Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus oral semaglutide.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.

Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

AWARE A novel web application to rapidly assess cardiovascular risk in type 2 diabetes mellitus.

AIM: To describe the development of the AWARE App, a novel web application for the rapid assessment of cardiovascular risk in Type 2 Diabetes Mellitus (T2DM) patients. We also tested the feasibility of using this App in clinical practice. METHODS: Based on 2019 European Society of Cardiology/European Association for the Study of Diabetes criteria for cardiovascular risk stratification in T2DM, the AWARE App classifies patients into very high (VHCVR), high (HCVR) and moderate (MCVR) cardiovascular risk categories. In this retrospective clinical study, we employed the App to assess the cardiovascular risk of T2DM patients, while also collecting data about current glycaemic control and pharmacological treatment. RESULTS: 2243 T2DM consecutive patients were evaluated. 72.2% of the patients were VHCVR, 8.9% were HCVR, 0.8% were MCVR while 18.2% did not fit into any of the risk categories and were classified as "moderate-to-high" (MHCVR). Compared with the other groups, patients with VHCVD were more frequently ≥ 65 years old (68.9%), with a longer disease duration (≥ 10 years [56.8%]), a history of cardiovascular disease (41.4%), organ damage (35.5%) and a higher numbers of cardiovascular risk factors. Patients with MHCVD generally had disease duration < 10 years (96%), younger age (50-60 years [55%]), no history of cardiovascular disease, no organ damage, and 1-2 cardiovascular risk factors (89%). Novel drugs such as Glucagon Like Peptyde 1 Receptor Agonists or Sodium-Glucose Linked Transporter 2 inhibitors were prescribed only to 26.3% of the patients with VHCVR and to 24.7% of those with HCVR. Glycaemic control was unsatisfactory in this patients population (HbA1c 7.5 ± 3.4% [58.7 ± 13.4 mmol/mol]). CONCLUSIONS: The AWARE App proved to be a practical tool for cardiovascular risk stratification of T2DM patients in real-world clinical practice.

Dapagliflozin acutely improves kidney function in type 2 diabetes mellitus. The PRECARE study.

Dapagliflozin has been demonstrated to improve glycemic control, blood pressure, and body weight in type 2 diabetes mellitus (T2D); indeed, it can also reduce the risk of progression to renal failure, of hospitalization for heart failure and of cardiovascular death. We aim to investigate the acute effect of Dapagliflozin on kidney function in the common clinical practice in T2D. This is a study including 1402 patients with T2D recruited from 11 centers in Lombardia, Italy, who were evaluated at baseline and after 6 months of treatment with Dapagliflozin 10 mg per day. The primary outcome of the study was the change in HbA1c, while the secondary outcomes were modification of weight, BMI, systolic and diastolic pressure, creatinine, eGFR and albuminuria status. After 24 weeks of treatment with Dapagliflozin, a reduction in Hb1Ac was observed (-0.6 ± 1.8%) as well as in BMI (-1.5 ± 5.2 kg/m2). Statistically significant changes were also found for systolic and diastolic blood pressure, cholesterol and triglycerides. Interestingly, a statistically significant acute improvement of kidney function was evident. Our analyses confirm the beneficial effects of dapagliflozin after 6 months of therapy, with improvements of glycemic and lipid profiles, blood pressure, BMI. Finally, an acute positive effect on albuminuria and KIDGO classes was observed during a 6 months treatment with dapagliflozin in patients with T2D.

Biliopancreatic Diversion (BPD), Long Common Limb Revisional Biliopancreatic Diversion (BPD + LCL-R), Roux-en-Y Gastric Bypass [RYGB] and Sleeve Gastrectomy (SG) mediate differential quantitative changes in body weight and qualitative modifications in body composition: a 5-year study.

AIMS: Bariatric surgeries induce profound weight loss (decrease in body mass index, BMI), through a decrease in fat mass (FM) and to a much lesser degree of fat-free mass (FFM). Some reports indicate that the weight which is lost after gastric bypass (RYGB) and sleeve gastrectomy (SG) is at least partially regained 2 years after surgery. Here we compare changes in BMI and body composition induced by four bariatric procedures in a 5 years follow-up study. METHODS: We analyzed retrospectively modifications in BMI, FM and FFM obtained through Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), biliopancreatic diversion (BPD) and a long common limb revisional biliopancreatic diversion (reduction of the gastric pouch and long common limb; BPD + LCL-R). Patients were evaluated at baseline and yearly for 5 years. Of the whole cohort of 565 patients, a subset of 180 patients had all yearly evaluations, while the remaining had incomplete evaluations. Setting University Hospital. RESULTS: In a total of 180 patients evaluated yearly for 5 years, decrease in BMI and FM up to 2 years was more rapid with RYGB and SG than BPD and BPD + LCL-R; with RYGB and SG both BMI and FM slightly increased in the years 3-5. At 5 years, the differences were not significant. When analysing the differences between 2 and 5 years, BPD + LCL-R showed a somewhat greater effect on BMI and FM than RYGB, BPD and SG. Superimposable results were obtained when the whole cohort of 565 patients with incomplete evaluation was considered. CONCLUSIONS: All surgeries were highly effective in reducing BMI and fat mass at around 2 years; with RYGB and SG both BMI and FM slightly increased in the years 3-5, while BPD and BPD + LCL-R showed a slight further decreases in the same time interval.

