Publications by authors named "Stefano Del Prato"

260 Publications

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials.

Lancet Diabetes Endocrinol 2021 Oct 20;9(10):653-662. Epub 2021 Aug 20.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.

Background: GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes.

Methods: We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age, and eGFR. We searched PubMed for eligible trials reporting MACE (ie, cardiovascular death, myocardial infarction, or stroke), up to June 9, 2021. We meta-analysed data from published randomised placebo-controlled trials testing either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes. We restricted the search to trials of more than 500 patients with a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This meta-analysis was registered on PROSPERO, CRD42021259711.

Findings: Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80-0·93]; p<0·0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups (all p≥0·14). GLP-1 receptor agonists reduced all-cause mortality by 12% (HR 0·88 [95% CI 0·82-0·94]; p=0·0001), hospital admission for heart failure by 11% (HR 0·89 [95% CI 0·82-0·98]; p=0·013), and the composite kidney outcome by 21% (HR 0·79 [95% CI 0·73-0·87]; p<0·0001), with no increase in risk of severe hypoglycaemia, retinopathy, or pancreatic adverse effects. In sensitivity analyses removing the only trial restricted to patients with an acute coronary syndrome (ELIXA), all benefits marginally increased, including the outcome of worsening of kidney function, based on eGFR change (HR 0·82 [95% CI 0·69-0·98]; p=0·030).

Interpretation: GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with type 2 diabetes.

Funding: None.
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http://dx.doi.org/10.1016/S2213-8587(21)00203-5DOI Listing
October 2021

A fully implantable device for intraperitoneal drug delivery refilled by ingestible capsules.

Sci Robot 2021 Aug;6(57)

BioRobotics Institute, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56127 Pisa, Italy.

Creating fully implantable robots that replace or restore physiological processes is a great challenge in medical robotics. Restoring blood glucose homeostasis in patients with type 1 diabetes is particularly interesting in this sense. Intraperitoneal insulin delivery could revolutionize type 1 diabetes treatment. At present, the intraperitoneal route is little used because it relies on accessing ports connecting intraperitoneal catheters to external reservoirs. Drug-loaded pills transported across the digestive system to refill an implantable reservoir in a minimally invasive fashion could open new possibilities in intraperitoneal delivery. Here, we describe PILLSID (PILl-refiLled implanted System for Intraperitoneal Delivery), a fully implantable robotic device refillable through ingestible magnetic pills carrying drugs. Once refilled, the device acts as a programmable microinfusion system for precise intraperitoneal delivery. The robotic device is grounded on a combination of magnetic switchable components, miniaturized mechatronic elements, a wireless powering system, and a control unit to implement the refilling and control the infusion processes. In this study, we describe the PILLSID prototyping. The device key blocks are validated as single components and within the integrated device at the preclinical level. We demonstrate that the refilling mechanism works efficiently in vivo and that the blood glucose level can be safely regulated in diabetic swine. The device weights 165 grams and is 78 millimeters by 63 millimeters by 35 millimeters, comparable with commercial implantable devices yet overcoming the urgent critical issues related to reservoir refilling and powering.
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http://dx.doi.org/10.1126/scirobotics.abh3328DOI Listing
August 2021

Telemonitoring, Telemedicine and Time in Range During the Pandemic: Paradigm Change for Diabetes Risk Management in the Post-COVID Future.

Diabetes Ther 2021 Sep 2;12(9):2289-2310. Epub 2021 Aug 2.

Abbott Diabetes Care, Wiesbaden, Germany.

People with diabetes are at greater risk for negative outcomes from COVID-19. Though this risk is multifactorial, poor glycaemic control before and during admission to hospital for COVID-19 is likely to contribute to the increased risk. The COVID-19 pandemic and restrictions on mobility and interaction can also be expected to impact on daily glucose management of people with diabetes. Telemonitoring of glucose metrics has been widely used during the pandemic in people with diabetes, including adults and children with T1D, allowing an exploration of the impact of COVID-19 inside and outside the hospital setting on glycaemic control. To date, 27 studies including 69,294 individuals with T1D have reported the effect of glycaemic control during the COVID-19 pandemic. Despite restricted access to diabetes clinics, glycaemic control has not deteriorated for 25/27 cohorts and improved in 23/27 study groups. Significantly, time in range (TIR) 70-180 mg/dL (3.9-10 mmol/L) increased across 19/27 cohorts with a median 3.3% (- 6.0% to 11.2%) change. Thirty per cent of the cohorts with TIR data reported an average clinically significant TIR improvement of 5% or more, possibly as a consequence of more accurate glucose monitoring and improved connectivity through telemedicine. Periodic consultations using telemedicine enables care of people with diabetes while limiting the need for in-person attendance at diabetes clinics. Reports that sustained hyperglycaemia and early-stage diabetic ketoacidosis may go untreated because of the lockdown and concerns about potential exposure to the risk of infection argue for wider access to glucose telemonitoring. Therefore, in this paper we have critically reviewed reports concerning use of telemonitoring in the acute hospitalized setting as well as during daily diabetes management. Furthermore, we discuss the indications and implications of adopting telemonitoring and telemedicine in the present challenging time, as well as their potential for the future.
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http://dx.doi.org/10.1007/s13300-021-01114-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327601PMC
September 2021

Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade.

