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Diabet Med. 2018 Nov 13. doi: 10.1111/dme.13863. [Epub ahead of print]

Associations of dietary macronutrient and fibre intake with glycaemia in individuals with Type 1 diabetes.

Author information

1
Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland.
2
Abdominal Centre Nephrology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
3
Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
4
National Institute for Health and Welfare, Chronic Disease Prevention Unit, Helsinki, Finland.
5
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Vic, Australia.

Abstract

AIMS:

To study the association between dietary intake and glycaemia in Type 1 diabetes.

METHODS:

Data on energy and nutrient intakes, and the mean and coefficient of variation of self-monitored blood glucose measurements were obtained from records completed by 1000 adults with Type 1 diabetes. Associations between these measures of glycaemia and dietary intake were investigated using generalized linear regression, with and without macronutrient substitution.

RESULTS:

In the first set of analyses, fibre intake was associated with lower mean self-monitored blood glucose values (β = -0.428, 95% CI -0.624 to -0.231; P<0.001). In these same analyses, carbohydrate (β = 0.011, 95% CI 0.002 to 0.020; P=0.014), alcohol (β = 0.013, 95% CI 0.003 to 0.023; P=0.009) and monounsaturated fatty acid intakes (β=0.012, 95% CI 0.001 to 0.023; P=0.029) were associated with higher variability in blood glucose measurements. In the macronutrient substitution analyses, substituting proteins for either carbohydrates (β = -0.026, 95% CI -0.040 to -0.013; P<0.001), fats (β = -0.018, 95% CI -0.033 to -0.004; P=0.014), or alcohol (β = -0.026, 95% CI -0.045 to -0.006; P=0.010), or fats for carbohydrates (β=-0.009, 95% CI -0.017 to -0.001; P=0.030), were all associated with lower variability in the measured blood glucose values. After adjusting for fibre intake, no significant results were observed in analyses of mean self-monitored blood glucose.

CONCLUSIONS:

This observational, cross-sectional study indicates that dietary fibre is associated with lower mean blood glucose concentrations in people with Type 1 diabetes. Glycaemic excursions were reduced when protein was substituted for other macronutrients and when fat replaced carbohydrate, after adjusting for fibre intake.

PMID:
30426566
DOI:
10.1111/dme.13863
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4.
Diabet Med. 2018 Nov 13. doi: 10.1111/dme.13862. [Epub ahead of print]

Carbohydrate restriction for glycaemic control in Type 2 diabetes: a systematic review and meta-analysis.

Author information

1
Birmingham Community Nutrition, Birmingham Community Healthcare NHS Foundation Trust, Birmingham, UK.
2
Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
3
Imperial College Healthcare NHS Trust, London, UK.
4
Warwick Medical School, University of Warwick, Coventry, UK.

Abstract

AIM:

To conduct a systematic review and meta-analysis to evaluate the effect of carbohydrate restriction on glycaemic control in Type 2 diabetes.

METHODS:

We searched Medline, EMBASE and CINAHL for the period between 1976 and April 2018. We included randomized controlled trials comparing carbohydrate restriction with a control diet which aimed to maintain or increase carbohydrate intake, and that reported HbA1c as an outcome and reported the amount of carbohydrate consumed during or at the end of the study, with outcomes reported at ≥3 months.

RESULTS:

We identified 1402 randomized controlled trials, 25 of which met the inclusion criteria, incorporating 2132 participants for the main outcome. Definitions of low carbohydrate varied among the studies. The pooled effect estimate from meta-analysis was a weighted mean difference of -0.09% [95% CI -0.27, 0.08 (P = 0.30); I2 72% (P <0.001)], suggesting no effect on HbA1c of restricting the quantity of carbohydrate. A subgroup analysis of diets containing 50-130 g carbohydrate resulted in a pooled effect estimate of -0.49% [95% CI -0.75, -0.23 (P <0.001); I2 0% (P = 0.56)], suggesting a clinically and statistically significant effect on HbA1c in favour of low-carbohydrate diets in studies of ≤6 months' duration.

