Heterogeneity of glycaemic phenotypes in type 1 diabetes.

AIMS/HYPOTHESIS: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. METHODS: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. RESULTS: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.

Basal Insulinotherapy in Patients Living with Diabetes in France: The EF-BI Study.

INTRODUCTION: Second-generation basal insulins like glargine 300 U/mL (Gla-300) have a longer duration of action and less daily fluctuation and interday variability than first-generation ones, such as glargine 100 U/mL (Gla-100). The EF-BI study, a nationwide observational, retrospective study, was designed to compare persistence, acute care complications, and healthcare costs associated with the initiation of such basal insulins (BI) in a real-life setting in France. METHODS: This study was conducted using the French healthcare claims database (SNDS). Adult patients living with type 1 or type 2 diabetes mellitus (T1DM or T2DM) initiating Gla-300 or Gla-100 ± other hypoglycemic medications between January 1, 2016 and December 31, 2020, and without any insulin therapy over the previous 6 months were included. Persistence was defined as remaining on the same insulin therapy until discontinuation defined by a 6 month period without insulin reimbursement. Hospitalized acute complications were identified using ICD-10 codes. Total collective costs were established for patients treated continuously with each basal insulin over 1-3 years. All comparisons were adjusted using a propensity score based on initial patient/treatment characteristics. RESULTS: A total of 235,894 patients with T2DM and 6672 patients with T1DM were included. Patients treated with Gla-300 were 83% (T1DM) and 44% (T2DM) less likely to discontinue their treatment than those treated with Gla-100 after 24 months (p < 0.0001). The annual incidence of acute hospitalized events in patients with T2DM treated with Gla-300 was 12% lower than with Gla-100 (p < 0.0001) but similar in patients with T1DM. Comparison of overall costs showed moderate but statistically significant differences in favor of Gla-300 versus Gla-100 for all patients over the first year, and in T2DM only over a 3-year follow-up. CONCLUSION: Use of Gla-300 resulted in a better persistence, less acute hospitalized events at least in T2DM, and reduced healthcare expenditure. These real-life results confirmed the potential interest of using Gla-300 rather than Gla-100.

Atherosclerotic cardiovascular disease risk stratification and management in type 2 diabetes: review of recent evidence-based guidelines.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality and morbidity in individuals with type 2 diabetes mellitus (T2DM). Accordingly, several scientific societies have released clinical practice guidelines to assist health professionals in ASCVD risk management in patients with T2DM. However, some recommendations differ from each other, contributing to uncertainty about the optimal clinical management of patients with T2DM and established ASCVD or at high risk for ASCVD. Thus, the purpose of this paper is to discuss recent evidence-based guidelines on ASCVD risk stratification and prevention in patients with T2DM, in terms of disparities and similarities. To close the gap between different guidelines, a multidisciplinary approach involving general practitioners, endocrinologists, and cardiologists may enhance the coordination of diagnosis, therapy, and long-term follow-up of ASCVD in patients with T2DM.

Management of Glucose-Lowering Therapy in Older Adults with Type 2 Diabetes: Challenges and Opportunities.

The population of older adults (≥65 years) with type 2 diabetes mellitus (T2DM) is diverse, encompassing individuals with varying functional capabilities, living arrangements, concomitant medical conditions, and life expectancies. Hence, their categorization into different patient profiles (ie, good health, intermediate health, poor health) may aid in clinical decision-making when establishing glycemic goals and pharmacological treatment strategies. Further granularity in assessing each patient profile through interdisciplinary collaboration may also add precision to therapeutic and monitoring decisions. In this review, we discuss with a multidisciplinary approach how to deliver the best benefit from advanced diabetes therapies and technologies to older adults with T2DM according to each patient profile. There remain however several areas that deserve further research in older adults with T2DM, including the efficacy and safety of continuous glucose monitoring and automated insulin delivery systems, the switch to once-weekly insulin, the effectiveness of multidisciplinary care models, and the use of supported telemedicine and remote blood glucose monitoring in the oldest-old (≥85 years) who particularly require the assistance of others.

The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.

Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.

Membrane estrogen receptor-α contributes to female protection against high-fat diet-induced metabolic disorders.

