Efficacy and Safety of Calcifediol in Young Adults with Vitamin D Deficiency: A Phase I, Multicentre, Clinical Trial-POSCAL Study.

Vitamin D deficiency is highly prevalent, and recent evidence suggests a possible association between vitamin D deficiency and various health conditions. The aim of this study was to assess monthly calcifediol treatments for vitamin D deficiency (or biweekly, if the deficiency was severe) in a young adult population with no associated comorbidities. This multicentre phase I trial started with a four month open-label treatment phase (TP) that included 101 participants (65% women with mean age 29.8 years). Eighty-two percent of the subjects (79/96) achieved 25(OH)D levels within the target range (20-60 ng/mL) by the end of the TP, and they were subsequently randomised and subjected to a double-blind, placebo-controlled, five month follow-up phase (FP). At the end of the FP, 89% of participants maintained vitamin D levels of >20 ng/mL with calcifediol, versus 49% with placebo (p < 0.001). Subjects receiving monthly calcifediol during both phases (n = 32) maintained 25(OH)D levels >20 ng/mL, whereas those on the placebo during the FP (n = 38) exhibited deficiency levels of 25(OH)D by the end of the study. No clinically relevant changes in bone metabolism parameters or toxic 25(OH)D levels were observed, and no serious adverse events were reported throughout the study. Calcifediol is a safe and effective treatment for vitamin D deficiency in the young adult population, but long-term use may be required to sustain optimal 25(OH)D levels.

Impacto de las fracturas por fragilidad en mujeres españolas con osteoporosis posmenopáusica / Impact of fragility fractures in postmenopausal Spanish women with osteoporosis

Objetivo: dada la repercusión que tienen las fracturas por fragilidad y sus secuelas en la vida de las mujeres con osteoporosis posmenopáusica (OPM), el objetivo de este estudio es describir y analizar su impacto en esta población. Material y métodos: se realizó una encuesta a mujeres posmenopáusicas con fractura por fragilidad en un diseño observacional transversal. Se recogieron variables sociodemográficas, impacto de la fractura (necesidad de cuidados, productividad laboral), calidad de vida relacionada con la salud (CVRS, mediante cuestionario QUALEFFO-31) y disposición a pagar (DAP) por recuperarla. Resultados: participaron 120 mujeres, promedio de edad 62 ± 7 años. Las fracturas más frecuentes fueron las de radio distal (29,9 %) y las vertebrales (21,3 %). Un 53,3 % necesitó cuidados durante su recuperación (76,5 % informales; 24,9 % formales) y un 4,2 % tuvo que ingresar en un centro/residencia sociosanitaria. De aquellas que trabajaban cuando se produjo la fractura (62,5 %), el 56 % vio su vida laboral afectada (69,3 % incapacidad temporal; 17,3 % incapacidad permanente; 10,7 % reducción de jornada; 10,7 % abandono laboral; 5,3 % permiso/excedencia; 3,6 % prejubilación). El impacto de la fractura se debió principalmente al dolor (71,7 %), dificultad para realizar actividades cotidianas (48,3 %), problemas de movilidad (46,7 %) y estado emocional (41,7 %). La mayor DAP se ofreció por recuperar la capacidad para realizar actividades cotidianas y el estado emocional. La puntuación total QUALEFFO-31 (0-100) fue 49,9 ± 10,8 (función mental: 68,3 ± 7,3; dolor: 56 ± 22,6; función física: 39,3 ± 15,5). Conclusiones: las fracturas por fragilidad tienen un alto impacto en la calidad de vida de las mujeres con OPM. Resulta fundamental poner en valor aquellos aspectos que más les preocupan para optimizar su abordaje. (AU)