CONCLUSIONS:

There was no overall pooled effect on HbA1c in favour of restricting carbohydrate; however, restriction of carbohydrate to 50-130 g per day had beneficial effects on HbA1c in trials up to 6 months. Future randomized controlled trials should be of >12 months' duration, assess pre-study carbohydrate intake, use recognized definitions of low-carbohydrate diets and examine reasons for non-adherence to prescribed diets in greater detail.

PMID:
30426553
DOI:
10.1111/dme.13862
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5.
Diabetes. 2018 Nov 13. pii: db180838. doi: 10.2337/db18-0838. [Epub ahead of print]

The Familiality of Rapid Renal Decline in Diabetes.

Author information

1
Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
2
Population Science, Huntsman Cancer Institute , University of Utah School of Medicine, Salt Lake City, Utah.
3
Hospital Information Technology Services, Enterprise Data Warehouse, University of Utah Hospital and Clinics, Salt Lake City, Utah.
4
Division of Nephrology, Intermountain Healthcare, Salt Lake City, Utah.
5
Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
6
Medicine Section and Research Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah.
7
Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah; marcus.pezzolesi@hsc.utah.edu.
8
Diabetes and Metabolism Center, University of Utah School of Medicine, Salt Lake City, Utah.

Abstract

Sustained and rapid loss of glomerular filtration rate (GFR) is the predominant clinical feature of diabetic kidney disease and a requisite for the development of end-stage renal disease. While GFR trajectories have been studied in several diabetic and non-diabetic cohorts, whether rapid renal decline clusters in diabetic families has not been examined. To determine this, we estimated GFR (eGFR) from serum creatinine measurements obtained from 15,612 patients with diabetes at the University of Utah Health Sciences Center and established their renal function trajectories. Patients with rapid renal decline (eGFR slope <-5 ml/min/1.73m2/year) were then mapped to pedigrees using extensive genealogical records from the Utah Population Database to identify high-risk rapid renal decline pedigrees. We identified 2,127 (13.6%) rapid decliners with a median eGFR slope of -8.0 mL/min/1.73m2/year and 51 high-risk pedigrees (ranging in size from 1,450-24,501 members) with excess clustering of rapid renal decline. Familial analysis showed that rapid renal decline aggregates in these families and is associated with its increased risk among first-degree relatives. Further study of these families is necessary to understand the magnitude of the influence of shared familial factors, including environmental and genetic factors, on rapid renal decline in diabetes.

PMID:
30425064
DOI:
10.2337/db18-0838
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6.
Diabetes. 2018 Nov 13. pii: db180845. doi: 10.2337/db18-0845. [Epub ahead of print]

NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation.

Author information

1
Department of Surgery, Division of Urology, Duke University Medical Center, Durham, NC. monty.hughes@duke.edu.
2
Department of Bioengineering. Clemson University. Clemson, SC.
3
Department of Surgery, Division of Urology, Duke University Medical Center, Durham, NC.
4
Duke Cancer Center Biostatistics, Duke University Medical Center, Durham, NC.
5
Department of Pediatrics, Duke University Medical Center, Durham, NC.

Abstract

The NLRP3 inflammasome senses diabetic metabolites and initiates inflammation implicated in diabetic complications and neurodegeneration. No studies have investigated NLRP3 in diabetic bladder dysfunction (DBD), despite a high clinical prevalence. In vitro, we found that numerous diabetic metabolites activate NLRP3 in primary urothelial cells. In vivo we demonstrate NLRP3 is activated in urothelia from a genetic Type 1 diabetic mouse (Akita) by week 15. We then bred a NLRP3-/- genotype into these mice and found this blocked bladder inflammation and cystometric markers of DBD. Analysis of bladder innervation established an NLRP3-dependent decrease in overall nerve density and Aδ-fibers in the bladder wall along with an increase in C-fiber populations in the urothelia, which potentially explains the decreased sense of bladder fullness reported by patients and overactivity detected early in DBD. Together, the results demonstrate the role of NLRP3 in the genesis of DBD and suggest specific NLRP3-mediated neuronal changes can produce specific DBD symptoms.