J Endocr Soc 2021 Sep 15;5(9):bvab093. Epub 2021 May 15.

Endocrinology Unit, Azienda Ospedaliero-Universitaria Pisana and Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56124, Italy.

Context: Thyrotoxicosis is a common immune-related adverse event in patients treated with programmed cell death protein-1 (PD1) or programmed cell death protein ligand-1 (PD-L1) blockade. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy, is lacking, as are data on response to treatment and follow-up.

Objective: The aim of this study was to better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and treatment.

Methods: We conducted a retrospective study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis on PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, technecium scintiscan, and longitudinal thyroid function tests.

Results: Five patients had normal or increased scintigraphic uptake (Sci+), no serum antibodies against the thyrotropin receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci-) and experienced destructive thyrotoxicosis followed by hypothyroidism (N = 9) or euthyroidism (N = 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter ( = .04). Among Sci- individuals, a larger thyroid volume was associated with a longer time to remission ( < .05). Methimazole (MMI) was effective only in Sci+ individuals ( < .05).

Conclusion: Administration of PD1- or PD-L1-blocking antibodies may induce 2 different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2, characterized by destructive and transient thyrotoxicosis that evolves to hypothyroidism or euthyroidism. Thyroid scintigraphy and ultrasound help in differentiating and managing these 2 forms of iatrogenic thyrotoxicosis.
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http://dx.doi.org/10.1210/jendso/bvab093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317632PMC
September 2021

Breaking Therapeutic Inertia With Alirocumab in an 80-Year-Old Patient With Severe Hypercholesterolemia: A Case Report.

Front Med (Lausanne) 2021 7;8:699477. Epub 2021 Jul 7.

Section of Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Therapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner as per evidence-based clinical guidelines, is an important barrier limiting optimal care in the elderly. Therefore, overcoming therapeutic inertia is the core challenge when dealing with geriatric patients. The patient was an 80-year-old man that attended our Outpatient Lipid Clinic (Pisa University Hospital) because of persistent high LDL cholesterol (LDLc) levels in a setting of a statin contraindication. He underwent five percutaneous coronary angioplasties with drug-eluting stents. In 2014, upon starting treatment with rosuvastatin for LDLc level of 7.59 mmol/L, the patient was admitted to the Emergency Room for a presumptive diagnosis of rhabdomyolysis (creatine kinase 6685 U/L) secondary to statin. Patient developed acute kidney injury treated with dialysis. After resolution, he was discharged with ezetimibe (10 mg daily). This treatment however failed to effectively reduce LDLc levels that ranged between 5.9 and 6.6 mmol/L for the ensuing 4-years. In 2018, at the time of our evaluation, in consideration of the age, we performed a comprehensive geriatric assessment that showed good functional and mental status supporting a reliable treatment with a proprotein convertase subtilisin-kexin type 9 inhibitor. Therefore, alirocumab was prescribed as add-on to ezetimibe. At 24-month follow-up, the geriatric assessment showed no significant changes, and alirocumab was well-tolerated. LDLc was 82% lower as compared to baseline values (from 6.6 to 1.2 mmol/L). This report describes a case of therapeutic inertia despite a very high-risk profile. It is also instrumental in highlightening that appropriate intensification of therapy in an elderly patient at high cardiovascular risk, by means of a patient-centered approach, may allow reaching therapeutic targets and overcoming the condition of therapeutic inertia.
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http://dx.doi.org/10.3389/fmed.2021.699477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292593PMC
July 2021

Use of non-nutritive-sweetened soft drink and risk of gestational diabetes.

Diabetes Res Clin Pract 2021 Aug 8;178:108943. Epub 2021 Jul 8.

Section of Diabetes, Azienda-Ospedaliero Universitaria Pisana, Pisa, Italy. Electronic address:

In this observational study, we assessed the association between use of non-nutritive-sweetened soft drink (NNSSD) and risk of gestational diabetes (GDM) in 376 pregnant women consecutively screened for GDM, observing that NNSSD consumption is common among pregnant women and is associated with an increased risk of GDM, independently from traditional risk factors.
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http://dx.doi.org/10.1016/j.diabres.2021.108943DOI Listing
August 2021

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.

N Engl J Med 2021 09 28;385(10):896-907. Epub 2021 Jun 28.

From the Population Health Research Institute, Hamilton Health Sciences (H.C.G., C.R., L.H., L.D.), and McMaster University (H.C.G.) - both in Hamilton, ON, Canada; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (N.S.); the Dallas Diabetes Research Center at Medical City, Dallas (J.R.); AdventHealth Translational Research Institute, Orlando, FL (R.P.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.); National Heart Centre Singapore and Duke-National University of Singapore, Singapore (C.S.P.L.); Sanofi, Bridgewater, NJ (N.S.K.); the Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (S.D.P.); and the Division of Cardiology, University of Washington, Seattle (K.B.).

Background: Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.

Methods: In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).

Results: A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.