Objective: Given the impact of fragility fractures and their consequences on the lives of women with postmenopausal osteoporosis (PMO), the objective of this study is to describe and analyze the impact of this kind of fractures on this population. Materials and methods: A survey was conducted among postmenopausal women with fragility fractures in a cross-sectional observational design. Sociodemographic variables, fracture impact (need for care, work productivity), and data on health-related quality of life (HRQoL, assessed using the QUALEFFO-31 questionnaire), and willingness to pay (WTP) to regain HRQoL were collected. Results: A total of 120 women participated, with a mean age of 62 ± 7 years. The most frequent fractures described were distal radius fractures (29.9 %), followed by vertebral fractures (21.3 %). A total of 53.3 % required care during their recovery (76.5 %, informal; 24.9 %, formal), and 4.2 % had to be admitted to a health care or nursing home. Among those who were working when the fracture occurred (62.5 %), 56 % had their working life affected (69.3 %, temporary disability; 17.3 %, permanent disability; 10.7 %, reduced working hours; 10.7 %, quit their jobs; 5.3 %, leave of absence; and 3.6 %, early retirement). The impact of the fracture was primarily due to pain (71.7 %), difficulty performing activities of daily living (48.3 %), mobility problems (46.7 %), and emotional state (41.7 %). The highest WTP was offered to regain the ability to perform activities of daily living and improve the emotional state. The overall QUALEFFO-31 score (0-100) was 49.9 ± 10.8 (mental function, 68.3 ± 7.3; pain, 56 ± 22.6; physical function, 39.3 ± 15.5). Conclusions: Fragility fractures play a significant role on the quality of life of women with PMO. It is of paramount importance to value the aspects that concern them the most to optimize their management. (AU)

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin.

BACKGROUND: Insulin icodec is an investigational once-weekly basal insulin analogue for diabetes management. METHODS: We conducted a 78-week randomized, open-label, treat-to-target phase 3a trial (including a 52-week main phase and a 26-week extension phase, plus a 5-week follow-up period) involving adults with type 2 diabetes (glycated hemoglobin level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive once-weekly insulin icodec or once-daily insulin glargine U100. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; the confirmatory secondary end point was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52. Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded. RESULTS: Each group included 492 participants. Baseline characteristics were similar in the two groups. The mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec [mean change, -1.55 percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, -1.35 percentage points]); the estimated between-group difference (-0.19 percentage points; 95% confidence interval [CI], -0.36 to -0.03) confirmed the noninferiority (P<0.001) and superiority (P = 0.02) of icodec. The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% vs. 66.9%; estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62]; P<0.001), which confirmed superiority. Rates of combined clinically significant or severe hypoglycemia were 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63; 95% CI, 1.02 to 2.61). No new safety signals were identified, and incidences of adverse events were similar in the two groups. CONCLUSIONS: Glycemic control was significantly better with once-weekly insulin icodec than with once-daily insulin glargine U100. (Funded by Novo Nordisk; ONWARDS 1 ClinicalTrials.gov number, NCT04460885.).

Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency.

BACKGROUND: In addition to the role of vitamin D in bone mineralization, calcium and phosphate homeostasis, and skeletal health, evidence suggests an association between vitamin D deficiency and a wide range of chronic conditions. This is of clinical concern given the substantial global prevalence of vitamin D deficiency. Vitamin D deficiency has traditionally been treated with vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol). Calcifediol (25-hydroxyvitamin D3) has recently become available more widely. METHODS: By means of targeted literature searches of PubMed, this narrative review overviews the physiological functions and metabolic pathways of vitamin D, examines the differences between calcifediol and vitamin D3, and highlights clinical trials conducted with calcifediol in patients with bone disease or other conditions. RESULTS: For supplemental use in the healthy population, calcifediol can be used at doses of up to 10 µg per day for children ≥ 11 years and adults and up to 5 µg/day in children 3-10 years. For therapeutic use of calcifediol under medical supervision, the dose, frequency and duration of treatment is determined according to serum 25(OH)D concentrations, condition, type of patient and comorbidities. Calcifediol differs pharmacokinetically from vitamin D3 in several ways. It is independent of hepatic 25-hydroxylation and thus is one step closer in the metabolic pathway to active vitamin D. At comparable doses to vitamin D3, calcifediol achieves target serum 25(OH)D concentrations more rapidly and in contrast to vitamin D3, it has a predictable and linear dose-response curve irrespective of baseline serum 25(OH)D concentrations. The intestinal absorption of calcifediol is relatively preserved in patients with fat malabsorption and it is more hydrophilic than vitamin D3 and thus is less prone to sequestration in adipose tissue. CONCLUSION: Calcifediol is suitable for use in all patients with vitamin D deficiency and may be preferable to vitamin D3 for patients with obesity, liver disease, malabsorption and those who require a rapid increase in 25(OH)D concentrations.