Obesity Is Strongly Associated With Low Testosterone and Reduced Penis Growth During Development.

CONTEXT: Growth of male genitalia represents an important marker of sexual development. Testicle size is the primary measure and little is known regards penile length changes during puberty. OBJECTIVE: This work aims to assess penis growth and testosterone levels in obese vs normal-weight children and adolescents, to evaluate a possible influence of obesity on genital development in boys, and to establish a new method for measuring penis length that allows comparison of normal-weight and overweight boys. METHODS: We assessed anthropometric and genital development in 1130 boys from birth to age 20 years. Testosterone levels were also measured. A new method for penile length measurement was employed to minimize errors when comparing obese and nonobese children. Penis length was measured with a gentle, painless, straight positioning on a centimetric ruler without stretching, which is doable from the first years of life until the end of adolescence. RESULTS: Penis length and testosterone are strongly related in children during puberty. Penile length growth is significantly decreased (by about 10%) in obese boys when compared to normal-weight boys, with concomitantly reduced testosterone levels, across puberal phases. CONCLUSION: Childhood obesity represents an important determinant of lower testosterone level and reduced penis development. A new method should be employed to improve penis measurement in normal-weight and overweight/obese boys. The possible significance of these observations for adult genital development and reproductive potential will require large longitudinal studies.

Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Accumulating experimental and clinical evidences over the last decade indicate that GLP-1 analogues have a series of central nervous system and peripheral target tissues actions which are able to significantly influence the liver metabolism. GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction. While the experimental and clinical data are robust, the precise mechanisms of action potentially involved in these protective multi-target effects need further investigation. Here we present a systematic review of the most recent literature data on the multi-target effects of GLP-1 analogues on the liver, on adipose and muscular tissue and on the nervous system, all capable of influencing significant aspects of the fatty liver disease physiopathology. From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.

Acute Kidney Injury in Diabetic Patients With Acute Myocardial Infarction: Role of Acute and Chronic Glycemia.

BACKGROUND: In acute myocardial infarction, acute hyperglycemia is a predictor of acute kidney injury (AKI), particularly in patients without diabetes mellitus. This emphasizes the importance of an acute glycemic rise rather than glycemia level at admission. We investigated whether, in diabetic patients with acute myocardial infarction, the combined evaluation of acute and chronic glycemic levels may have better prognostic value for AKI than admission glycemia. METHODS AND RESULTS: At admission, we prospectively measured glycemia and estimated average chronic glucose levels (mg/dL) using glycosylated hemoglobin (HbA1c), according to the following formula: 28.7×HbA1c (%)-46.7. We evaluated the association with AKI of the acute/chronic glycemic ratio and of the difference between acute and chronic glycemia (ΔA-C). We enrolled 474 diabetic patients with acute myocardial infarction. Of them, 77 (16%) experienced AKI. The incidence of AKI increased in parallel with the acute/chronic glycemic ratio (12%, 14%, 22%; P=0.02 for trend) and ΔA-C (13%, 13%, 23%; P=0.01) but not with admission glycemic tertiles (P=0.22). At receiver operating characteristic analysis, the acute/chronic glycemic ratio (area under the curve: 0.62 [95% confidence interval, 0.55-0.69]; P=0.001) and ΔA-C (area under the curve: 0.62 [95% confidence interval, 0.54-0.69]; P=0.002) accurately predicted AKI, without difference in the area under the curve between them (P=0.53). At reclassification analysis, the addition of the acute/chronic glycemic ratio and ΔA-C to acute glycemia allowed proper AKI risk prediction in 16% of patients. CONCLUSIONS: In diabetic patients with acute myocardial infarction, AKI is better predicted by the combined evaluation of acute and chronic glycemic values than by assessment of admission glycemia alone.