Conclusions: In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).
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http://dx.doi.org/10.1056/NEJMoa2108269DOI Listing
September 2021

Bariatric surgery restores visual cortical plasticity in nondiabetic subjects with obesity.

Int J Obes (Lond) 2021 08 17;45(8):1821-1829. Epub 2021 May 17.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background/objectives: Obesity leads to changes in synaptic plasticity. We aimed at investigating the impact of bariatric surgery (RYGB) on visual neural plasticity (NP) and its relationship with the main gut peptides, leptin, and brain-derived neurotrophic factor (BDNF).

Subjects/methods: NP was assessed testing binocular rivalry before and after 2 h of monocular deprivation (index of visual brain plasticity) in 15 subjects with obesity (age 42.3 ± 9.8 years; BMI 46.1 ± 4.9 kg/m) before and after RYGB. Gut peptides, leptin, and BDNF were obtained at baseline and 6 months after surgery in 13 subjects.

Results: A significant reduction in BMI (p < 0.001 vs. baseline) and a significant increase of disposition index (DI, p = 0.02 vs baseline) were observed after RYGB. Total and active GLP-1 release in response to glucose ingestion significantly increased after RYGB, while no changes occurred in VIP, GIP, and BDNF levels. Fasting leptin concentration was lower after RYGB (p = 0.001 vs. baseline). Following RYGB, NP was progressively restored (p < 0.002). NP was correlated with DI and fasting glucose at baseline (r = 0.75, p = 0.01; r = -0.7, p = 0.02; respectively), but not with BMI. A positive correlation between post-pre-RYGB changes in AUC and NP was observed (r = 0.70, p < 0.01). Leptin was inversely correlated with NP 6 months after surgery (r = -0.63, p = 0.02). No correlation was observed between GIP, VIP, BDNF, and NP.

Conclusions: Visual plasticity is altered in subjects with obesity, and it can be restored after RYGB. The improvement may be mediated by amelioration of insulin sensitivity, increased GLP-1 levels, and reduced leptin levels.
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http://dx.doi.org/10.1038/s41366-021-00851-0DOI Listing
August 2021

From glucose lowering agents to disease/diabetes modifying drugs: a "SIMPLE" approach for the treatment of type 2 diabetes.

Cardiovasc Diabetol 2021 04 28;20(1):92. Epub 2021 Apr 28.

The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, P.O. Box 12000, 9112001, Jerusalem, Israel.

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.
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http://dx.doi.org/10.1186/s12933-021-01281-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082901PMC
April 2021

Accuracy of 1-Hour Plasma Glucose During the Oral Glucose Tolerance Test in Diagnosis of Type 2 Diabetes in Adults: A Meta-analysis.

Diabetes Care 2021 04;44(4):1062-1069

Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.

Objective: One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard.

Research Design And Methods: We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA. We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3).

Results: Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%.

Conclusions: The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted.
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http://dx.doi.org/10.2337/dc20-1688DOI Listing
April 2021

Impact of COVID-19 lockdown on glucose control of elderly people with type 2 diabetes in Italy.

Diabetes Res Clin Pract 2021 Apr 17;174:108750. Epub 2021 Mar 17.

Department of Clinical & Experimental Medicine, Section of Metabolic Diseases & Diabetes, University of Pisa, Pisa, Italy. Electronic address:

Aims: to evaluate the effect of home confinement related to COVID-19 lockdown on metabolic control in subjects with T2DM in Italy.

Methods: we evaluated the metabolic profile of 304 individuals with T2DM (65% males; age 69 ± 9 years; diabetes duration 16 ± 10 years) attending our Diabetes Unit early at the end of lockdown period (June 8 to July 7, 2020) and compared it with the latest one recorded before lockdown.

Results: There was no significant difference in fasting plasma glucose (8.6 ± 2.1 vs 8.8 ± 2.5 mmol/L; P = 0.353) and HbA1c (7.1 ± 0.9 vs 7.1 ± 0.9%; P = 0.600) before and after lockdown. Worsening of glycaemic control (i.e., ΔHbA1c ≥ 0.5%) occurred more frequently in older patients (32.2% in > 80 years vs 21.3% in 61-80 years vs 9.3% in < 60 years; P = 0.05) and in insulin users (28.8 vs 16.5%; P = 0.012). On multivariable analysis, age > 80 years (OR 4.62; 95%CI: 1.22-16.07) and insulin therapy (OR 1.96; 95%CI: 1.10-3.50) remained independently associated to worsening in glycaemic control.

Conclusions: Home confinement related to COVID-19 lockdown did not exert a negative effect on glycaemic control in patients with T2DM. However, age and insulin therapy can identify patients at greatest risk of deterioration of glycaemic control.
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http://dx.doi.org/10.1016/j.diabres.2021.108750DOI Listing
April 2021

Diabetes and acute bacterial skin and skin structure infections.

Diabetes Res Clin Pract 2021 Apr 5;174:108732. Epub 2021 Mar 5.

Department of Clinical and Experimental Medicine, Infectious Diseases Unit, University of Pisa, Pisa, Italy.

