Development of a New Model of Insulin Sensitivity in Patients With Type 2 Diabetes and Association With Mortality.

CONTEXT: Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies. OBJECTIVE: To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality. METHODS: One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015. RESULTS: The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality. CONCLUSION: We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognostication.

Advanced Hybrid Closed-Loop System Achieves and Maintains Recommended Time in Range Levels for Up To 2 Years: Predictors of Best Efficacy.

Aim: To evaluate the long-term efficacy, up to 2 years, of an advanced hybrid closed-loop (AHCL) system and to assess predictors of best results of the therapy. Methods: We retrospectively evaluated 296 adults with type 1 diabetes mellitus [mean age 42.8 ± 16.5 years, men 42.9%, duration of diabetes 22.5 ± 12.8 years, body mass index 24.9 ± 4.7 kg/m2, baseline glycated hemoglobin (HbA1c) 63.4 ± 12.2 mmol/mol (8.0 ± 1.1%) ] who used the MiniMed™ 780G system. Demographic and clinical data were recorded. Continuous glucose monitoring (CGM)-derived metrics and insulin requirement were analyzed from the 4 weeks before and from every quarter after the switch to the AHCL system. Results: In the first quarter of AHCL treatment, all CGM metrics improved. Time in range (TIR) increased from 58.1 ± 17.5% to 70.3 ± 9.5% (P < 0.0001). The improvement lasted for up to 2 years of observation regardless of previous insulin therapies. Throughout the period of observation, 53.4% of participants achieved mean TIR >70%, 92.6% mean time below range <4%, and 46% mean glucose management indicator <53 mmol/mol (7.0%). At univariable logistic regression older age, lower baseline HbA1c and insulin requirement were associated with mean TIR >70%. At multivariable analysis, lower HbA1c remained independently associated with a better glycemic control. However, mean TIR increased more in participants with a higher baseline HbA1c. Conclusions: Switching to an AHCL leads to a rapid improvement in glycemic control lasting for up to 24 months along with a low risk for hypoglycemia, confirming the safety of the system. Lower baseline HbA1c was the main predictor of better efficacy of therapy, although higher baseline HbA1c was associated with the greatest improvement in mean TIR.

Switching to the Minimed™ 780G system achieves clinical targets for CGM in adults with type 1 diabetes regardless of previous insulin strategy and baseline glucose control.

AIMS: Advanced hybrid closed-loop (AHCL) systems represent the latest introduction in the treatment of type 1 diabetes (T1DM). Randomized controlled trials and real-world evidence studies showed that AHCL systems are a safe and effective insulin management strategy. Aim of this retrospective, single-center, real-life study was to evaluate the effect on metabolic control, evaluated by continuous glucose monitoring (CGM) metrics, of the switch from four available insulin strategies to an AHCL system in adult patients with type 1 diabetes. METHODS: A total of 102 patients with T1DM (mean age 42.1 ± 16.3 years, males/females 47/55, duration of diabetes 21.4 ± 13.3 years, BMI 24.4 ± 4.5 kg/m2, HbA1c 59.9 ± 9.6 mmol/mol or 7.6 ± 0.9%), treated with four different insulin therapies [multiple daily insulin (MDI) therapy, continuous subcutaneous insulin infusion (CSII), sensor-augmented pump (SAP) with predictive low-glucose suspend (PLGS), and hybrid closed loop (HCL) system] were evaluated before hand, two months and six months after switching to an AHCL (Minimed™ 780G system, Medtronic, Northridge, CA) system. RESULTS: Two months after the switch, mean GCM metrics improved in all four treatment groups. Six months after the switch, the participants of all four groups achieved a mean GMI < 53 mmol/mol, TIR > 70%, TBR < 4%, and CV < 36%, which is recommended by the ADA Standard of Medical Care in Diabetes 2022, including the MDI group with worse baseline glycemic control. CONCLUSIONS: Switching to an AHCL leads to a rapid improvement in glycemic control lasting for up to six months independently of previous insulin treatment and baseline conditions.

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.

Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study.

OBJECTIVE: Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS: In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020. RESULTS: Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29-0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS: In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.