Long-Term Treatment and Effect of Discontinuation of Calcifediol in Postmenopausal Women with Vitamin D Deficiency: A Randomized Trial.

Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short-term clinical trials, its effects after long-term monthly administration have been studied less extensively. This report describes the results of a 1-year, phase III-IV, double-blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention-to-treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment-related safety issues were reported in any of the groups. The results confirm that long-term treatment with monthly calcifediol in vitamin D-deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long-term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5.

OBJECTIVE: This study evaluated the effect of once-weekly semaglutide 2.4 mg on 2-year control of eating. METHODS: In STEP 5, adults with overweight/obesity were randomized 1:1 to semaglutide 2.4 mg or placebo, plus lifestyle modification, for 104 weeks. A 19-item Control of Eating Questionnaire was administered at weeks 0, 20, 52, and 104 in a subgroup of participants. P values were not controlled for multiplicity. RESULTS: In participants completing the Control of Eating Questionnaire (semaglutide, n = 88; placebo, n = 86), mean body weight changes were -14.8% (semaglutide) and -2.4% (placebo). Scores significantly improved with semaglutide versus placebo for Craving Control and Craving for Savory domains at weeks 20, 52, and 104 (p < 0.01); for Positive Mood and Craving for Sweet domains at weeks 20 and 52 (p < 0.05); and for hunger and fullness at week 20 (p < 0.001). Improvements in craving domain scores were positively correlated with reductions in body weight from baseline to week 104 with semaglutide. At 104 weeks, scores for desire to eat salty and spicy food, cravings for dairy and starchy foods, difficulty in resisting cravings, and control of eating were significantly reduced with semaglutide versus placebo (all p < 0.05). CONCLUSIONS: In adults with overweight/obesity, semaglutide 2.4 mg improved short- and longer-term control of eating associated with substantial weight loss.

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial.

The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m-2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was -15.2% in the semaglutide group (n = 152) versus -2.6% with placebo (n = 152), for an estimated treatment difference of -12.6 %-points (95% confidence interval, -15.3 to -9.8; P < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430.

Benefits of SGLT2i for the Treatment of Heart Failure Irrespective of Diabetes Diagnosis: A State-of-the-Art Review.

Morbidity and mortality associated with heart failure (HF) has remained high despite advances in therapy. Furthermore, HF-associated risk in patients with type 2 diabetes mellitus (T2D) is even higher than in patients without T2D owing to the strong reciprocal relationship between conditions. However, until recently, no therapy to treat patients with diabetes also reduced cardiovascular risks related to HF. Recent clinical studies (DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved, SOLOIST-WHF trial) and meta-analysis have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) are among the first antidiabetic drugs capable of reducing cardiovascular risks related to HF and improving the prognosis of patients with and without diabetes. Their pleiotropic mechanisms of action place them at the intersection of hemodynamic, metabolic, and neurohumoral pathways, with clear advantages for treating these patients independent of its glucose-lowering effect. Moreover, the benefits of SGLT2i were consistent across the cardiorenal continuum in different populations and clinical settings, which has led to different guidelines introducing SGLT2i as a first-line treatment for HF.