Acute bacterial skin and skin structures infections (ABSSSIs) are associated with high morbidity, costs and mortality in patients with diabetes mellitus. Their appropriate management should include several figures and a well-organized approach. This review aims to highlight the interplay between diabetes and ABSSSIs and bring out the unmet clinical needs in this area. Pathogenetic mechanisms underlying the increased risk of ABSSSIs in diabetes mellitus are multifactorial: high glucose levels play a crucial pathogenetic role in the tissue damage and delayed clinical cure. Moreover, the presence of diabetes complications (neuropathy, vasculopathy) further complicates the management of ABSSSIs in patients with diabetes. Multidrug resistance organisms should be considered in this population based on patient risk factors and local epidemiology and etiological diagnosis should be obtained whenever possible. Moreover, drug-drug interactions and drug-related adverse events (such as nephrotoxicity) should be considered in the choice of antibiotic therapy. Reducing unnecessary hospitalizations and prolonged length of hospital stay is of primary importance now, more than ever. To achieve these objectives, a better knowledge of the interplay between acute and chronic hyperglycemia, multidrug resistant etiology, and short and long-term outcome is needed. Of importance, a multidisciplinary approach is crucial to achieve full recovery of these patients.
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http://dx.doi.org/10.1016/j.diabres.2021.108732DOI Listing
April 2021

A few clinical features improve the prediction of mortality and cardiovascular outcomes in patients with type 2 diabetes.

Eur J Prev Cardiol 2020 Sep 27. Epub 2020 Sep 27.

CORESEARCH - Center for Outcomes Research and Clinical Epidemiology, via Tiziano Vecellio 2, 65124 Pescara, Italy.

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http://dx.doi.org/10.1093/eurjpc/zwaa002DOI Listing
September 2020

Translating iGlarLixi Evidence for the Management of Frequent Clinical Scenarios in Type 2 Diabetes.

Adv Ther 2021 04 23;38(4):1715-1731. Epub 2021 Feb 23.

Dallas Diabetes Research Center at Medical City, Dallas, TX, USA.

Treatment of type 2 diabetes (T2D) requires progressive therapy intensification to reach and maintain individualized glycemic targets. iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide (Lixi), has been shown to provide robust HbA reductions allowing more people to reach HbA targets compared with separate administration of iGlar or Lixi. The purpose of this review is to help clinicians understand treatment intensification using iGlarLixi by presenting typical clinical scenarios supported by research evidence. These cases will focus on individuals with T2D inadequately controlled by oral antihyperglycemic drugs, basal insulin, or glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and take into consideration T2D duration, body mass index, incidence of adverse events, and regimen simplicity. Clinical evidence on the efficacy, effectiveness, and safety of iGlarLixi from randomized controlled trials and real-world studies will be discussed in the context of these cases.
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http://dx.doi.org/10.1007/s12325-020-01614-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004501PMC
April 2021

Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism?

Diabetes Care 2021 03;44(3):647-654

Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Since the UK Prospective Diabetes Study (UKPDS), metformin has been considered the first-line medication for patients with newly diagnosed type 2 diabetes. Though direct evidence from specific trials is still lacking, several studies have suggested that metformin may protect from diabetes- and nondiabetes-related comorbidities, including cardiovascular, renal, neurological, and neoplastic diseases. In the past few decades, several mechanisms of action have been proposed to explain metformin's protective effects, none being final. It is certain, however, that metformin increases lactate production, concentration, and, possibly, oxidation. Once considered a mere waste product of exercising skeletal muscle or anaerobiosis, lactate is now known to act as a major energy shuttle, redistributed from production sites to where it is needed. Through the direct uptake and oxidation of lactate produced elsewhere, all end organs can be rapidly supplied with fundamental energy, skipping glycolysis and its possible byproducts. Increased lactate production (and consequent oxidation) could therefore be considered a positive mechanism of action of metformin, except when, under specific circumstances, metformin and lactate become excessive, increasing the risk of lactic acidosis. We are proposing that, rather than considering metformin-induced lactate production as dangerous, it could be considered a mechanism through which metformin exerts its possible protective effect on the heart, kidneys, and brain and, to some extent, its antineoplastic action.
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http://dx.doi.org/10.2337/dc20-1964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896249PMC
March 2021

Switching to iGlarLixi versus continuation of a daily or weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) in insufficiently controlled type 2 diabetes: A LixiLan-G trial subgroup analysis by HbA1c and GLP-1 RA use at screening.

Diabetes Obes Metab 2021 06 4;23(6):1331-1341. Epub 2021 May 4.

School of Medicine, University of Pisa, Pisa, Italy.

Aim: In people with type 2 diabetes (T2D) requiring intensification beyond glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and oral antihyperglycaemic drugs (OADs), switching to iGlarLixi was shown to be efficacious and well-tolerated in the LixiLan-G trial. This exploratory analysis of LixiLan-G assessed the efficacy and safety of switching to iGlarLixi versus continuing GLP-1 RA therapy, stratified by screening HbA1c level (≥7.0 to ≤7.5 %; >7.5 to ≤8.0 %; >8.0 to ≤9.0 % [≥53 to ≤58 mmol/mol; >58 to ≤64 mmol/mol; >64 to ≤75 mmol/mol]) and previous GLP-1 RA regimen at screening (once/twice daily or once weekly).

