Fracture Risk Assessment Tool-Based Screening for Osteoporosis in Older Adults in Resource-Limited Settings.

PURPOSE: Osteoporosis is a pressing public health concern among older adults, contributing to substantial mortality and morbidity rates. Low- to middle-income countries (LMICs) often grapple with limited access to dual-energy X-ray absorptiometry (DXA), the gold standard for early osteoporosis detection. This study aims to assess the performance of the FRAX® score as a population-wide screening tool for predicting osteoporosis risk, rather than fracture, in individuals aged 50 and above within an LMIC context. METHODS: This retrospective cohort study (n=864) assessed the performance of the FRAX® score for predicting osteoporosis risk using comparative c-statistics from Receiver Operating Characteristic (ROC) curves. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated, with p-values <0.05 indicating statistically significant. RESULTS: The 10-year FRAX® probability for hip fracture, calculated without bone mass density (BMD), exhibited significantly superior performance compared to the 10-year FRAX® probability for major fracture in predicting osteoporosis risk (AUROC: 0.71 versus 0.67, p<0.001). Within 2 to 10 years of follow-up, the 10-year FRAX® probability for hip fracture showed both greater predictive performance and net benefit in the decision curve compared to the FRAX® 10-year probability for major fracture. A newly established cutoff of 1.9 % yielded a negative predictive value of 92.9 % (95 %CI: 90.4-94.8 %) for the 10-year FRAX® probability for hip fracture. CONCLUSION: The 10-year FRAX® probability for hip fracture estimated without BMD emerges as an effective 10-year screening tool for identifying osteoporosis risk in aged 50 and older, especially when confronted with limited access to DXA scans in LMICs. MINI ABSTRACT: The Fracture Risk Assessment Tool score performance as an osteoporosis screening tool was assessed in areas with limited dual-energy X-ray access. The hip fracture probability showed better performance than major fracture probability within 2 to 10 years. The tool emerges as effective for screening osteoporosis risk in individuals over 50.

Comparative effectiveness and cost-effectiveness of cardioprotective glucose-lowering therapies for type 2 diabetes in Brazil: a Bayesian network model.

BACKGROUND: The escalating prevalence of type 2 diabetes (T2DM) poses an unparalleled economic catastrophe to developing countries. Cardiovascular diseases remain the primary source of costs among individuals with T2DM, incurring expenses for medications, hospitalizations, and surgical interventions. Compelling evidence suggests that the risk of cardiovascular outcomes can be reduced by three classes of glucose-lowering therapies (GLT), including SGLT2i, GLP-1A, and pioglitazone. However, an evidence-based and cost-effective protocol is still unavailable for many countries. The objective of the current study is to compare the effectiveness and cost-effectiveness of GLT in individuals with T2DM in Brazil. METHODS: We employed Bayesian Networks to calculate the incremental cost-effectiveness ratios (ICER), expressed in international dollars (Int$) per disease-adjusted life years [DALYs] averted. To determine the effectiveness of GLT, we conducted a systematic review with network meta-analysis (NMA) to provide insights for our model. Additionally, we obtained cardiovascular outcome incidence data from two real-world cohorts comprising 851 and 1337 patients in primary and secondary prevention, respectively. Our cost analysis took into account the perspective of the Brazilian public health system, and all values were converted to Int$. RESULTS: In the NMA, SGLT2i [HR: 0.81 (95% CI 0.69-0.96)], GLP-1A [HR: 0.79 (95% CI 0.67-0.94)], and pioglitazone [HR: 0.73 (95% CI 0.59-0.91)] demonstrated reduced relative risks of non-fatal cardiovascular events. In the context of primary prevention, pioglitazone yielded 0.2339 DALYs averted, with an ICER of Int$7,082 (95% CI 4,521-10,770) per DALY averted when compared to standard care. SGLT2i and GLP-1A also increased effectiveness, resulting in 0.261 and 0.259 DALYs averted, respectively, but with higher ICERs of Int$12,061 (95% CI: 7,227-18,121) and Int$29,119 (95% CI: 23,811-35,367) per DALY averted. In the secondary prevention scenario, all three classes of treatments were deemed cost-effective at a maximum willingness-to-pay threshold of Int$26,700. Notably, pioglitazone consistently exhibited the highest probability of being cost-effective in both scenarios. CONCLUSIONS: In Brazil, pioglitazone presented a higher probability of being cost-effective both in primary and secondary prevention, followed by SGLT2i and GLP-1A. Our findings support the use of cost-effectiveness models to build optimized and hierarchical therapeutic strategy in the management of T2DM. TRIAL REGISTRATION: CRD42020194415.