Prognostic Value of the Acute-to-Chronic Glycemic Ratio at Admission in Acute Myocardial Infarction: A Prospective Study.

OBJECTIVE: Acute hyperglycemia is a powerful predictor of poor prognosis in acute myocardial infarction (AMI), particularly in patients without diabetes. This emphasizes the importance of an acute glycemic rise rather than glycemia level at admission alone. We investigated in AMI whether the combined evaluation of acute and chronic glycemic levels, as compared with admission glycemia alone, may have a better prognostic value. RESEARCH DESIGN AND METHODS: We prospectively measured admission glycemia and estimated average chronic glucose levels (mg/dL) by the following formula: [(28.7 × glycosylated hemoglobin %) - 46.7], and calculated the acute-to-chronic (A/C) glycemic ratio in 1,553 consecutive AMI patients (mean ± SD age 67 ± 13 years). The primary end point was the combination of in-hospital mortality, acute pulmonary edema, and cardiogenic shock. RESULTS: The primary end point rate increased in parallel with A/C glycemic ratio tertiles (5%, 8%, and 20%, respectively; P for trend <0.0001). A parallel increase was observed in troponin I peak value (15 ± 34 ng/mL, 34 ± 66 ng/mL, and 68 ± 131 ng/mL; P < 0.0001). At multivariable analysis, A/C glycemic ratio remained an independent predictor of the primary end point and of troponin I peak value, even after adjustment for major confounders. At reclassification analyses, A/C glycemic ratio showed the best prognostic power in predicting the primary end point as compared with glycemia at admission in the entire population (net reclassification improvement 12% [95% CI 4-20]; P = 0.003) and, particularly, in patients with diabetes (27% [95% CI 14-40]; P < 0.0001). CONCLUSIONS: In AMI patients with diabetes, A/C glycemic ratio is a better predictor of in-hospital morbidity and mortality than glycemia at admission.

Clinical evidence continuous medical education: a randomised educational trial of an open access e-learning program for transferring evidence-based information - ICEKUBE (Italian Clinical Evidence Knowledge Utilization Behaviour Evaluation) - study protocol.

BACKGROUND: In an effort to ensure that all physicians have access to valid and reliable evidence on drug effectiveness, the Italian Drug Agency sponsored a free-access e-learning system, based on Clinical Evidence, called ECCE. Doctors have access to an electronic version and related clinical vignettes. Correct answers to the interactive vignettes provide Continuing Medical Education credits. The aims of this trial are to establish whether the e-learning program (ECCE) increases physicians' basic knowledge about common clinical scenarios, and whether ECCE is superior to the passive diffusion of information through the printed version of Clinical Evidence. DESIGN: All Italian doctors naïve to ECCE will be randomised to three groups. Group one will have access to ECCE for Clinical Evidence chapters and vignettes lot A and will provide control data for Clinical Evidence chapters and vignettes lot B; group two vice versa; group three will receive the concise printed version of Clinical Evidence. There are in fact two designs: a before and after pragmatic trial utilising a two by two incomplete block design (group one versus group two) and a classical design (group one and two versus group three). The primary outcome will be the retention of Clinical Evidence contents assessed from the scores for clinical vignettes selected from ECCE at least six months after the intervention. To avoid test-retest effects, we will randomly select vignettes out of lot A and lot B, avoiding repetitions. In order to preserve the comparability of lots, we will select vignettes with similar, optimal psychometric characteristics.

Feasibility of a web-based continuing medical education program in dermatology: the DermoFAD experience in Italy.

BACKGROUND: Web-based systems are increasingly being considered for medical education. A draft legislation on distance-learning programs was licensed in Italy by the National Commission for Continuous Education in November 2003. A series of pilot studies were developed, among these the DermoFAD project, based on five simulated clinical cases of acne and a systematic appraisal of the evidence for their clinical management. From July 1 to August 27, 2004, a total of 500 medical doctors participated in a free of charge evaluation program of the project. OBSERVATIONS: Users were distributed all over Italy. Two hundred and eighty-one (56.2%) were primary care physicians, 83 (16.6%) dermatologists, and 136 (27.2%) other medical specialists. A wide range of connecting times was observed. The pass rate of each individual case, at first attempt, ranged from 44 to 77%. When asked to assess the overall distance-learning experience, 98% of the doctors considered it to be enjoyable. A total of 2,152 continuing medical education (CME) credits were awarded. Over 50% of the users stated they would still use the system if they had to pay for it. CONCLUSIONS: Our experience shows that distance learning is feasible and is well accepted by physicians. The DermoFAD program was an efficient means of delivering CME to the Italian medical community at large.