Materials And Methods: Endpoints for all subgroups included: change in HbA1c, achievement of HbA1c <7 % and hypoglycaemia events. Adverse events and changes in fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG), 2-hour PPG excursion and weight were analysed according to previous GLP-1 RA regimen.

Results: Switching to iGlarLixi in all subgroups resulted in significantly greater reductions in HbA1c and proportions of participants reaching HbA1c <7 % (including with no documented hypoglycaemia) at Week 26 compared with continued GLP-1 RA treatment. Switching to iGlarLixi also led to significantly greater reductions in FPG, 2-hour PPG, and 2-hour PPG excursion, irrespective of previous GLP-1 RA regimen. Rates of hypoglycaemia were low, but slightly higher in those who switched to iGlarLixi for all subgroups. Modest weight gain was seen with iGlarLixi, irrespective of previous GLP-1 RA regimen.

Conclusions: Switching to iGlarLixi improved glycaemic control, regardless of screening HbA1c or previous GLP-1 RA type, offering a simple, efficacious and well-tolerated treatment intensification option for people with T2D inadequately controlled by GLP-1 RAs and OADs.
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http://dx.doi.org/10.1111/dom.14345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252076PMC
June 2021

Metformin: an inexpensive and effective treatment in people with diabetes and COVID-19?

Lancet Healthy Longev 2021 Jan 3;2(1):e6-e7. Epub 2020 Dec 3.

Department of Clinical & Experimental Medicine, University of Pisa, Pisa 56124, Italy.

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http://dx.doi.org/10.1016/S2666-7568(20)30047-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834400PMC
January 2021

Durable Effects of iGlarLixi Up to 52 Weeks in Type 2 Diabetes: The LixiLan-G Extension Study.

Diabetes Care 2021 03 19;44(3):774-780. Epub 2021 Jan 19.

MedStar Health Research Institute, Hyattsville, MD.

Objective: In the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes uncontrolled with GLP-1 RAs over 26 weeks versus continuing prior GLP-1 RA. A prespecified, 26-week, single-arm extension of LixiLan-G aimed to determine the durability of iGlarLixi efficacy and safety over 52 weeks.

Research Design And Methods: Participants with type 2 diabetes uncontrolled by GLP-1 RAs (glycated hemoglobin [HbA] 7-9% [53-75 mmol/mol]) were initially randomized to switch to iGlarLixi or continue prior GLP-1 RA. Those randomized to iGlarLixi who completed the 26-week primary end point period could continue iGlarLixi open-label treatment over a 26-week extension to assess durability of efficacy and safety.

Results: Glycemic control achieved with iGlarLixi at week 26 (mean HbA 6.7% [50 mmol/mol]) was maintained at week 52 (mean HbA 6.7% [50 mmol/mol]; mean ± SD change from baseline at week 52: -1.0 ± 0.9% [11 ± 10 mmol/mol]). Proportions of participants reaching HbA <7% (53 mmol/mol) with iGlarLixi were similar at week 26 (62%) and 52 (64%), as were those reaching this target without documented symptomatic (<3.0 mmol/L) hypoglycemia (57% and 58%). Safety of iGlarLixi was similar at weeks 26 and 52, with low rates of documented symptomatic hypoglycemia and gastrointestinal events.

Conclusions: The efficacy and safety of iGlarLixi at the end of the 26-week randomized treatment period was maintained over the 26-week extension period in the LixiLan-G trial.
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http://dx.doi.org/10.2337/dc20-2023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896258PMC
March 2021

Risk factors associated with postpartum impaired glucose regulation in women with previous gestational diabetes.

J Diabetes Complications 2021 04 9;35(4):107854. Epub 2021 Jan 9.

Section of Diabetes, Azienda-Ospedaliero Universitaria Pisana, Pisa, Italy.

Aims: For women with previous gestational diabetes (GDM), international guidelines recommend 75 g oral glucose tolerance test (OGTT) at 4-12 weeks after delivery to assess glucose tolerance, considering their increased risk of type 2 diabetes. We evaluated prevalence of postpartum impaired glucose regulation (IGR) and identified associated risk factors.

Methods: We retrospectively collected data from 749 women with previous GDM (IADPSG criteria) who underwent postpartum OGTT for type 2 diabetes screening between 2011 and 2019. IGR was identified according to ADA criteria.

Results: Prevalence of IGR was 12.7%, lower in women with pre-pregnancy normal weight, higher in women with family history of type 2 diabetes and in those treated with insulin during pregnancy. Prevalence of IGR raised with increasing number of altered glucose values at OGTT performed during pregnancy for GDM screening. HbA1c and triglycerides measured during the third trimester of pregnancy were higher in women with postpartum IGR. At postpartum screening, women with IGR had higher BMI, waist, blood pressure. At multivariate logistic regression analysis, family history of diabetes (OR 2.21; 95% CI: 1.33-3.69; p < 0.01) and presence of all three glucose values exceeding threshold at OGTT during pregnancy (OR 2.89; 95% CI: 1.42-5.86; p < 0.01) were independently associated with IGR.