PMID:
30425063
DOI:
10.2337/db18-0845
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7.
Diabetes. 2018 Nov 13. pii: db180712. doi: 10.2337/db18-0712. [Epub ahead of print]

Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy.

Author information

1
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia; zhonglin.chai@monash.edu.
2
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
3
Ozgene Pty Ltd, Bentley, Western Australia, Australia.
4
Department of Commercialization, Baker Heart and Diabetes Institute, Melbourne, Australia.
5
Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, China.

Abstract

Targeting Cell Division Autoantigen 1 (CDA1) is postulated to attenuate the profibrotic actions of transforming growth factor-β in diabetic nephropathy. This study has identified a regulatory protein for CDA1 and has then used genetic and pharmacological approaches to test in vivo if strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1, was identified as critical in regulating the profibrotic activity of CDA1. Genetic deletion of CDA1BP1 attenuated key parameters of renal fibrosis in diabetic mice. Furthermore, a series of short synthetic CDA1BP1 peptides competitively inhibited CDA1-CDA1BP1 binding in vitro with a hybrid peptide, CHA-050, containing a 12mer CDA1BP1 peptide and a previously known "Cell Penetrating Peptide", dose-dependently reducing expression of collagens I and III in HK-2 cells. In vivo, a D-amino acid retro-inverso peptide, CHA-061, significantly attenuated diabetes-associated increases in renal expression of genes involved in fibrotic and pro-inflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes associated molecular and pathological changes within the kidney. Specifically, CHA-061 attenuated significantly renal extracellular matrix accumulation and glomerular injury. Taken together, targeting the CDA1/CDA1BP1 axis is a safe, efficacious and feasible approach to retard experimental diabetic nephropathy.

PMID:
30425061
DOI:
10.2337/db18-0712
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8.
Diabetes Care. 2018 Dec;41(12):2648-2668. doi: 10.2337/dci18-0052.

Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association.

Author information

1
Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA silva.arslanian@chp.edu.
2
Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
3
Children's Nutrition Research Center, Texas Children's Hospital and Baylor College of Medicine, Houston, TX.
4
Yale School of Nursing, New Haven, CT.
5
Yale School of Medicine, New Haven, CT.
6
University of Pittsburgh School of Medicine, Pittsburgh, PA.
7
Washington University School of Medicine in St. Louis, St. Louis, MO.
8
Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO.

Publication type

Publication type

9.
J Clin Endocrinol Metab. 2018 Nov 13. doi: 10.1210/jc.2018-01000. [Epub ahead of print]

Plasma acylcarnitines and risk of type 2 diabetes in a Mediterranean population at high cardiovascular risk.

Author information

1
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
2
Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Health Research Institute, Rovira i Virgili University, Reus, Spain.
3
CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
4
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
5
University of Navarra, Department of Preventive Medicine and Public Health, IDISNA (Health Research Institute of Navarra), Pamplona, Spain.
6
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7
State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
8
Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
9
Department of Preventive Medicine, University of Valencia, Valencia, Spain.
10
Department of Internal Medicine, Department of Endocrinology and Nutrition Biomedical Research Institute August Pi Sunyer (IDI- BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
11
Lipid Clinic, Department of Endocrinology and Nutrition Biomedical Research Institute August Pi Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
12
Cardiovascular and Nutrition Research Group (Regicor Study Group), Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
13
Department of Cardiology, OSI ARABA. University Hospital, University of the Basque Country UPV/EHU. Vitoria-Gasteiz. Spain.
14
Institute of Health Sciences IUNICS, University of Balearic Islands and Hospital Son Espases, Palma de Mallorca, Spain.
15
Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain.
16
Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria and Service of Preventive Medicine, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Canary Health Service, Las Palmas de Gran Canaria, Spain.
17
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Abstract

Context:

The potential associations between acylcarnitine profiles and incidence of T2D, and whether acylcarnitines can be used to improve diabetes prediction remains unclear.