Background: Estrogen Receptor α (ERα) is a significant modulator of energy balance and lipid/glucose metabolisms. Beyond the classical nuclear actions of the receptor, rapid activation of intracellular signaling pathways is mediated by a sub-fraction of ERα localized to the plasma membrane, known as Membrane Initiated Steroid Signaling (MISS). However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified. Methods: Male and female C451A-ERα mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates (WT-ERα) were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). Body weight gain, body composition and glucose tolerance were monitored. Insulin sensitivity and energy balance regulation were further investigated in HFD-fed female mice. Results: C451A-ERα genotype had no influence on body weight gain, adipose tissue accumulation and glucose tolerance in NCD-fed mice of both sexes followed up to 7 months of age, nor male mice fed a HFD for 12 weeks. In contrast, compared to WT-ERα littermates, HFD-fed C451A-ERα female mice exhibited: 1) accelerated fat mass accumulation, liver steatosis and impaired glucose tolerance; 2) whole-body insulin resistance, assessed by hyperinsulinemic-euglycemic clamps, and altered insulin-induced signaling in skeletal muscle and liver; 3) significant decrease in energy expenditure associated with histological and functional abnormalities of brown adipose tissue and a defect in thermogenesis regulation in response to cold exposure. Conclusion: Besides the well-characterized role of ERα nuclear actions, membrane-initiated ERα extra-nuclear signaling contributes to female, but not to male, protection against HFD-induced obesity and associated metabolic disorders in mouse.

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial.

Importance: Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes. Objective: To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes. Design, Setting, and Participants: Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol). Interventions: Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294). Main Outcomes and Measures: The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes. Results: Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01). Conclusions and Relevance: Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups. Trial Registration: ClinicalTrials.gov Identifier: NCT04795531.

Combining glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM).

Due to their cardiovascular protective effect, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent breakthrough therapies for type 2 diabetes mellitus (T2DM). In this review article, we discuss the mechanistic and clinical synergies that make the combined use of GLP-1RAs and SGLT2is appealing in patients with T2DM. Overall, the presented cumulative evidence supports the benefits of GLP-1RA plus SGLT2i combination therapy on metabolic-cardiovascular-renal disease in patients with T2DM, with a low hypoglycemia risk. Accordingly, we encourage the adoption of GLP-1RA plus SGLT2i combination therapy in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (i.e., age ≥ 55 years, overweight/obesity, dyslipidemia, hypertension, current tobacco use, left ventricular hypertrophy, and/or proteinuria). Regarding renal effects, the evidence of SGLT2is in preventing kidney failure is more abundant than for GLP-1RAs, which showed a beneficial effect on albuminuria but not on hard kidney endpoints. Hence, in case of persistent albuminuria and/or uncontrolled metabolic risks (i.e., inadequate glycemic control, hypertension, overweight/obesity) on SGLT2i therapy, GLP-1RAs should be considered as the preferential add-on therapy in T2DM patients with chronic kidney disease. Despite the potential clinical benefits of GLP-1RA plus SGLT2i combination therapy in patients with T2DM, several factors may delay this combination to become a common practice soon, such as reimbursement and costs associated with polypharmacy. Altogether, when administering GLP-1RA plus SGLT2i combination therapy, it is important to adopt an individualized approach to therapy taking into account individual preferences, costs and coverage, toxicity profile, consideration of kidney function and glucose-lowering efficacy, desire for weight loss, and comorbidities.

Nocturnal hypoglycemia is underdiagnosed in older people with insulin-treated type 2 diabetes: The HYPOAGE observational study.