Conclusions: In women with GDM, persistence of IGR in the immediate postpartum period is associated with family history of diabetes and the presence of all three glucose values exceeding diagnostic threshold for GDM at OGTT in pregnancy, suggesting that these women should undergo specific diabetes monitoring and prevention programs.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107854DOI Listing
April 2021

Identification and management of cardiometabolic risk in subjects with schizophrenia spectrum disorders: A Delphi expert consensus study.

Eur Psychiatry 2021 Jan 8;64(1):e7. Epub 2021 Jan 8.

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM, Madrid, Spain.

Background: Patients with schizophrenia spectrum disorders (SSD) have worse physical health and reduced life expectancy compared to the general population. In 2009, the European Psychiatric Association, the European Society of Cardiology and the European Association for the Study of Diabetes published a position paper aimed to improve cardiovascular and diabetes care in patients with severe mental illnesses. However, the initiative did not produce the expected results. Experts in SSD or in cardiovascular and metabolic diseases convened to identify main issues relevant to management of cardiometabolic risk factors in schizophrenia patients and to seek consensus through the Delphi method.

Methods: The steering committee identified four topics: 1) cardiometabolic risk factors in schizophrenia patients; 2) cardiometabolic risk factors related to antipsychotic treatment; 3) differences in antipsychotic cardiometabolic profiles; 4) management of cardiometabolic risk. Twelve key statements were included in a Delphi questionnaire delivered to a panel of expert European psychiatrists.

Results: Consensus was reached for all statements with positive agreement higher than 85% in the first round. European psychiatrists agreed on: 1) high cardiometabolic risk in patients with SSD, 2) importance of correct risk management of cardiometabolic diseases, from lifestyle modification to treatment of risk factors, including the choice of antipsychotic drugs with a favourable cardiometabolic profile. The expert panel identified the psychiatrist as the central coordinating figure of management, possibly assisted by other specialists and general practitioners.

Conclusions: This study demonstrates high level of agreement among European psychiatrists regarding the importance of cardiovascular risk assessment and management in subjects with SSD.
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http://dx.doi.org/10.1192/j.eurpsy.2020.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057390PMC
January 2021

Predictors of post-traumatic complication of mild brain injury in anticoagulated patients: DOACs are safer than VKAs.

Intern Emerg Med 2021 Jun 1;16(4):1061-1070. Epub 2021 Jan 1.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Although mild traumatic brain injury (MTBI) in people on oral anticoagulant treatment (OAT) is a frequent challenge for Emergency Department (ED), strong guidelines recommendations are lacking. In the attempt to assess the safety profile of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs), we have recruited 473 patients with a MTBI on OAT (43.6% males; age 81.8 ± 8.7 years), admitted to the Pisa's University Hospital ED (Jan 2016-Oct 2018). All patients underwent a head CT scan with those with no sign of acute bleedings remaining under clinical observation for the ensuing 24 h. Fifty patients (10.6%, 95% CI: 8.1-13.7%) had immediate intracranial hemorrhage (ICH), with a prevalence of patient-important outcomes due to immediate ICH of 1.1% (95% CI 0.4-2.4%); 3 patients died (0.6%, 95% CI 0.2-1.8) and 2 required neurosurgical intervention. Immediate ICHs were more frequent in VKA-treated than in DOAC-treated patients (15.9 vs. 6.4%. RR 2.5. 95%CI 1.4-4.4. p < 0.05). Multivariate analysis identified that post-traumatic amnesia, evidence of trauma above clavicles, high blood glucose, high blood pressure (BP) at arrival, and low prothrombin activity were predictors of immediate ICH. The prevalence of delayed ICH was 1.0% (95%CI 0.4-2.5%) without differences between DOACs and VKAs. Despite ICH being a frequent complication of MTBI in patients on OAT, immediate and delayed patient-important outcomes are rare. DOACs have a better safety profile than VKAs. Simple clinical parameters such as blood pressure at arrival or blood glucose might provide useful predictors of immediate ICH.Trial registration number: 11924_CIPRIANO. Local ethics committee approval number 33096.
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http://dx.doi.org/10.1007/s11739-020-02576-wDOI Listing
June 2021

Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist.

Diabetes Obes Metab 2021 02 22;23(2):318-323. Epub 2020 Oct 22.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Aim: The effect of the weekly exendin-based glucagon-like peptide-1 receptor agonist efpeglenatide on cardiovascular (CV) outcomes in high-risk patients with type 2 diabetes (T2DM) with and without chronic kidney disease (CKD) is unknown.

