Rationale, design, and methods for the Medical Optimization and Management of Pregnancies with Overt Type 2 Diabetes (MOMPOD) study

IntroductionInvestigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year.Research design and methodsIn this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight.ResultsIn total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were included in the 24-week extension (mean A1C of 7.0% and 7.3%, respectively, at week 28). From weeks 28–52, patients who switched from exenatide two times per day to exenatide QWS-AI had additional A1C reductions of approximately 0.5% (mean A1C change from baseline of –1.4% at week 52) and further reductions from baseline in FPG. Patients who continued exenatide QWS-AI treatment for 52 weeks showed clinically relevant A1C reductions (mean A1C change from baseline of –1.3% at week 52). Body-weight reductions achieved through week 28 were sustained at week 52 in both groups. There were no unexpected safety concerns or changes in the safety profile among patients who switched from exenatide two times per day to exenatide QWS-AI or those who continued exenatide QWS-AI treatment for 52 weeks.ConclusionsSwitching from exenatide two times per day to exenatide QWS-AI resulted in further A1C reductions and maintenance of earlier decreases in body weight, while continued therapy with exenatide QWS-AI for 52 weeks maintained A1C and body-weight reductions, without additional safety or tolerability concerns.Trial registration numberNCT01652716.

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Increased stress, weight gain and less exercise in relation to glycemic control in people with type 1 and type 2 diabetes during the COVID-19 pandemic

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-002035 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002035

Author(s):

Merel M Ruissen ◽

Hannah Regeer ◽

Cyril P Landstra ◽

Marielle Schroijen ◽

Ingrid Jazet ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Weight Gain ◽

Glycemic Control ◽

Perceived Stress ◽

Medical Center ◽

Short Term ◽

Design And Methods

IntroductionLockdown measures have a profound effect on many aspects of daily life relevant for diabetes self-management. We assessed whether lockdown measures, in the context of the COVID-19 pandemic, differentially affect perceived stress, body weight, exercise and related this to glycemic control in people with type 1 and type 2 diabetes.Research design and methodsWe performed a short-term observational cohort study at the Leiden University Medical Center. People with type 1 and type 2 diabetes ≥18 years were eligible to participate. Participants filled out online questionnaires, sent in blood for hemoglobin A1c (HbA1c) analysis and shared data of their flash or continuous glucose sensors. HbA1c during the lockdown was compared with the last known HbA1c before the lockdown.ResultsIn total, 435 people were included (type 1 diabetes n=280, type 2 diabetes n=155). An increase in perceived stress and anxiety, weight gain and less exercise was observed in both groups. There was improvement in glycemic control in the group with the highest HbA1c tertile (type 1 diabetes: −0.39% (−4.3 mmol/mol) (p<0.0001 and type 2 diabetes: −0.62% (−6.8 mmol/mol) (p=0.0036). Perceived stress was associated with difficulty with glycemic control (p<0.0001).ConclusionsAn increase in perceived stress and anxiety, weight gain and less exercise but no deterioration of glycemic control occurs in both people with relatively well-controlled type 1 and type 2 diabetes during short-term lockdown measures. As perceived stress showed to be associated with glycemic control, this provides opportunities for healthcare professionals to put more emphasis on psychological aspects during diabetes care consultations.

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Plasma heat shock protein response to euglycemia in type 2 diabetes

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-002057 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002057

Author(s):

Alexander S Atkin ◽

Abu Saleh Md Moin ◽

Ahmed Al-Qaissi ◽

Thozhukat Sathyapalan ◽

Stephen L Atkin ◽

...

Keyword(s):