BACKGROUND: There is a lack of real-life data regarding the frequency and predictive factors of hypoglycemia in older patients with type 2 diabetes (T2D). This study aimed to determine the frequency and predictors of hypoglycemia in older patients with insulin-treated T2D. METHODS: This prospective multicenter study included 155 insulin-treated T2D patients aged 75 years and older with ≥2 self-monitoring of blood glucose (SMBG) daily controls. Participants underwent a geriatric and diabetic assessment and received ambulatory blinded continuous glucose monitoring (CGM) for 28 consecutive days with FreeStyle Libre Pro® sensor. Study population (n = 141) has >70% CGM active time. Multivariable logistic regressions were used to identify factors associated with SMBG confirmed hypoglycemia (≥70 mg/dL) and with nocturnal level 2 time below range (glucose concentration <54 mg/dL during ≥15 consecutive min between 0.00 and 6.00 am). RESULTS: The mean age of the 141 analyzed patients was 81.5 ± 5.3 years and 56.7% were male. The mean baseline HbA1c was 7.9% ± 1.0%. After geriatric assessment, 102 participants (72.3%) were considered as complex and 39 (27.7%) as healthy. The primary endpoint (confirmed SMBG <70 mg/dL) occurred in 37.6% patients. In multivariable analysis, the risk of SMBG-confirmed hypoglycemia was positively associated with a longer duration of diabetes (OR (+1 year) =1.04, (1.00-1.08), p = 0.04) and glycemic variability assessed by CGM (CV %) (OR (+1%) = 1.12, [1.05-1.19], p = <0.001). Nighty-two patients (65.2%) experienced nocturnal time in hypoglycemia (i.e., <54 mg/dL during ≥15 consecutive min between midnight and 6 a.m.). In multivariable analyses, cognitive impairment (OR: 9.31 [2.59-33.4]), heart failure (OR: 4.81 [1;48-15.6]), and depressive disorder (OR: 0.19 [0.06-0.53]) were associated with nocturnal time in hypoglycemia. CONCLUSION: Nocturnal hypoglycemia is very common and largely underdiagnosed in older patients with insulin-treated T2D. CGM is a promising tool to better identify hypoglycemia and adapt diabetes management in this population.

Glycaemic Control in People with Type 2 Diabetes Mellitus Switching from Basal Insulin to Insulin Glargine 300 U/ml (Gla-300): Results from the REALI Pooled Database.

INTRODUCTION: Using pooled data from the REALI European database, we evaluated the impact of previous basal insulin (BI) type on real-life effectiveness and safety of switching to insulin glargine 300 U/ml (Gla-300) in people with suboptimally controlled type 2 diabetes. METHODS: Patient-level data were pooled from 11 prospective, open-label, 24-week studies. Participants were classified according to the type of prior BI. Of the 4463 participants, 1282 (28.7%) were pre-treated with neutral protamine Hagedorn (NPH) insulin and 2899 (65.0%) with BI analogues (BIAs), and 282 (6.3%) had undetermined prior BI. RESULTS: There were no meaningful differences in baseline characteristics between subgroups, except for a higher prevalence of diabetic neuropathy in the NPH subgroup (21.6% versus 7.8% with BIAs). Mean ± standard deviation haemoglobin A1c (HbA1c) decreased from 8.73 ± 1.15% and 8.35 ± 0.95% at baseline to 7.71 ± 1.09% and 7.82 ± 1.06% at week 24 in the NPH and BIA subgroups, respectively. Least squares (LS) mean change in HbA1c was - 0.85% (95% confidence interval - 0.94 to - 0.77) in NPH subgroup and - 0.70% (- 0.77 to - 0.64) in BIA subgroup, with a LS mean absolute difference between subgroups of 0.16 (0.06-0.26; p = 0.002). Gla-300 mean daily dose was slightly increased at week 24 by 0.07 U/kg/day (approximately 6 U/day) in both subgroups. Incidences of symptomatic and severe hypoglycaemia were low, without body weight change. CONCLUSIONS: Irrespective of previous BI therapy (NPH insulin or BIAs), switching to Gla-300 improved glycaemic control without weight gain and with low symptomatic and severe hypoglycaemia incidences. However, a slightly greater glucose-lowering effectiveness was observed in people pre-treated with NPH insulin.

Associations of microvascular complications with all-cause death in patients with diabetes and COVID-19: The CORONADO, ABCD COVID-19 UK national audit and AMERICADO study groups.

AIM: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD-19. MATERIALS AND METHODS: We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID-19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all-cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID-19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer. RESULTS: Among 2951 CORONADO, 3387 ABCD COVID-19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all-cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66-3.83), OR 1.24 (95% CI 1.00-1.56) and OR 1.66 (95% CI 1.40-1.95) in the CORONADO, the ABCD COVID-19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all-cause death during hospital stay in the CORONADO, the ABCD COVID-19 diabetes national audit and the AMERICADO studies: adjusted OR (adj OR) 2.57 (95% CI 1.69-3.92), adj OR 1.22 (95% CI 1.00-1.52) and adj OR 1.33 (95% CI 1.15-1.53), respectively. In meta-analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all-cause death during hospital stay of 2.05 (95% CI 1.42-2.97), which decreased to 1.62 (95% CI 1.19-2.119) after adjustment for age and sex, and to 1.50 (1.12-2.02) after hypertension and CVD were further added to the model. CONCLUSION: Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID-19.