Objective:

To evaluate the associations between baseline and 1-year changes in acylcarnitines, and their diabetes predictive ability beyond traditional risk factors.

Design, setting and participants:

We designed a case-cohort study within the PREDIMED Study including all incident cases of T2D(n=251) and 694 randomly selected participants at baseline(follow-up:3.8-years).Plasma acylcarnitines were measured using a targeted approach by liquid chromatography-tandem mass spectrometry(LC-MS).We tested the associations between baseline and 1-year changes in individual acylcarnitines and T2D risk using weighted Cox regression models.We used elastic net regressions to select acylcarnitines for T2D prediction and compute a weighted score using a cross-validation approach.

Results:

An acylcarnitine profile, especially including short-chain and long-chain, was significantly associated with a higher risk of T2D independent of traditional risk factors.The relative risk of T2D per SD increment of the predictive model scores were 4.03(95%CI,3.00-5.42;P<0.001) for the conventional model, and 4.85(95%,3.65-6.45;P<0.001) for the model including acylcarnitines, with a HR of 1.33 (95%CI,1.08-1.63;P<0.001) attributed to the acylcarnitines.Including the acylcarnitines into the model did not significantly improve the area under the receiver operator characteristic(ROC) curve (0.86 to 0.88,P=0.61).One-year increase in C4OH-carnitine was associated with higher risk of T2D[per SD increment: 1.44(1.03-2.01)].

Conclusions:

An acylcarnitines profile, mainly including short- and long- chain acylcarnitines, was significantly associated with higher T2D risk in participants at high cardiovascular risk.The inclusion of acylcarnitines into the model did not significantly improve the T2D prediction c-statistics beyond traditional risk factors including fasting glucose.

10.
J Clin Endocrinol Metab. 2018 Nov 9. doi: 10.1210/jc.2018-01522. [Epub ahead of print]

Association of plasma vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study.

Author information

1
MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
2
University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
3
Vitas AS, Oslo, Norway.
4
Navarra Public Health Institute, and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
5
CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain.
6
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
7
Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
8
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
9
Inserm U1018, Center for Research in Epidemiology and Population Health (CESP), Paris-South Paris Saclay University, Gustave Roussy, Villejuif, France.
10
Department of Clinical Sciences, Lund University, Malmö, Sweden.
11
International Agency for Research on Cancer, Lyon, France.
12
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
University of Oxford, UK.
14
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
15
Department of Functional Biology, Faculty of Medicine, University of Oviedo. Asturias, Spain.
16
Public Health Division of Gipuzkoa, Biodonostia Research Institute, San Sebastian, Spain.
17
Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
18
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
19
Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
20
Umeå University, Umeå, Sweden.
21
Epidemiology and Prevention Unit, Milan, Italy.
22
Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs and Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
23
Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy.
24
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
25
Danish Cancer Society Research Center, Copenhagen, Denmark.
26
ASP Ragusa, Italy.
27
MRC/BHF Cardiovascular Epidemiology Unit and NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
28
School of Public Health, Imperial College London, London, UK.
29
British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, and Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Abstract

Background:

Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: non-epimeric and epimeric 25(OH)D3 stereoisomers; and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D.

Methods:

This analysis in the EPIC-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13562 subcohort members. Plasma vitamin D metabolites were quantified by liquid-chromatography mass-spectrometry. We used multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates combined across countries using random-effects meta-analysis.

Results:

The mean concentrations (standard deviation) of total 25(OH)D, non-epimeric 25(OH)D3, epimeric 25(OH)D3 and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and non-epimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1-SD=0.81 (95%CI: 0.77, 0.86) for both variables], while epimeric 25(OH)D3 was positively associated: per 1-SD HR=1.16 (1.09, 1.25). There was no statistically significant association with T2D for 25(OH)D2 [per 1-SD HR=0.94 (0.76, 1.18)].