Materials And Methods: People with T2DM and glycated haemoglobin >7%, ≥18 years old with previous CV disease, or ≥50 years old with CKD [defined as an estimated glomerular filtration rate (eGFR) of 25-59.9 mL/min/1.73 m ], and one or more additional CV risk factors were recruited. Participants were randomized in a 1:1:1 ratio, stratified by current, intended or neither current nor intended use of a sodium-glucose cotransporter-2 (SGLT2) inhibitor to receive weekly injections of efpeglenatide (4 mg or 6 mg) or masked placebo. The primary outcome is a major adverse CV event defined as non-fatal myocardial infarction, non-fatal stroke or CV death. Secondary outcomes include a composite kidney outcome (new onset macroalbuminuria with an increase from baseline of ≥30%, sustained 40% decrease in eGFR, renal replacement therapy, or sustained eGFR <15 mL/min/1.73 m ). The trial will continue until ≥330 participants have had a major adverse CV event outcome and the sample size was based on accruing enough outcomes to detect non-inferiority of efpeglenatide versus placebo.

Results: Recruitment of 4076 participants (33% women, mean age 64.5 years) occurred between 11 May 2018 and 25 April 2019 at 344 sites in 28 countries. Mean baseline glycated haemoglobin was 8.9% (1.5), 31.6% had an eGFR <60 mL/min/1.73 m , 89.5% had previous CV disease and 15.0% were on an SGLT2 inhibitor.

Conclusions: The results of the AMPLITUDE O trial will inform the use of exendin-based glucagon-like peptide-1 receptor agonist to people with T2DM and high CV risk, with and without CKD, in the presence and absence of an SGLT2 inhibitor.
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http://dx.doi.org/10.1111/dom.14223DOI Listing
February 2021

Type 1 diabetes and COVID-19: The "lockdown effect".

Diabetes Res Clin Pract 2020 Dec 25;170:108468. Epub 2020 Sep 25.

Section of Metabolic Diseases & Diabetes, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy; Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy. Electronic address:

Aims: The aim of this study was to evaluate the effect the lockdown imposed during COVID-19 outbreak on the glycemic control of people with Type 1 diabetes (T1D) using Continuous (CGM) or Flash Glucose Monitoring (FGM).

Materials And Methods: We retrospectively analyzed glucose reading obtained by FGM or CGM in T1D subjects. Sensor data from 2 weeks before the lockdown (Period 0, P), 2 weeks immediately after the lockdown (period 1, P), in mid-lockdown (Period 2, P) and immediately after end of lockdown (Period 3, P) were analyzed.

Results: The study included 63 T1D patients, (FGM: 52, 82%; CGM:11, 18%). Sensor use (91%) were slightly reduced. Despite this reduction, Time in Range increased in P (62%), P (61%) and P (62%) as compared to P (58%, all p < 0.05 or less) with concomitant reduction in the Time Above Range (P: 38%; P: 34%, P: 34%, P: 32%, all p < 0.05 or less vs. P). Average glucose and GMI improved achieving statistical difference in P (165 vs. 158 mg/dl, p = 0.040 and 7.2% (55 mmol/mol) vs. 7.0% (53 mmol/mol), p = 0.016) compared to P0. Time Below Range (TBR) and overall glucose variability remained unchanged. Bi-hourly analysis of glucose profile showed an improvement particularly in the early morning hours.

Conclusions: In T1D subjects with good glycemic control on CGM or FGM, the lockdown had no negative impact. Rather a modest but significant improvement in glycemic control has been recorded, most likely reflecting more regular daily life activities and reduces work-related distress.
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http://dx.doi.org/10.1016/j.diabres.2020.108468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518840PMC
December 2020

Insights from VERIFY: Early Combination Therapy Provides Better Glycaemic Durability Than a Stepwise Approach in Newly Diagnosed Type 2 Diabetes.

Diabetes Ther 2020 Nov 25;11(11):2465-2476. Epub 2020 Sep 25.

Global Medical Affairs, Established Medicines, Diabetes, Novartis Pharma AG, Basel, Switzerland.

The treatment aims for type 2 diabetes are to prevent complications and premature mortality, and improve quality of life. Glycaemic control is central to these aims; clinical guidelines have sought to achieve this with a stepwise approach starting with lifestyle measures and metformin, adding further medications once glycated haemoglobin (HbA) levels rise above a predefined threshold. However, treatment intensification can be delayed when HbA levels increase, and HbA levels become inadequately controlled in many patients. Clinical inertia can result in sustained elevated levels of HbA; when combined with a late diagnosis, this negatively impacts patients' prognosis. Early combination therapy using medications with complementary modes of action could achieve optimal glycaemic targets and alter the course of the disease more than metformin alone. The multinational VERIFY study (clinicaltrials.gov NCT01528254) provided evidence accrued over 5 years, demonstrating the potential of early combination therapy: time to loss of glycaemic control was nearly doubled, and more than twice the number of patients experienced extended glycaemic control, with a vildagliptin-metformin combination therapy versus metformin alone. The study also showed a delay in secondary treatment failure in patients receiving the combination. Early combination therapy therefore offers a different trajectory to the stepwise approach. Translating these findings into clinical practice will require early detection and diagnosis of type 2 diabetes plus a shift in disease management. Nonetheless, the potential benefits of sustained and continuous disease control that early combination therapy offers represent the start of a new era in early diagnosis and intensive management, to achieve the treatment aims of type 2 diabetes.
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http://dx.doi.org/10.1007/s13300-020-00926-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547931PMC
November 2020

Early combination therapy delayed treatment escalation in newly diagnosed young-onset type 2 diabetes: A subanalysis of the VERIFY study.