Effective Overall Glycaemic Control with Fast-Acting Insulin Aspart Across Patients with Different Baseline Characteristics: A Post Hoc Analysis of the Onset 9 Trial.

AIMS: To investigate the efficacy and safety of fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) in participants with type 2 diabetes (T2D) across different subgroups. METHODS: We report on a post hoc analysis of onset 9, a 16-week trial of participants with T2D randomised to faster aspart (n = 546) or IAsp (n = 545). Participants were grouped by baseline HbA1c (< 7.0%, ≥ 7.0%), meal test bolus insulin dose (≤ 10 units [U], > 10 U to ≤ 20 U, > 20 U), body mass index (< 30 kg/m2, ≥ 30 to < 35 kg/m2, ≥ 35 kg/m2), and age (< 65 years, ≥ 65 years). Outcomes assessed were change from baseline in HbA1c and in 1-h postprandial glucose (PPG) increment, and severe or blood glucose (BG)-confirmed hypoglycaemia. RESULTS: Faster aspart provided reductions in HbA1c comparable to IAsp across all subgroups, with improved 1-h PPG control compared with IAsp in several subgroups. Faster aspart had comparable or improved rates of severe or BG-confirmed hypoglycaemia versus IAsp, particularly in participants with good glycaemic control (HbA1c < 7.0%), the elderly (≥ 65 years old), and those with insulin resistance (> 20 U meal test bolus insulin dose). CONCLUSIONS: Faster aspart provides effective overall glycaemic control, with improved early PPG control compared with IAsp across a range of patient characteristics. CLINICAL TRIAL REGISTRATION: NCT03268005.

Fast-acting insulin aspart (faster aspart) is a type of insulin used at mealtimes to reduce the spike in blood sugar resulting from that meal. Faster aspart works in the body more quickly and more effectively than insulin aspart (IAsp), the previous version of this insulin. The properties of insulins in the body can change according to certain patient characteristics. In this study, the researchers wanted to find out if there were differences between various subgroups of patients in the effectiveness and safety of faster aspart compared with IAsp in the treatment of type 2 diabetes. Data were used from a clinical trial (onset 9), in which 546 patients were treated with faster aspart and 545 were treated with IAsp. Patients were grouped by baseline glycated haemoglobin (HbA1c), meal test actual bolus insulin dose, body mass index, and age. Faster aspart provided reductions in HbA1c comparable to IAsp across all subgroups, with improved glucose control 1 hour after a meal compared with IAsp, in several subgroups. Faster aspart had comparable or improved rates of hypoglycaemia versus IAsp, particularly in participants with good glucose control, the elderly (≥ 65 years old), and those with insulin resistance. In summary, the researchers found that faster aspart provides effective overall glucose control, with improved early mealtime glucose control compared with IAsp across patients with a range of baseline characteristics.

Glycaemic variability in patients with type 2 diabetes mellitus treated with dulaglutide, with and without concomitant insulin: Post hoc analyses of randomized clinical trials.

AIM: To investigate the association between treatment with dulaglutide and glycaemic variability (GV) in adult patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Post hoc analyses of six randomized, phase 3 studies were conducted to investigate the association between treatment with dulaglutide 1.5 mg once weekly and GV in adult patients with T2D. Using data from seven- and eight-point self-monitored plasma glucose (SMPG) profiles over up to 28 weeks of treatment, GV in within- and between-day SMPG, and between-day fasting glucose from SMPG (FSMPG) was assessed according to standard deviation and coefficient of variation. RESULTS: Pooled data from five studies with dulaglutide as monotherapy or added to oral glucose-lowering medication, without concomitant insulin treatment, revealed clinically meaningful reductions in within- and between-day SMPG, and between-day FSMPG variability from baseline in the dulaglutide group. Comparisons between treatment groups in two studies demonstrated that reductions from baseline in within-day and between-day SMPG, and between-day FSMPG variability were greater for treatment with dulaglutide compared with insulin glargine, as well as for treatment with dulaglutide when added to insulin glargine compared with insulin glargine alone. CONCLUSIONS: In patients with T2D, treatment with dulaglutide as monotherapy or added to oral glucose-lowering medication, without concomitant insulin treatment, was potentially associated with a reduction in GV. Treatment with dulaglutide was associated with a reduction in GV to a greater degree than insulin glargine. When added to insulin glargine, treatment with dulaglutide was associated with greater decreases in GV compared with insulin glargine alone. As reduced GV may be associated with better outcomes, these findings may have clinical relevance.

Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial.

BACKGROUND: Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. METHODS: In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. FINDINGS: Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. INTERPRETATION: In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. FUNDING: Eli Lilly and Company.

Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial.

Vitamin D has shown to play a role in multiple diseases due to its skeletal and extraskeletal actions. Furthermore, vitamin D deficiency has become a worldwide health issue. Few supplementation guidelines mention calcifediol treatment, despite being the direct precursor of calcitriol and the biomarker of vitamin D status. This 1-year, phase III-IV, double-blind, randomized, controlled, multicenter clinical trial assessed the efficacy and safety of calcifediol 0.266 mg soft capsules in vitamin D-deficient postmenopausal women, compared to cholecalciferol. Results reported here are from a prespecified interim analysis, for the evaluation of the study's primary endpoint: the percentage of patients with serum 25-hydroxyvitamin D (25(OH)D) levels above 30 ng/ml after 4 months. A total of 303 patients were enrolled, of whom 298 were included in the intention-to-treat (ITT) population. Patients with baseline levels of serum 25(OH)D <20 ng/ml were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months, calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months, and cholecalciferol 25,000 IU/month for 12 months. At month 4, 35.0% of postmenopausal women treated with calcifediol and 8.2% of those treated with cholecalciferol reached serum 25(OH)D levels above 30 ng/ml (p < 0.0001). The most remarkable difference between both drugs in terms of mean change in serum 25(OH)D levels was observed after the first month of treatment (mean ± standard deviation change = 9.7 ± 6.7 and 5.1 ± 3.5 ng/ml in patients treated with calcifediol and cholecalciferol, respectively). No relevant treatment-related safety issues were reported in any of the groups studied. These results thus confirm that calcifediol is effective, faster, and more potent than cholecalciferol in raising serum 25(OH)D levels and is a valuable option for the treatment of vitamin D deficiency. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Coexistence of dyschondrosteosis associated to SHOX deficiency, pseudohypoparathyroidism 1B, and chronic autoimmune thyroiditis: a case report.

We present an unusual case of SHOX deficiency associated with Léri-Weill dyschondrosteosis (LWD), Hashimoto's thyroiditis and pseudohypoparathyroidism 1B in a young woman. To our knowledge, this is the first ever report of these disorders coexisting. At the age of nine years, the proband was diagnosed of hypothyroidism due to Hashimoto's thyroiditis, and developed biochemical abnormalities consistent with hyperphosphatemia, mild hypocalcemia and elevated parathyroid hormone without any clinical symptoms except short stature. Replacement therapy with levothyroxine, calcium and alphacalcidol was initiated. The diagnosis of pseudohypoparathyroidism 1B was confirmed at the age of 17.5 years with the demonstration of methylation alteration at the GNAS locus. At the age of 16 years, 3.5 years after her menarche, she presented clear features of LWD. A large deletion of the SHOX gene was confirmed. Family genetic tests were not doable since she was adopted. We discuss the diagnostic challenges of these coexisting rare endocrinopathies.

The Benefit of Insulin Degludec/Liraglutide (IDegLira) Compared With Basal-Bolus Insulin Therapy is Consistent Across Participant Subgroups With Type 2 Diabetes in the DUAL VII Randomized Trial.