Type 2 Diabetes ◽

Heat Shock ◽

Protein Interactions ◽

Glucose Variability ◽

Interacting Protein ◽

Ubiquitin Conjugating Enzyme ◽

Shock Proteins ◽

Protein Response ◽

Design And Methods

IntroductionGlucose variability is associated with mortality and macrovascular diabetes complications. The mechanisms through which glucose variability mediates tissue damage are not well understood, although cellular oxidative stress is likely involved. As heat shock proteins (HSPs) play a role in the pathogenesis of type 2 diabetes (T2D) complications and are rapidly responsive, we hypothesized that HSP-related proteins (HSPRPs) would differ in diabetes and may respond to glucose normalization.Research design and methodsA prospective, parallel study in T2D (n=23) and controls (n=23) was undertaken. T2D subjects underwent insulin-induced blood glucose normalization from baseline 7.6±0.4 mmol/L (136.8±7.2 mg/dL) to 4.5±0.07 mmol/L (81±1.2 mg/dL) for 1 hour. Control subjects were maintained at 4.9±0.1 mmol/L (88.2±1.8 mg/dL). Slow Off-rate Modified Aptamer-scan plasma protein measurement determined a panel of HSPRPs.ResultsAt baseline, E3-ubiquitin-protein ligase (carboxyl-terminus of Hsc70 interacting protein (CHIP) or HSPABP2) was lower (p=0.03) and ubiquitin-conjugating enzyme E2G2 higher (p=0.003) in T2D versus controls. Following glucose normalization, DnaJ homolog subfamily B member 1 (DNAJB1 or HSP40) was reduced (p=0.02) in T2D, with HSP beta-1 (HSPB1) and HSP-70-1A (HSP70-1A) (p=0.07 and p=0.09, respectively) also approaching significance relative to T2D baseline levels.ConclusionsKey HSPRPs involved in critical protein interactions, CHIP and UBE2G2, were altered in diabetes at baseline. DNAJB1 fell in response to euglycemia, suggesting that HSPs are reacting to basal stress that could be mitigated by tight glucose control with reduction of glucose variability.

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TheType 2 Deiodinase Thr92Ala PolymorphismIs Associated with Worse Glycemic Control in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Journal of Diabetes Research ◽

10.1155/2016/5928726 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Xiaowen Zhang ◽

Jie Sun ◽

Wenqing Han ◽

Yaqiu Jiang ◽

Shiqiao Peng ◽

...

Keyword(s):

Diabetes Mellitus ◽

Systematic Review ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Glycemic Control ◽

Meta Analysis ◽

Increased Risk ◽

Design And Methods ◽

Hba1c Levels

Objective. Type 2 deiodinase (Dio2) is an enzyme responsible for the conversion of T4 to T3. The Thr92Ala polymorphism has been shown related to an increased risk for developing type 2 diabetes mellitus (T2DM). The aim of this study is to assess the association between this polymorphism and glycemic control in T2DM patients as marked by the HbA1C levels.Design and Methods.The terms “rs225014,” “thr92ala,” “T92A,” or “dio2 a/g” were used to search for eligible studies in the PubMed, Embase, and Cochrane databases and Google Scholar. A systematic review and meta-analysis of studies including both polymorphism testing and glycated hemoglobin (HbA1C) assays were performed.Results. Four studies were selected, totaling 2190 subjects. The pooled mean difference of the studies was 0.48% (95% CI, 0.18–0.77%), indicating that type 2 diabetics homozygous for the Dio2 Thr92Ala polymorphism had higher HbA1C levels.Conclusions. Homozygosity for the Dio2 Thr92Ala polymorphism is associated with higher HbA1C levels in T2DM patients. To confirm this conclusion, more studies of larger populations are needed.

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

10.2337/figshare.13369553 ◽

2021 ◽

Author(s):

Lawrence Blonde ◽

Julio Rosenstock ◽

Juan Frias ◽

Andreas L. Birkenfeld ◽

Elisabeth Niemoeller ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fixed Ratio ◽

Efficacy And Safety ◽

Open Label ◽

Once Daily ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Design And Methods ◽

Extension Period

Objective <a>In the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine </a>100 units/mL and the glucagon-like peptide-1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes (T2D) 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 T2D uncontrolled by GLP-1 RAs (HbA1c 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 endpoint 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 HbA1c 6.7 % [50 mmol/mol]) was maintained at week 52 (mean HbA1c 6.7 % [50 mmol/mol]; mean ± standard deviation change from baseline at week 52: −1.0 ± 0.9 % [11 ± 10 mmol/mol]). Proportions of participants reaching HbA1c <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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Type 2 Diabetes Subtype Responsive to ACCORD Intensive Glycemia Treatment

10.2337/figshare.14109806.v2 ◽

2021 ◽

Author(s):

Arshiya Mariam ◽

Galen Miller-Atkins ◽

Kevin M. Pantalone ◽

Robert S. Zimmerman ◽

John Barnard ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Controlled Trial ◽