Subclinical Hypothyroidism is Not Associated with Femoral Osteoporosis in Individuals Aged 50 Years or Older.

BACKGROUND: Thyroid dysfunction and osteoporosis are conditions strongly associated with aging, and the prevalence of both conditions is expected to increase in the coming decades. Thyroid hormones regulate bone metabolism, and the role of subclinical hypothyroidism on bone mineral density (BMD) is still controversial. Hence, this study aims to assess the association of subclinical hypothyroidism with femoral osteopenia and osteoporosis in individuals aged 50 years or older. METHODOLOGY: This retrospective cohort study was carried out with 864 outpatients having at least one result for TSH levels before the first record of dual-energy X-ray absorptiometry (DXA). The primary endpoints were osteopenia (-2.5 standard deviation (SD)

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known. OBJECTIVES: To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i. METHODS: Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane. RESULTS: A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [-1.7 (5.9) vs. -1.1 (5.3); p < 0.001). CONCLUSIONS: In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

Risk factors of transplant renal artery stenosis in kidney transplant recipients.

BACKGROUND: Transplant Renal Artery Stenosis (TRAS) is a recognized vascular complication after kidney transplantation. The overall risk predictors of TRAS are poorly understood. METHODS: Retrospective analysis of patients with suspected TRAS (Doppler ultrasound PSV > 200 cm/s) who underwent angiographic study in a single center between 2007 and 2014. All patients with stenosis > 50% were considered with TRAS. Stenosis restricted in the body of the artery was also analyzed in a subgroup. RESULTS: 274 patients were submitted to a renal angiography and 166 confirmed TRAS. TRAS group featured an older population (46.3 ± 11.0 vs. 40.9 ±14.2 years; p = 0.001), more frequent hypertensive nephropathy (30.1% vs. 15.7%; p = 0.01), higher incidence of Delayed Graft Function (DGF) (52.0% vs. 25.6%; p < 0.001) and longer Cold Ischemia Time (CIT) (21.5 ± 10.6 vs. 15.7 ± 12.9h; p < 0.001). In multivariable analyses, DGF (OR = 3.31; 95% CI 1.78‒6.30; p < 0.0001) was independent risk factors for TRAS. DM and CIT showed a tendency towards TRAS. The compound discriminatory capacity of the multivariable model (AUC = 0.775; 95% CI 0.718‒0.831) is significantly higher than systolic blood pressure and creatinine alone (AUC = 0.62; 95% CI 0.558-0.661). In body artery stenosis subgroup, DGF (OR = 1.86; 95% CI 1.04‒3.36; p = 0.03) and Diabetes Mellitus (DM) (OR = 2.44; 95% CI 1.31‒4.60; p = 0.005) were independent risk factors for TRAS. CONCLUSION: In our transplant population, DGF increased more than 3-fold the risk of TRAS. In the subgroup analysis, both DGF and DM increases the risk of body artery stenosis. The addition of other factors to hypertension and renal dysfunction may increase diagnostic accuracy. TRAS TRIAL REGISTRED: clinicaltrials.gov (n° NCT04225338).

Dapagliflozin increases the lean-to total mass ratio in type 2 diabetes mellitus.