BACKGROUND: Insulin degludec/liraglutide (IDegLira) results in glycated hemoglobin (HbA1c) levels comparable with basal-bolus (BB) therapy. Here, we assessed the effect of once-daily IDegLira compared with BB (once-daily insulin glargine 100 U/mL and insulin aspart ≤4 times/day) across subgroups with varying characteristics. MATERIALS AND METHODS: DUAL VII trial participants (type 2 diabetes [T2D], HbA1c 53-86 mmol/mol [7.0%-10.0%]) were subgrouped post hoc based on the following baseline characteristics: HbA1c (≤58.5, >58.5 to ≤69.4, and >69.4 mmol/mol; ≤7.5%, >7.5 to ≤8.5%, and >8.5%), body mass index (<30, ≥30 to <35, and ≥35 kg/m2), age (18 to <65 and ≥65 years), duration of diabetes (≥0 to 10 and ≥10 years), total pretrial daily basal insulin dose (20 to <30, ≥30 to <40, and ≥40 to ≤50 U), and fasting plasma glucose (<7.2 mmol/L/<130 mg/dL and ≥7.2 mmol/L/≥130 mg/dL). RESULTS: Compared with BB, and in all subgroups, IDegLira treatment consistently gave similar HbA1c reductions, less severe or blood glucose-confirmed hypoglycemia, lower end-of-trial (EOT) total daily insulin dose, and weight loss. In all subgroups, mean EOT HbA1c was ≤53 mmol/mol (≤7.0%). The greatest HbA1c reduction occurred in the highest baseline HbA1c subgroup. Overall, mean EOT daily insulin dose was 0.43 to 0.52 U/kg with IDegLira and 0.74 to 1.07 U/kg with BB. More participants achieved the triple composite endpoint (HbA1c <53 mmol/mol [<7.0%] without weight gain or hypoglycemia) with IDegLira vs BB across the baseline HbA1c subgroups (≤58.5 mmol/mol [44.6% vs 7.0%], >58.5 to ≤69.4 mmol/mol [41.1% vs 8.3%], and >69.4 mmol/mol [23.8% vs 3.4%]). CONCLUSION: These results support initiating IDegLira in patients with varying baseline characteristics and uncontrolled T2D on basal insulin. CLINICALTRIALS.GOV REGISTRATION: NCT02420262.

The impact of repeat fine-needle aspiration in thyroid nodules categorized as atypia of undetermined significance or follicular lesion of undetermined significance: A single center experience.

BACKGROUND: Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) is the most controversial category of the Bethesda System. The present study was conducted to compare the histological findings in a series of thyroid nodules diagnosed with AUS/FLUS after single or repeat fine needle aspiration (FNA) cytology. METHODS: Retrospective analysis of our institution's series of 514 patients with an initial diagnosis of AUS/FLUS between 11/2011 and 02/2020. RESULTS: Of 4887 FNA samples, 11.8% were classified as AUS/FLUS. Of patients with an initial AUS/FLUS diagnosis, 11.5% (59/514) underwent surgery after a single FNA, 55.4% (285/514) had a repeat FNA, and 32.7% (168/514) were either observed or lost to follow-up. Surgical pathology was available in 123 cases (23.9%), and malignancy was confirmed in 32.5% (40/123) cases, with similar rates in the single 32.2% (19/59) and repeat FNA 32.8% (21/64) groups. Repeat FNA reclassified 78.9% of the AUS/FLUS cases to a different category: 57.2% were reclassified as benign, 10.5% as follicular neoplasm, and 5.6% as suspicious for malignancy or malignant. The rates of nonneoplastic benign lesions were 52.5% (31/59) and 31.2% (20/64) in the single and repeat FNA groups, respectively (P = .018). The rates of follicular adenomas were higher when repeat FNA was performed (23/64, 35.9%) compared with a single FNA (9/59; 15.2%) (P = .013). CONCLUSION: In this series, a repeat FNA in cases of AUS/FLUS increased detection of follicular adenomas but not the detection of malignancy. Repeat FNA reduced the rate of benign nonneoplastic lesions by 40% in the surgical samples.