Clinical Group ◽

Cvd Risk ◽

Group 4 ◽

Novel Approach ◽

Genome Wide ◽

Design And Methods

Objective Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk, and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. Research Design and Methods ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D reduced CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. Results We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD outcomes (HR=0.34, P=2.01x10-3) and microvascular outcomes (HR=0.86, P=.015) than standard treatment. A single nucleotide polymorphism, rs220721, in MAS1, reached suggestive significance with C4 (P=4.34x10-7). The PS predicted C4 with high accuracy (AUC=0.98), and predicted C4 displayed reduced CVD risk on intensive versus standard glycemia treatment (HR=0.53, P=4.02x10-6), but not for microvascular outcomes (P<.05). Mendelian randomization indicated causality between the PS, on-trial HbA1c, and reduction in CVD outcomes (P<.05). Conclusions We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership of this group can be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development for this landmark clinical trial warranting further investigation.

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Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults with Overweight or Obesity and Type 2 Diabetes Mellitus: A 54-Week Randomized Phase 2b Study

10.2337/figshare.14272955.v1 ◽

2021 ◽

Author(s):

Rajaa Nahra ◽

Tao Wang ◽

Kishore M. Gadde ◽

Jan Oscarsson ◽

Michael Stumvoll ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Body Weight ◽

Ad Hoc ◽

Open Label ◽

Double Blind ◽

Glucagon Receptor ◽

Nonalcoholic Fatty Liver ◽

Design And Methods

<a>Objective: </a>Cotadutide, a <a>dual GLP-1 and glucagon receptor agonist</a>, is under development for nonalcoholic steatohepatitis (NASH) and type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes. Research Design and Methods: In this phase 2b study, 834 adults with BMI ≥25kg/m2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A1c [HbA1c] of 7.0%─10.5% [53─91 mmol/mol]) were randomized to double-blind cotadutide 100µg (n=100), 200µg (n=256), or 300µg (n=256), placebo (n=110), or open-label liraglutide 1.8mg (n=110), all administered subcutaneously (NCT03235050). Coprimary endpoints were changes in HbA1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed. Results: Cotadutide significantly decreased HbA1c and body weight at weeks 14 and 54 versus placebo (all P<0.001). Improvements in lipid profile, aspartate aminotransferase and alanine aminotransferase levels, <a>PRO-C3 level, fibrosis-4 index</a>, and <a>nonalcoholic fatty liver disease fibrosis score</a> were observed with cotadutide 300µg versus placebo, but not with liraglutide. Weight loss with cotadutide 200µg was similar to liraglutide 1.8mg, and greater with cotadutide 300µg versus liraglutide 1.8mg. <a>The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time. </a> Conclusions: Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.

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Profibrotic circulating proteins and risk of early progressive renal decline in Type 2 Diabetes patients with and without albuminuria

10.2337/figshare.12808433.v1 ◽

2020 ◽

Author(s):

Katsuhito Ihara ◽

Jan Skupien ◽

Hiroki Kobayashi ◽

Zaipul I. Md Dom ◽

Jonathan M. Wilson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Core Domain ◽

Fibrotic Process ◽

Baseline Levels ◽

Design And Methods ◽

Circulating Levels ◽

Index Combination

OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and MMP-7 (Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with eGFR ≥60 ml/min/1.73m2 were followed for 6-12 years to ascertain fast early progressive renal decline defined as eGFR loss ≥5 ml/min/1.73m2/year. RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and ACR at baseline were 97 ml/min/1.73m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups risk of renal decline increased with increasing baseline levels of WFDC2 (p <0.0001) and MMP-7 (p <0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the Fibrosis Index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (OR 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria. CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in development of early renal decline.