Diabetes Obes Metab 2021 01 29;23(1):245-251. Epub 2020 Sep 29.

Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Pisa, Italy.

We analysed glycaemic durability (sustained glycaemic control) with early combination therapy (metformin plus vildagliptin) versus metformin monotherapy, among patients with type 2 diabetes diagnosed before (young-onset [YOD]) and after (late-onset [LOD]) the age of 40 years, enrolled in the VERIFY trial. The primary endpoint was time to initial treatment failure (TF), defined as HbA1c of 7.0% or higher at two consecutive scheduled visits after randomization. The time to secondary TF was assessed when both groups were receiving and failing on the combination. A total of 186 (9.3%) patients had YOD and 1815 (90.7%) had LOD with a mean age difference of 20.4 years. Compared with metformin monotherapy, early combination reduced the risk of time to initial TF for both YOD (48%, P < .0006) and LOD (46%, P < .0001). With early combination, risk for time to secondary TF was reduced by 48% (P < .0035) in YOD and 24% (P < .0009) in LOD. Both treatment approaches were well tolerated with no unexpected safety concerns. In treatment-naïve patients with YOD (HbA1c 6.5%-7.5%), an early combination strategy improved attainment of the glycaemic target with durability and delayed treatment escalation compared with initial metformin monotherapy.
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http://dx.doi.org/10.1111/dom.14192DOI Listing
January 2021

Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy.

Diabetologia 2020 11 22;63(11):2423-2433. Epub 2020 Aug 22.

Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.

Aims/hypothesis: The glucosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA. We hypothesised that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys.

Methods: This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30-65 years old, with a BMI of 25-35 kg/m and stable body weight (±2 kg) over the preceding 3 months, and HbA <42 mmol/mol (6.0%). Participants had undergone renal transplant with and without removal of native kidneys and were on a stable dose of immunosuppressive medications. Participants received a single dose of dapagliflozin 10 mg or placebo on two separate days, at a 5- to 14-day interval, according to randomisation performed by our hospital pharmacy, which provided dapagliflozin and matching placebo, packaged in bulk bottles that were sequentially numbered. Both participants and investigators were blinded to group assignment.

Results: Twenty non-diabetic renal transplant patients (ten with residual native kidneys, ten with bilateral nephrectomy) participated in the study. Dapagliflozin induced greater glucosuria in individuals with residual native kidneys vs nephrectomised individuals (8.6 ± 1.1 vs 5.5 ± 0.5 g/6 h; p = 0.02; data not shown). During the 6 h study period, plasma glucose decreased only slightly and similarly in both groups, with no difference compared with placebo (data not shown). Following administration of placebo, there was a progressive time-related decline in EGP that was similar in both nephrectomised individuals and individuals with residual native kidneys. Following dapagliflozin administration, EGP declined in both groups, but the differences between the decrement in EGP with dapagliflozin and placebo in the group with bilateral nephrectomy (Δ = 1.11 ± 0.72 μmol min kg) was significantly lower (p = 0.03) than in the residual native kidney group (Δ = 2.56 ± 0.33 μmol min kg). In the population treated with dapagliflozin, urinary glucose excretion was correlated with EGP (r = 0.34, p < 0.05). Plasma insulin, C-peptide, glucagon, prehepatic insulin:glucagon ratio, lactate, alanine and pyruvate concentrations were similar following placebo and dapagliflozin treatment. β-Hydroxybutyrate increased with dapagliflozin treatment in the residual native kidney group, while a small increase was observed only at 360 min in the nephrectomy group. Plasma adrenaline (epinephrine) did not change after dapagliflozin and placebo treatment in either group. Following dapagliflozin administration, plasma noradrenaline (norepinephrine) increased slightly in the residual native kidney group and decreased in the nephrectomy group.

Conclusions/interpretation: In nephrectomised individuals, the hepatic compensatory response to acute SGLT2 inhibitor-induced glucosuria was attenuated, as compared with individuals with residual native kidneys, suggesting that SGLT2 inhibitor-mediated stimulation of hepatic glucose production via efferent renal nerves occurs in an attempt to compensate for the urinary glucose loss (i.e. a renal-hepatic axis).

Trial Registration: ClinicalTrials.gov NCT03168295 FUNDING: This protocol was supported by Qatar National Research Fund (QNRF) Award No. NPRP 8-311-3-062 and NIH grant DK024092-38. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05254-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527374PMC
November 2020

Tackling obesity during the COVID-19 pandemic.

Diabetes Metab Res Rev 2021 03 29;37(3):e3393. Epub 2020 Aug 29.

Diabetes Unit, Department of Endocrinology and Metabolism, Faculty of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

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http://dx.doi.org/10.1002/dmrr.3393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435354PMC
March 2021

Insulin Resistance and Risk of Major Vascular Events and All-Cause Mortality in Type 1 Diabetes: A 10-Year Follow-up Study.

Diabetes Care 2020 10 13;43(10):e139-e141. Epub 2020 Aug 13.

Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

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http://dx.doi.org/10.2337/dc20-0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510021PMC
October 2020
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