Incidence and costs of cardiovascular events in Spanish patients with type 2 diabetes mellitus: a comparison with general population, 2015.

INTRODUCTION: Cardiovascular (CV) disease affects a high percentage of patients with type 2 diabetes mellitus (T2DM), especially in the hospital setting, impacting on mortality, complications, quality of life and use of health resources. The aim of this study was to estimate the incidence, mean length of hospital stay (LOHS) and costs attributable to hospital admissions due to CV events in patients with T2DM versus patients without diabetes mellitus (non-DM) in Spain. RESEARCH DESIGN AND METHODS: Retrospective observational study based on the Spanish National Hospital Discharge Database for 2015. Hospital admissions for patients aged ≥35 years with a diagnosis of CV death, non-fatal acute myocardial infarction (AMI), non-fatal stroke, unstable angina, heart failure and revascularization were evaluated. The International Classification of Diseases, Ninth Revision (250.x0 or 250.x2) coding was used to classify records of patients with T2DM. For each CV complication, the hospital discharges of the two groups, T2DM and non-DM, were precisely matched and the number of hospital discharges, patients, LOHS and mean cost were quantified. Additional analyses assessed the robustness of the results. RESULTS: Of the 276 925 hospital discharges analyzed, 34.71% corresponded to patients with T2DM. A higher incidence was observed in all the CV complications studied in the T2DM population, with a relative risk exceeding 2 in all cases. The mean LOHS (days) was longer in the T2DM versus the non-DM group for: non-fatal AMI (7.63 vs 7.02, p<0.001), unstable angina (5.11 vs 4.78, p=0.009) and revascularization (7.96 vs 7.57, p<0.001). The mean cost per hospital discharge was higher in the T2DM versus the non-DM group for non-fatal AMI (€6891 vs €6876, p=0.029) and unstable angina (€3386 vs €3304, p<0.001). CONCLUSIONS: Patients with T2DM had a higher incidence and number of hospital admissions per patient due to CV events versus the non-DM population. This generates a significant clinical and economic burden given the longer admission stay and higher costs associated with some of these complications.

Semaglutide improves health-related quality of life versus placebo when added to standard of care in patients with type 2 diabetes at high cardiovascular risk (SUSTAIN 6).

AIM: To assess what drives change in health-related quality of life (HRQoL) in type 2 diabetes in the SUSTAIN 6 trial and identify potential mediators of the treatment effect of semaglutide on HRQoL scores. MATERIALS AND METHODS: The Short Form (SF)-36v2® questionnaire [comprising physical component summary (PCS) and mental component summary (MCS)] was used to assess changes in HRQoL from baseline to week 104, by treatment, in a prespecified analysis. This post-hoc analysis assessed change in PCS and MCS using the following factors as parameter/covariate, using descriptive statistics and linear regressions: major adverse cardiac events, hypoglycaemia, gastrointestinal adverse events, at least one episode of nausea, vomiting or diarrhoea, and change in glycated haemoglobin (HbA1c), body weight, blood pressure, heart rate and estimated glomerular filtration rate. RESULTS: Mean change in overall PCS score was +1.0 with semaglutide versus +0.4 with placebo, and +0.5 versus -0.2 for MCS. The treatment effect of semaglutide versus placebo (unadjusted estimate) was 0.7 [(95% confidence interval 0.1, 1.2); P = 0.018] on PCS and this was reduced when adjusted for change in HbA1c [0.4 (-0.2, 1.0), P = .167] and body weight [0.3 (-0.3, 0.9), P = .314]. The unadjusted treatment effect on MCS [0.7 (-0.0, 1.5), P = .054] was only reduced when adjusted for change in HbA1c [0.3 (-0.4, 1.1), P = .397]. When adjusting for all other parameters separately, the estimated effect of semaglutide on PCS and MCS qualitatively did not change. CONCLUSIONS: Semaglutide improved HRQoL versus placebo; greater improvements with semaglutide versus placebo were possibly mediated, in part, by change in HbA1c and body weight. Clinicaltrials.gov: NCT01720446 (SUSTAIN 6).