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Plasma Trimethylamine N-Oxide and Risk of Cardiovascular Events in Patients With Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa188 ◽

2020 ◽

Vol 105 (7) ◽

pp. 2371-2380 ◽

Cited By ~ 1

Author(s):

Mikael Croyal ◽

Pierre-Jean Saulnier ◽

Audrey Aguesse ◽

Elise Gand ◽

Stéphanie Ragot ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Tumor Necrosis Factor Receptor ◽

Density Lipoprotein ◽

Major Adverse Cardiovascular Events ◽

Cox Models ◽

Increased Risk ◽

All Cause Mortality ◽

Design And Methods

Abstract Objective Even though trimethylamine N-oxide (TMAO) has been demonstrated to interfere with atherosclerosis and diabetes pathophysiology, the association between TMAO and major adverse cardiovascular events (MACE) has not been specifically established in type 2 diabetes (T2D). Research Design and Methods We examined the association of plasma TMAO concentrations with MACE and all-cause mortality in a single-center prospective cohort of consecutively recruited patients with T2D. Results The study population consisted in 1463 SURDIENE participants (58% men), aged 65 ± 10 years. TMAO concentrations were significantly associated with diabetes duration, renal function, high-density lipoprotein cholesterol, soluble tumor necrosis factor receptor 1 (sTNFR1) concentrations (R2 = 0.27) and were significantly higher in patients on metformin, even after adjustment for estimated glomerular filtration rate (eGFR): 6.7 (8.5) vs 8.5 (13.6) µmol/L, respectively (PeGFR-adjusted = 0.0207). During follow-up (median duration [interquartile range], 85 [75] months), 403 MACE and 538 deaths were registered. MACE-free survival and all-cause mortality were significantly associated with the quartile distribution of TMAO concentrations, patients with the highest TMAO levels displaying the greatest risk of outcomes (P < 0.0001). In multivariate Cox models, compared with patients from the first 3 quartiles, those from the fourth quartile of TMAO concentration had an independently increased risk for MACE: adjusted hazard ratio (adjHR) 1.32 (1.02-1.70); P = 0.0325. Similarly, TMAO was significantly associated with mortality in multivariate analysis: adjHR 1.75 (1.17-2.09); P = 0.0124, but not when sTNFR1 and angiopoietin like 2 were considered: adjHR 1.16 (0.95-1.42); P = 0.1514. Conclusions We revealed an association between higher TMAO concentrations and increased risk of MACE and all-cause mortality, thereby opening some avenues on the role of dysbiosis in cardiovascular risk, in T2D patients.

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Incidence and outcomes of hospitalization for community-acquired, ventilator-associated and non-ventilator hospital-acquired pneumonias in patients with type 2 diabetes mellitus in Spain

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001447 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001447

Author(s):

Ana Lopez-de-Andres ◽

Romana Albadalejo-Vicente ◽

Javier de Miguel-Diez ◽

Valentin Hernandez-Barrera ◽

Zichen Ji ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Incidence Rates ◽

Community Acquired Pneumonia ◽

Older Age ◽

Hospital Acquired Pneumonia ◽

Design And Methods ◽

Hospital Acquired

IntroductionTo describe the incidence and compare in-hospital outcomes of community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP) and non-ventilator hospital-acquired pneumonia (NV-HAP) among patients with or without type 2 diabetes mellitus (T2DM) using propensity score matching.Research design and methodsThis was a retrospective observational epidemiological study using the 2016–2017 Spanish Hospital Discharge Records.ResultsOf 245 221 admissions, CAP was identified in 227 524 (27.67% with T2DM), VAP was identified in 2752 (18.31% with T2DM) and NV-HAP was identified in 14 945 (25.75% with T2DM). The incidence of pneumonia was higher among patients with T2DM (CAP: incidence rate ratio (IRR) 1.44, 95% CI 1.42 to 1.45; VAP: IRR 1.24, 95% CI 1.12 to 1.37 and NV-HAP: IRR 1.38, 95% CI 1.33 to 1.44). In-hospital mortality (IHM) for CAP was 12.74% in patients with T2DM and 14.16% in matched controls (p<0.001); in patients with VAP and NV-HAP, IHM was not significantly different between those with and without T2DM (43.65% vs 41.87%, p=0.567, and 29.02% vs 29.75%, p=0.484, respectively). Among patients with T2DM, older age and dialysis were factors associated with IHM for all types of pneumonia. In patients with VAP, the risk of IHM was higher in females (OR 1.95, 95% CI 1.28 to 2.96).ConclusionThe incidence rates of all types of pneumonia were higher in patients with T2DM. Higher mortality rates in patients with T2DM with any type of pneumonia were associated with older age, comorbidities and dialysis.

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