In premenopausal women, the use of third- and fourth-generation oral contraceptives is associated with an improved lipid profile and lower risk of arterial thrombosis. Data were inconclusive regarding the rest of outcomes assessed. This review was registered in PROSPERO with CRD42020211133.

Background. The short cosyntropin test is widely used for adrenal insufficiency screening and diagnosis. Lower cosyntropin doses may have greater sensitivity vs. the standard dose in detecting adrenal dysfunction. Obesity and overweight are increasing, impacting the clinical presentation of some diseases. Currently more than 50% of the subjects diagnosed with autoimmune adrenal insufficiency have a BMI greater than 25, and hence individuals living with overweight and obesity are more frequently requiring evaluation of the adrenal cortical function. Fixed-dose cosyntropin stimulation may not be appropriate for individuals with obesity. Objective. The primary objective was to compare cortisol response to a weight-adapted cosyntropin dose vs. a fixed low dose (1 µg) and a more physiologically fixed dose (10 µg). Methods. Twenty individuals with obesity and 20 age-matched healthy controls underwent in a randomized sequence at least one-week apart, to the The short cosyntropin test with three different doses, 0.2 µg/kg of body weight, 1 or 10 µg fixed dose stimuli. The assessment and data analysis were blinded to the individual and the investigator. Results. Cortisol response was reduced in the group with obesity with the 1 µg fixed dose stimuli at 30 minutes (median, IQR) 649.6 µg, 567.3–738.4 µg for the control group vs. 568.6 µg, 528.4–623.13 µg, p = 0.04 ; there was a lower cortisol peak at 60′ in all the three evaluated doses, with a dose-dependent trend. A weight-adapted cosyntropin dose of 0.2 µg in obesity produces a similar response to the one observed in individuals without obesity. The 1 µg ACTH test falls short on stimulating the cortisol adrenal response in individuals with obesity.

Evidence has raised concerns regarding the association between funding sources and doubtful data. Our main outcome was to analyze trends on funding sources in articles published from 1990 to 2020 in the more influential journals of internal and general medicine. In this meta-epidemiological study, we included peer-reviewed studies from the 10 highest impact journals in general and internal medicine published between January 1990 and February 2020 based on published original research according to the 2018 InCites Journal of Citation Reports, these consisted of the following: The New England Journal of Medicine, The Lancet, JAMA, BMJ, JAMA Internal Medicine, Annals of Internal Medicine, PLOS Medicine, Cachexia, BMC Medicine, and Mayo Clinic Proceedings. Two reviewers working in duplicate extracted data regarding year of publication, study design, and sources of funding. In total, 496 articles were found; of these, 311 (62.7%) were observational studies, 167 (33.7%) were experimental, and 16 (3.2%) were secondary analyses. Percentages of grant sources through the years were predominantly from government (60%), industry (23.83%), and non-governmental (16.06%) organizations. The percentage of industry subsidies tended to decrease, but this was not significant in a linear regression model (r=0.02, p≥0.05). Government and non-government funding sources showed a trend to decrease in the same univariate analysis with both significant associations (r=0.21, p ≤0.001 and r=0.10, p≤0.001, respectively). The main funding source in medical research has consistently been government aid. Despite previous reported data, no association was found between the source of funding and statistically significant results favoring study authors’ hypothesis.

Abstract The degree to which COVID-19 severity influences the development of acute cerebrovascular events (ACVE) is unknown. Therefore, we aimed to describe the prevalence and risk of ACVE in patients with severe and nonsevere COVID-19. We systematically reviewed MEDLINE, EMBASE, Web of Science, and Scopus and identified observational and interventional studies of patients with COVID-19 allocated by respiratory severity that reported ACVE development. Case reports/series were excluded. The main outcome assessed was the pooled rate of ACVE in patients with severe and nonsevere COVID-19. To determine the risk of ACVE development by COVID-19 severity, a meta-analysis was performed. PROSPERO registration number: CRD42020178905. About 19 of 5758 identified studies were analyzed. From 11,886 COVID-19 patients analyzed, 421 had at least one ACVE [3.6%, 95% confidence interval (CI) 2.904–4.179]. Severe COVID-19 increased the risk of ACVE (odds ratio 1.96, 95% CI 1.22–3.15; P = 0.005; I 2 = 64%), specifically hemorrhagic stroke (4.12, 2.0–8.53; P = 0.001; I 2 = 0%). There was no difference in the risk of developing ischemic stroke between patients with severe and nonsevere COVID-19 (1.53, 0.87–2.7; P = 0.14; I 2 = 52%). From the patients who developed any ACVE, those with severe COVID-19 had a greater mortality risk than those with nonsevere COVID-19 (3.85, 1.08–13.70; P = 0.04; I 2 = 0%). The main limitations of our study were the heterogeneity found in the main meta-analysis studies and in their reported definition for COVID-19 severity. In conclusion, our findings provide evidence that COVID-19 respiratory severity could lead to ACVE development that increases mortality. The effect of COVID-19 management in ACVE needs to be evaluated.

Purpose The association between subclinical hypothyroidism (SCH) and cardiovascular risk, particularly with a TSH <10 µIU/ml, remains controversial. The objective of our study was to assess the association between SCH and cardiovascular risk through carotid intima-media thickness, and alternatively, to evaluate its change after treatment with levothyroxine. Methods A total of 54 individuals were included in the study: 18 with SCH; 18 with overt hypothyroidism (OH); and 18 healthy controls (HC). The carotid intima-media thickness was measured in each group. In SCH, follow-up was performed at three and six months after the start of levothyroxine treatment. Results The mean age of the total population at baseline was 35.8 years. The median TSH in SCH was 6.15 µIU/ml. The carotid intima-media thickness (mean and standard deviation) was greater in SCH in comparison to the HC group: right common carotid artery (RCCA), 0.486 ± 0.106 mm and 0.413 ± 0.075 mm in SCH and HC, respectively, p=0.01 and left common carotid artery (LCCA), 0.511 ± 0.144 mm and 0.427 mm ± 0.090 in SCH and HC, respectively, p=0.03). In patients with SCH, there was a decrease in the carotid intima-media thickness after treatment with levothyroxine (RCCA and LCCA, p <0.05 at three and six months). Conclusions There was an association between increased carotid intima-media thickness in patients with SCH in comparison with HC, even with a TSH <10 µIU/ml. The increase was reversed with levothyroxine therapy. The association of this increased thickness with important cardiovascular outcomes remains uncertain and should be evaluated in future studies.