Once-weekly dulaglutide versus insulin glargine in the early control of fasting serum glucose and HbA1c.

AIMS: To determine the early benefit:risk balance of dulaglutide versus insulin glargine in patients with type 2 diabetes mellitus (T2DM). METHODS: This post hoc analysis used data from a randomized, open-label study (AWARD-2; modified intention-to-treat group) in which suboptimally controlled metformin + glimepiride-treated patients received dulaglutide 1.5 mg (n = 273) or insulin glargine (n = 262). Two composite endpoints were used: for weeks 2-20, fasting serum glucose (FSG) <130 mg/dL (<7.2 mmol/L) without hypoglycemia (blood glucose ≤70 mg/dL [≤3.9 mmol/L] or severe hypoglycemia); at week 26, patients with glycated hemoglobin (HbA1c) <7.0% (<53.0 mmol/mol) or reduction from baseline ≥1.0% (≥10.9 mmol/mol), no hypoglycemia (as defined above) and no weight gain. Odds ratios (ORs) were generated using logistic regression analysis. RESULTS: The probability of reaching the FSG target without hypoglycemia was higher with dulaglutide than with insulin glargine at weeks 4 (OR 1.78; 95% confidence interval [CI] 1.22-2.60) and 8 (OR 1.69; 95% CI 1.15-2.48). The proportion of patients achieving the 26-week endpoint was higher with dulaglutide (37.4% vs. 10.3%; OR 5.28; 95% CI 3.28-8.48). CONCLUSIONS: Dulaglutide's balanced efficacy-to-safety profile compares favorably with that of insulin glargine and is apparent soon after treatment initiation and after 6 months of therapy.

Once-Weekly Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Common OAD: a Subgroup Analysis from SUSTAIN 2-4 and 10.

INTRODUCTION: Despite treatment with oral antidiabetic drugs (OADs), achieving effective glycaemic control in type 2 diabetes (T2D) remains a challenge. The objective of this post hoc analysis of data from the SUSTAIN 2, 3, 4 and 10 active-controlled trials was to assess the efficacy and safety of the once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide in patients on background treatment with metformin (MET), with or without a sulphonylurea (SU). METHODS: Data from the randomised phase 3 trials SUSTAIN 2, 3, 4 and 10 for subjects who received background MET alone or MET + SU were analysed. Change from baseline in HbA1c and body weight at the end of treatment visit (week 30 in SUSTAIN 4 and 10, week 56 in SUSTAIN 2 and 3), and rates of hypoglycaemia and adverse events leading to premature treatment discontinuation were assessed. RESULTS: In total, 3411 subjects were included in the full analysis set (3410 in the safety analysis set). Across the four trials, semaglutide significantly reduced HbA1c (estimated treatment difference [ETD] - 0.32 to - 0.79%-points for semaglutide 0.5 mg, and - 0.38 to - 1.07%-points for semaglutide 1.0 mg vs comparators; p < 0.01) in subjects receiving both MET and MET + SU. Regardless of background OAD, semaglutide significantly reduced body weight (ETD - 2.35 to - 4.72 kg for semaglutide 0.5 mg, and - 2.96 to - 6.76 kg for semaglutide 1.0 mg vs comparators; p < 0.0001). Across the trials, hypoglycaemic events were more common with background MET + SU than MET alone, in subjects receiving either semaglutide or a comparator. The rate of adverse events (AEs) leading to premature treatment discontinuations in subjects treated with semaglutide were generally consistent regardless of background therapy. CONCLUSION: Semaglutide 0.5 mg and 1.0 mg significantly improve glycaemic control (HbA1c) and body weight in subjects with T2D, with a similar tolerability profile, regardless of whether they receive background MET or MET + SU. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4) and NCT03191396 (SUSTAIN 10).