Conclusions:

Plasma non-epimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

11.
J Clin Endocrinol Metab. 2018 Nov 9. doi: 10.1210/jc.2018-01656. [Epub ahead of print]

Association Between Triglyceride Level and Glycemic Control Among Insulin-treated Patients With Type 2 Diabetes.

Zheng D1,2, Dou J3,4, Liu G1,2, Pan Y1,2, Yan Y1,2, Liu F1,2, Gaisano HY5, Lu J3, He Y1,2.

Author information

1
Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.
2
Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China.
3
Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.
4
Department of Endocrinology, Hainan Branch of Chinese PLA General Hospital, Sanya, China.
5
Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada.

Abstract

Context:

Elevated blood triglyceride levels are known to increase the risk of diabetes and prediabetes. However, it is still unclear whether elevated triglyceride levels are associated with inadequate glycemic control in type 2 diabetic patients.

Objective:

To investigate the association between elevated triglyceride levels and inadequate glycemic control among insulin-treated patients with type 2 diabetes.

Design, Setting, and Patients:

We recruited 20,108 type 2 diabetic patients who were treated with a sufficient dose of insulin. These patients were from the 2013 China National HbA1c Surveillance System study, which was a multi-center study conducted in Mainland China. Multivariate logistic regressions were used to assess the association of the triglyceride level with the inadequate glycemic control.

Results:

Overall, 56.0% of the included study subjects had elevated triglyceride levels (≥1.70mmol/L), and prevalence of HbA1c ≥7.0% (53 mmol/mol) and ≥6.5% (48 mmol/mol) was 67.2% and 83.4%, respectively. The adjusted odds ratios of HbA1c ≥7.0% were 1.06 (0.98-1.15), 1.35 (1.23-1.48) and 3.12 (2.76-3.53), respectively, for those with triglyceride levels in ranges of 1.70-2.29, 2.30-3.39 and ≥3.40 mmol/L compared to those with triglyceride levels of <1.70 mmol/L. There was a similar association between triglyceride levels and HbA1c ≥6.5%. This positive association was confirmed by subgroup analyses among different subpopulations. There was also a strong nonlinear dose-response relationship between the triglyceride level and inadequate glycemic control.

Conclusions:

Elevated triglyceride levels were strongly associated with inadequate glycemic control, thus suppressing triglyceride levels might benefit in attaining a more optimal glycemic control in type 2 diabetic patients.

12.
Lancet. 2019 Jan 5;393(10166):31-39. doi: 10.1016/S0140-6736(18)32590-X. Epub 2018 Nov 10.

SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.

Author information

1
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
2
The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine, Jerusalem, Israel.
3
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
4
Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
5
Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6
Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
7
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: msabatine@bwh.harvard.edu.

Abstract

BACKGROUND:

The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined.

METHODS:

We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.

FINDINGS:

We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.

INTERPRETATION:

SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.

FUNDING:

None.

PMID:
30424892
DOI:
10.1016/S0140-6736(18)32590-X
[Indexed for MEDLINE]
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13.
N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389. [Epub ahead of print]

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.

Author information

1
From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital (S.D.W., M.P.B., T.A.Z., J.F.K., S.A.M., D.L.B., C.T.R., M.S.S.), and the Cardiology Division, Massachusetts General Hospital (M.G.S.) - both in Boston; the Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem (I.R., O.M., A.C.); the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (E.T.K.); Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); the Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (D.K.M.); Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom (J.P.H.W.); and AstraZeneca Gothenburg, Mölndal, Sweden (I.A.M.G.-N., M.F., P.A.J., A.-M.L.).

Abstract

BACKGROUND:

The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.

METHODS:

We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.

RESULTS:

We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).

CONCLUSIONS:

In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

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