ANDREW: A Multicenter, Prospective, Observational Study in Patients with Type 2 Diabetes on Persistent Treatment with Dulaglutide.

INTRODUCTION: Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), became available in Italy in April 2016. The aim of ANDREW (Active Notes on Dulaglutide in the REal World), a multicenter, prospective, observational study, was to evaluate glycemic control and weight (co-primary outcomes) for up to 24 months in the real-life setting in consecutive outpatients with type 2 diabetes (T2D) who initiated dulaglutide. Co-secondary outcomes were durability of treatment effects on both glycated hemoglobin (HbA1c) and body weight. METHODS: Overall, 1584 subjects (696 women, 888 men) with T2D (mean age [± standard deviation] 61.7 ± 10.2 years; mean T2D duration 9.9 ± 6.9 years) were treated with dulaglutide (0.75 or 1.5 mg once weekly) between April 2016 and December 2019. RESULTS: A total of 1130 patients completed 12 months of follow-up, while 170 patients interrupted treatment before the 12-month endpoint. At 12 months, average HbA1c and average fasting plasma glucose (FPG) were significantly lower compared to baseline levels (- 10 mmol/mol and - 24.9 mg/dL, respectively), as were body weight (- 3.4 kg) and waist circumference (- 3.3 cm) values (all p < 0.0001). Among subjects that completed 24 months of follow-up (n = 270), the rapid decline in HbA1c and FPG values in the first 12 months was followed by stabilization in the following 12 months (p value for 12-24 months trend: 0.4 and 0.6, respectively). CONCLUSIONS: Dulaglutide is an effective drug for the treatment of T2D that is administered once weekly using a simple auto-injector device. Real-life data confirm the observations in randomized controlled trials that persistent treatment with dulaglutide may help patients with T2D achieve an improvement in some metabolic features and in body weight. It is important that the benefits of therapy with dulaglutide, i.e., the effects of the "glycemic" and the so-called "extra-glycemic" actions of GLP-1RAs, are supported by diabetes care teams emphasizing the need for patients to maintain a healthy lifestyle.

Switching from Suspend-Before-Low Insulin Pump Technology to a Hybrid Closed-Loop System Improves Glucose Control and Reduces Glucose Variability: A Retrospective Observational Case-Control Study.

There are no data whether hybrid closed-loop (HCL) systems are superior to sensor-augmented pump (SAP) therapy with predictive low glucose suspend (PLGS) feature in improving glucose control. Aim of our study was to evaluate the effect on metabolic control and glucose variability of the switch from SAP therapy with PLGS to a HCL system in type 1 diabetic individuals. Forty adults with type 1 diabetes, who had been using SAP therapy with PLGS feature (Minimed 640G; Medtronic, Northridge, CA) for at least 12 months were evaluated in a 6-month case-control observational retrospective study. Twenty subjects who consecutively switched from Minimed 640G to a HCL system (Minimed 670G; Medtronic) (670G group) were compared with a control group consisting of 20 subjects who continued with the MiniMed 640G pump (640G group) matched for age, gender, and HbA1c. At the end of the study there was a significant reduction in average HbA1c levels (-4.9 ± 6.4 mmol/mol [-0.4% ± 0.6%], P < 0.01), sensor glucose concentrations (-15.4 ± 17.7 mg/dL, P < 0.005), coefficient of variation of sensor glucose concentrations (-3.8% ± 3.6%, P < 0.01), percentage time spent in both hyperglycemic range 181-250 mg/dL (-5.1% ± 4.5%, P < 0.05), and >250 mg/dL (-6.1% ± 6.9%, P < 0.05) in the 670G group, whereas they remained unchanged in the 640G group. Percentage of time spent in euglycemic range significantly increased (11.6% ± 8.3%, P < 0.005) only in the 670G group. There was no change in time spent in hypoglycemic range in both groups. In adults with type 1 diabetes, switching from a 640G to a 670G system significantly improved glucose control and reduced glucose variability, thus reaching in most cases the recommended targets for time spent in euglycemic and hyperglycemic ranges without increasing the risk of hypoglycemia.

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.

BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.