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Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

ABSTRACT: OBJECTIVE:To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN:Prospective observational study. SETTING:23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS:4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES:Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes. RESULTS:The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS:In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA(1c) is likely to reduce the risk of complications, with the lowest risk being in those with HbA(1c) values in the normal range (<6.0%).

SUBMITTER: Stratton IM

PROVIDER: S-EPMC27454 | biostudies-literature | 2000 Aug

REPOSITORIES: biostudies-literature

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Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

Stratton I M IM Adler A I AI Neil H A HA Matthews D R DR Manley S E SE Cull C A CA Hadden D D Turner R C RC Holman R R RR

BMJ (Clinical research ed.) 20000801 7258

<h4>Objective</h4>To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes.<h4>Design</h4>Prospective observational study.<h4>Setting</h4>23 hospital based clinics in England, Scotland, and Northern Ireland.<h4>Participants</h4>4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included ...[more]

PMID: 10938048

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Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina's Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina's Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

Project description:IntroductionThis retrospective cohort study investigated the relation between different measures of glycemic exposure and micro- and macrovascular complications among patients with type 2 diabetes.MethodsThe analysis included patients receiving oral antihyperglycemic agents between 1 January 2006 and 31 December 2014 from the General Practitioner Database from the PHARMO Database Network. All recorded HbA1c levels during follow-up were used to express glycemic exposure in four ways: index HbA1c, time-dependent HbA1c, exponential moving average (EMA) and glycemic burden. Association between glycemic exposure and micro-/macrovascular complications was analyzed by estimating hazard ratios and 95% confidence intervals using an adjusted (time-dependent) Cox proportional hazards model.ResultsThe analysis included 32,725 patients (median age, 65 years; 47% female). Median follow-up was 5.4 years; median number of HbA1c measurements per patient was 18.0. From all measures, HbA1c at index showed the weakest relation between all micro-/macrovascular complications, with coronary artery disease (CAD) having the highest HR (95% CI): 1.18 (1.04-1.34) for HbA1c ≥64 mmol/mol (8%). The time-dependent HbA1c model showed a significant association only for microvascular complications, with retinopathy having the highest HR (95% CI): 1.55 (1.40-1.73) for HbA1c ≥64 mmol/mol (8%). EMA-defined exposure showed similar findings, although the effect of retinopathy was more pronounced [HR (95% CI): 1.81 (1.63-2.02) for HbA1c ≥64 mmol/mol (8%)] and was also predictive for CAD [HR (95% CI): 1.29 (1.10-1.50) for HbA1c ≥64 mmol/mol (8%)]. A statistically significant relation with glycemic burden was found for all selected micro-/macrovascular complications, with retinopathy having the highest HR (95%): 2.60 (2.19-3.07) for glycemic burden years >3.ConclusionThis study shows that greater and more prolonged exposure to hyperglycemia increases the risk of micro- and macrovascular complications.FundingJanssen Pharmaceutica NV.

Dataset Information

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

Publications

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

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