We compared the effect of dapagliflozin versus glibenclamide on the ratio of lean-to total mass in patients with type 2 diabetes mellitus, carotid subclinical atherosclerosis, HbA1c 7.0-9.0% and 40-70 years-old. Ninety-eight patients (61% male; mean age 57 ± 7 years) were randomized into dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin. Body composition was measured by Dual Energy X-Ray at randomization and after 12 weeks of treatment. Glycemic control was equivalent in both groups. Dapagliflozin decreased total body mass (-2741 g [95% CI: -3360 to 1945]; p < 0.001) and lean mass (-347 g [95% CI: -761 to -106]; p < 0.001), while glibenclamide increased total body mass (1060 g [95% CI: 140 to 1836]; p < 0.001) and lean mass (929 g [95% CI: 575 to 1283]; p < 0.001) for the differences between arms. The lean-to-total mass ratio increased by 1.2% in the dapagliflozin group and 0,018% in the glibenclamide group (p < 0.001). Dapagliflozin reduced the risk of a negative balance in the lean-to total mass ratio [OR: 0.16 (95% CI: 0.05 to 0.45); p < 0.001] even after adjustment for baseline lean-to total mass ratio, waist circumference, HOMAIR, HbA1c, mean of the two hands handgrip strength and gait speed [OR: 0.13 (95% CI: 0.03-0.57); p < 0.007]. In conclusion, under equivalent glycemic control, dapagliflozin reduced total body mass but increased the ratio of lean-to-total mass when compared with glibenclamide.

Intra-operative esmolol and pain following mastectomy: A randomised clinical trial.

BACKGROUND: Esmolol is a beta-1 selective blocker that has been shown to reduce postoperative pain. Its antinociceptive effects have not been tested following mastectomy. OBJECTIVE: To evaluate the safety, efficacy and antinociception of intra-operative esmolol infusion after mastectomy. DESIGN: Randomised, double-blinded, placebo-controlled trial. SETTING: Tertiary referral centre, Brasília, Brazil. Recruitment: July 2015 to July 2017. PATIENTS: Seventy women scheduled for mastectomy, ASA I to III, aged 18 to 75 years. Four were excluded. INTERVENTIONS: All underwent general anaesthesia. The intervention group received a bolus of 0.5 mg kg-1 of esmolol over 10 min followed by a continuous infusion of 100 µg kg-1 min-1. The placebo group received saline. MAIN OUTCOME MEASURES: The primary outcome was pain at rest 24 h after mastectomy as measured by a 0 to 10 numeric rating scale. RESULTS: Pain scores at rest 24 h after mastectomy were lower in esmolol-treated patients compared with placebo (mean difference = -1.51, 95% confidence interval (CI), -2.36 to -0.65, P = 0.001). On arrival in the postanaesthesia care unit (PACU), the occurrence of pain was also lower in the esmolol group, at rest and on effort (P = 0.009 and P = 0.013, respectively), on discharge from PACU (P = 0.009 and P = 0.015), 12 h (P = 0.01 and P = 0.007) and on effort in the 24 postoperative hours (P = 0.003). Mean morphine consumption was reduced by 77% in the esmolol group compared with the placebo group (mean difference  = -2.52 mg, 95% CI = -3.67 to -1.38, P < 0.001). The length of hospital stay was shorter for the esmolol group (mean difference = -6.9 h, 95% CI, -13.4 to -0.31, P = 0.040). CONCLUSION: Esmolol was well tolerated, allowed a notable reduction in the dose of rescue analgesics and demonstrated superior efficacy compared to placebo for pain management after mastectomy. TRIAL REGISTRATION: ClinicalTrials/NCT02466542.

Excess weight mediates changes in HDL pool that reduce cholesterol efflux capacity and increase antioxidant activity.