Initiation of the Fixed Combination IDegLira in Patients with Type 2 Diabetes on Prior Injectable Therapy: Insights from the EASY French Real-World Study.

INTRODUCTION: Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system. METHODS: A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers. Baseline characteristics, reasons for IDegLira initiation, and modes of implementation were collected from the medical records. Changes in HbA1c and body weight were determined in patients with available follow-up data (nearest 6-month visit). RESULTS: IDegLira was initiated in 629 patients previously treated with GLP-1RA alone (11.6%), insulin alone (31.5% including 16.5% with BI and 14.9% with multiple daily injections [MDI]) or a free combination of GLP-1RA and insulin (56.9% including 44.8% with BI and 12.1% with MDI), associated or not with oral agents. IDegLira starting dose (mean of 29 ± 11 dose steps) most often exceeded the recommended dose, and was significantly correlated with prior BI but not GLP-1RA dosage. At initiation, mean age, body mass index (BMI) and HbA1c were 60.1 ± 10.2 years, 33.4 ± 6.2 kg/m2 and 8.8 ± 1.7%, respectively. In 461 patients with available follow-up (median 178 days), HbA1c decreased in all subgroups submitted to treatment intensification (- 1.7 ± 1.8% [p < 0.0001], - 1.2 ± 1.8% [p < 0.001] and - 0.8 ± 1.8% [p = 0.0026] in patients with prior GLP-1RA, BI or MDI therapy, respectively) but also in those switching from BI and GLP-1RA free combination (- 0.2 ± 0.9%, p = 0.0419). Significant body weight gain occurred in patients previously treated with GLP-1RA alone (+ 1.5 ± 5.8 kg, p = 0.0572) or combined to BI (+ 1.0 ± 3.1 kg, p < 0.0001) while those on BI (- 1.4 ± 4.6 kg, p = 0.0139) or MDI (- 1.4 ± 5.0 kg, p = 0.0484) experienced weight loss. CONCLUSIONS: While providing new information on the use of IDegLira in the French healthcare system, these data confirm the effectiveness of this fixed-ratio combination in the management of T2D.

The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19).

BACKGROUND: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. METHODS: We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020-October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. RESULTS: Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83-2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29-1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31-0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40-0.68], I2 37%) were significantly lower for people with previous macrovascular disease. CONCLUSIONS: This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity.

In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the ß3-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.

Impact of diabetes on COVID-19 prognosis beyond comorbidity burden: the CORONADO initiative.

AIMS/HYPOTHESIS: Diabetes has been recognised as a pejorative prognostic factor in coronavirus disease 2019 (COVID-19). Since diabetes is typically a disease of advanced age, it remains unclear whether diabetes remains a COVID-19 risk factor beyond advanced age and associated comorbidities. We designed a cohort study that considered age and comorbidities to address this question. METHODS: The Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) initiative is a French, multicentric, cohort study of individuals with (exposed) and without diabetes (non-exposed) admitted to hospital with COVID-19, with a 1:1 matching on sex, age (±5 years), centre and admission date (10 March 2020 to 10 April 2020). Comorbidity burden was assessed by calculating the updated Charlson comorbidity index (uCCi). A predefined composite primary endpoint combining death and/or invasive mechanical ventilation (IMV), as well as these two components separately, was assessed within 7 and 28 days following hospital admission. We performed multivariable analyses to compare clinical outcomes between patients with and without diabetes. RESULTS: A total of 2210 pairs of participants (diabetes/no-diabetes) were matched on age (mean±SD 69.4±13.2/69.5±13.2 years) and sex (36.3% women). The uCCi was higher in individuals with diabetes. In unadjusted analysis, the primary composite endpoint occurred more frequently in the diabetes group by day 7 (29.0% vs 21.6% in the no-diabetes group; HR 1.43 [95% CI 1.19, 1.72], p<0.001). After multiple adjustments for age, BMI, uCCi, clinical (time between onset of COVID-19 symptoms and dyspnoea) and biological variables (eGFR, aspartate aminotransferase, white cell count, platelet count, C-reactive protein) on admission to hospital, diabetes remained associated with a higher risk of primary composite endpoint within 7 days (adjusted HR 1.42 [95% CI 1.17, 1.72], p<0.001) and 28 days (adjusted HR 1.30 [95% CI 1.09, 1.55], p=0.003), compared with individuals without diabetes. Using the same adjustment model, diabetes was associated with the risk of IMV, but not with risk of death, within 28 days of admission to hospital. CONCLUSIONS/INTERPRETATION: Our results demonstrate that diabetes status was associated with a deleterious COVID-19 prognosis irrespective of age and comorbidity status. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324736.