BACKGROUND AND AIM: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. We investigated if potentially other HDL protective actions may be affected with weight gain and these changes may occur even before the obesity range in a cross-sectional analysis. METHODS AND RESULTS: Lipid profile, body mass index (BMI), biochemical measurements, and carotid intima-media thickness (cIMT) were obtained in this cross-sectional study with 899 asymptomatic individuals. Lipoproteins were separated by ultracentrifugation and HDL physical-chemical characterization, CEC, antioxidant activity, anti-inflammatory activity, HDL-mediated platelet aggregation inhibition were measured in a randomly-selected subgroup (n = 101). Individuals with increased HDL-C had an attenuated increase in cIMT with elevation of BMI (interaction effect ß = -0.054; CI 95% -0.0815, -0.0301). CEC, HDL-C, HDL size and HDL-antioxidant activity were negatively associated with cIMT. BMI was inversely correlated with HDL-mediated inhibition of platelet aggregation (Spearman's rho -0.157, p < 0.03) and CEC (Spearman's rho -0.32, p < 0.001), but surprisingly it was directly correlated with the antioxidant activity (Spearman's rho 0.194, p = 0.052). Thus, even in non-obese, non-diabetic individuals, increased BMI is associated with a wide change in protective functions of HDL, reducing CEC and increasing antioxidant activity. In these subjects, decreased HDL concentration, size or function are related to increased atherosclerotic burden. CONCLUSION: Our findings demonstrate that in non-obese, non-diabetic individuals, the increasing values of BMI are associated with impaired protective functions of HDL and concomitant increase in atherosclerotic burden.

Correction to: GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data.

Following publication of the original article [1], based on the authors review, the GLP1 receptor agonists in type 2 diabetes published in Cardiovascular Diabetology, a meta-analysis of GLP-1 and non-GLP-1 based therapies was performed on cardiovascular outcomes.

GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data.

Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina and heart failure (major adverse cardiovascular events). In recent years, introduction of the new drug class of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has changed the treatment landscape as GLP-1RAs have become well-established therapies in T2DM. The benefits of GLP-1RAs are derived from their pleiotropic effects, which include appetite control, glucose-dependent secretion of insulin and inhibition of glucagon secretion. Importantly, their beneficial effects extend to the cardiovascular system. Large clinical trials have evaluated the cardiovascular effects of GLP-1RAs in patients with T2DM and elevated risk of cardiovascular disease and the results are very promising. However, important aspects still require elucidation, such as the specific mechanisms involved in the cardioprotective effects of these drugs. Careful interpretation is necessary because of the heterogeneity across the trials concerning the definition of cardiovascular risk or cardiovascular disease, baseline characteristics, routine care and event rates. The aim of this review is to describe the main clinical aspects of the GLP-1RAs, compare them using data from both the mechanistic and randomized controlled trials and discuss potential reasons for improved cardiovascular outcomes observed in these trials. This review may help clinicians to decide which treatment is most appropriate in reducing cardiovascular risk in patients with T2DM.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years.

OBJECTIVE: Like mutations with loss of function in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, inhibitors of PCSK9 (PCSK9i) may potentially favor the manifestation of diabetes. RESEARCH DESIGN AND METHODS: A meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i versus placebo in the primary hypercholesterolemia setting. Statins and ezetimibe were used in 98.4% of these studies and balanced between PCSK9i and placebo. We calculated relative risks (RRs) and 95% CIs using random- and fixed-effect models. RESULTS: We included 68,123 participants (20 RCTs) with median follow-up of 78 weeks. PCSK9i increased fasting blood glucose (weighted mean difference 1.88 mg/dL [95% CI 0.91-2.68]; I2 = 0%; P < 0.001) and HbA1c (0.032% [0.011-0.050]; I2 = 15.5%; P < 0.001) when compared with placebo. This effect was not sufficient to increase incidence of diabetes (RR 1.04 [0.96-1.13]; I2 = 0%; P = 0.427). Exploratory meta-regression analyses indicated an association between the increased risk of diabetes and the potency (P = 0.029) and duration (P = 0.026) of PCSK9i treatment. CONCLUSIONS: In the short term, PCSK9i therapy favors a small but significant increase in plasma glycemia and HbA1c.