Association of statin and/or renin-angiotensin-aldosterone system modulating therapy with mortality in adults with diabetes admitted to hospital with COVID-19: A retrospective multicentre European study.

BACKGROUND & AIMS: To assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with pre-existing diabetes. METHODS: Retrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19 pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis. RESULTS: Complete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25-50% neither RAASi nor statin therapy, 14-36% both RAASi and statin therapy, 9-24% RAASi therapy alone, 12-36% statin alone. Overall, 20-37% of patients died within 28 days. Meta-analysis found no evidence of an association between mortality and prescription of RAASi therapy (OR 1.09, CI 0.78-1.52 (I2 22.2%)), statin (OR 0.97, CI 0.59-1.61 (I2 72.9%)) or both (OR 1.14, CI 0.67-1.92 (I2 78.3%)) compared to those prescribed neither drug class. CONCLUSIONS: This large multicentre, multinational study found no evidence of an association between mortality from COVID-19 infection in people with diabetes and use of either RAASi, statin or combination therapy. This provides reassurance that clinicians should not change their RAASi and statin therapy prescribing practice in people with diabetes during the COVID-19 pandemic.

The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.

Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated. Insulin action partly depends on changes in insulin receptor (IR)-dependent gene expression. Here, we use hepatocyte-restricted gene deletion of IR to evaluate its role in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in the adult mouse liver. We find that, in the absence of IR, the rhythmicity of core-clock gene expression is altered in response to day-restricted feeding. This change in core-clock gene expression is associated with defective reprogramming of liver gene expression. Our data show that an intact hepatocyte insulin receptor is required to program the liver clock and associated rhythmic gene expression.

Cost-Effectiveness Evaluation of a Remote Monitoring Programme Including Lifestyle Education Software in Type 2 Diabetes: Results of the Educ@dom Study.

INTRODUCTION: Telemedicine programs using health technological innovation to remotely monitor the lifestyles of patients with type 2 diabetes (T2D) can improve glycaemic control and thus reduce the incidence of complications as well as management costs. In this context, an assessment was made of the 1-year and 2-year cost-effectiveness of the EDUC@DOM telemonitoring and tele-education program. METHODS: The EDUC@DOM study was a multicentre randomized controlled trial conducted between 2013 and 2017 that compared a telemonitoring group (TMG) to a control group (CG) merged with health insurance databases to extract economic data on resource consumption. Economic analysis was performed from the payer perspective, and direct costs and indirect costs were considered. The clinical outcome used was the intergroup change in glycated haemoglobin (HbA1c) levels from baseline. Missing economic data were imputed using multiple imputation, and fitted values from a generalized linear mixed model were used to calculate the incremental cost-effectiveness ratio (ICER). Bootstrapped 95% confidence ellipses were drawn in the cost-effectiveness plan. RESULTS: The main analysis included data from 256 patients: 126 in the TMG and 130 in the CG. Incremental costs over 1 and 2 years were equal to €2129 and €5101, respectively, in favour of the TMG. Once imputed and adjusted for confounding factors, the TMG trends to a 21% cost decrease over 1 and 2 years of follow-up (0.79 [0.58; 1.08], p = 0.1452 and 0.79 [0.61; 1.03], p = 0.0879, respectively). The EDUC@DOM program led to a €1334 cost saving and a 0.17 decrease in HbA1c over 1 year and a €3144 cost saving and a 0.14 decrease in HbA1c over 2 years. According to the confidence ellipse, EDUC@DOM was a cost-effective strategy. CONCLUSION: This study provides additional economic information on telemonitoring and tele-education programs to enhance their acceptance and promote their use. In the light of this work, the EDUC@DOM program is a cost-saving strategy in T2D management. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Database on 27 September 2013 under no. NCT01955031 and bears ID-RCB no. 2013-A00391-44.