R L Coleman

Performance of the UK Prospective Diabetes Study Risk Engine and the Framingham Risk Equations in Estimating Cardiovascular Disease in the EPIC- Norfolk Cohort

OBJECTIVE The purpose of this study was to examine the performance of the UK Prospective Diabetes Study (UKPDS) Risk Engine (version 3) and the Framingham risk equations (2008) in estimating cardiovascular disease (CVD) incidence in three populations: 1) individuals with known diabetes; 2) individuals with nondiabetic hyperglycemia, defined as A1C ≥6.0%; and 3) individuals with normoglycemia defined as A1C <6.0%. RESEARCH DESIGN AND METHODS This was a population-based prospective cohort (European Prospective Investigation of Cancer-Norfolk). Participants aged 40–79 years recruited from U.K. general practices attended a health examination (1993–1998) and were followed for CVD events/death until April 2007. CVD risk estimates were calculated for 10,137 individuals. RESULTS Over 10.1 years, there were 69 CVD events in the diabetes group (25.4%), 160 in the hyperglycemia group (17.7%), and 732 in the normoglycemia group (8.2%). Estimated CVD 10-year risk in the diabetes group was 33 and 37% using the UKPDS and Framingham equations, respectively. In the hyperglycemia group, estimated CVD risks were 31 and 22%, respectively, and for the normoglycemia group risks were 20 and 14%, respectively. There were no significant differences in the ability of the risk equations to discriminate between individuals at different risk of CVD events in each subgroup; both equations overestimated CVD risk. The Framingham equations performed better in the hyperglycemia and normoglycemia groups as they did not overestimate risk as much as the UKPDS Risk Engine, and they classified more participants correctly. CONCLUSIONS Both the UKPDS Risk Engine and Framingham risk equations were moderately effective at ranking individuals and are therefore suitable for resource prioritization. However, both overestimated true risk, which is important when one is using scores to communicate prognostic information to individuals.

Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials

BACKGROUND Intensive glucose control is understood to prevent complications in adults with type 2 diabetes. We aimed to more precisely estimate the effects of more intensive glucose control, compared with less intensive glucose control, on the risk of microvascular events. METHODS In this meta-analysis, we obtained de-identified individual participant data from large-scale randomised controlled trials assessing the effects of more intensive glucose control versus less intensive glucose control in adults with type 2 diabetes, with at least 1000 patient-years of follow-up in each treatment group and a minimum of 2 years average follow-up on randomised treatment. The prespecified and standardised primary outcomes were kidney events (a composite of end-stage kidney disease, renal death, development of an estimated glomerular filtration rate <30 mL/min per 1·73m2, or development of overt diabetic nephropathy), eye events (a composite of requirement for retinal photocoagulation therapy or vitrectomy, development of proliferative retinopathy, or progression of diabetic retinopathy), and nerve events (a composite of new loss of vibratory sensation, ankle reflexes, or light touch). We used a random-effects model to calculate overall estimates of effect. FINDINGS We included four trials (ACCORD, ADVANCE, UKPDS, and VADT) with 27 049 participants. 1626 kidney events, 795 eye events, and 7598 nerve events were recorded during the follow-up period (median 5·0 years, IQR 4·5-5·0). Compared with less intensive glucose control, more intensive glucose control resulted in an absolute difference of -0·90% (95% CI -1·22 to -0·58) in mean HbA1c at completion of follow-up. The relative risk was reduced by 20% for kidney events (hazard ratio 0·80, 95% CI 0·72 to 0·88; p<0·0001) and by 13% for eye events (0·87, 0·76 to 1·00; p=0·04), but was not reduced for nerve events (0·98, 0·87 to 1·09; p=0·68). INTERPRETATION More intensive glucose control over 5 years reduced both kidney and eye events. Glucose lowering remains important for the prevention of long-term microvascular complications in adults with type 2 diabetes. FUNDING None.

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Prognostic Significance of Silent Myocardial Infarction in Newly Diagnosed Type 2 Diabetes Mellitus

Background— We aimed to determine the prevalence of silent myocardial infarction (SMI) in people with newly diagnosed type 2 diabetes mellitus and its relationships to future myocardial infarction (MI) and all-cause mortality. Methods and Results— We examined data from the 5102 patients in the 30-year UK Prospective Diabetes Study (UKPDS) and used Cox proportional hazards regression to examine outcomes by SMI status. Of 1967 patients with complete baseline data, 326 (16.6%) had ECG evidence of SMI (Minnesota codes 1.1 or 1.2) at enrollment. Those with SMI were more likely to be older, female, sedentary, and nonsmokers compared with those without SMI. Their mean blood pressure was greater despite more intensive antihypertensive treatment; they were more likely to be taking aspirin and lipid-lowering therapy; and they had a greater prevalence of microangiopathy. Fully adjusted hazard ratios for those with versus those without SMI in multivariate models that included UKPDS Risk Engine variables were 1.58 (95% confidence interval, 1.22–2.05) for fatal MI and 1.31 (95% confidence interval, 1.10–1.56) for all-cause mortality. Hazard ratios for first fatal or nonfatal MI and for first nonfatal MI were nonsignificant. The net reclassification index showed no improvement when SMI was added to these models, and the integrated discrimination index showed that SMI marginally improved the prediction of fatal MI and all-cause mortality. Conclusions— About 1 in 6 UKPDS patients with newly diagnosed type 2 diabetes mellitus had evidence of SMI, which was independently associated with an increased risk of fatal MI and all-cause mortality. However, identification of SMI does not add substantively to current UKPDS Risk Engine predictive variables. Clinical Trial Registration— URL: http://www.controlled-trials.com. Identifier: ISRCTN number 75451837.

Ethnicity and long‐term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83)

Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long‐term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes.

Association Between More Intensive vs Less Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease Stages 3 to 5: A Systematic Review and Meta-analysis

Importance Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all-cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown. Objectives To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5. Data Sources Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases. Study Selection All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016. Data Extraction and Synthesis Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials. Main Outcome and Measure All-cause mortality during the active treatment phase of each trial. Results This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups. Conclusions and Relevance Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.

Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes.

Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively.

Framingham risk equations underestimate coronary heart disease risk in diabetes

I wish to commend the authors of ‘Comparison of pioglitazone and metformin efficacy using homeostasis model assessment’ (February 2004). They have done much to advocate the scientific selection of drug regimens for the treatment of Type 2 diabetes. Many algorithms and flowcharts have been offered to guide clinicians in the selection of drugs, but these guidelines are based on little science. Though it may be difficult to apply the reported findings to typical Type 2 diabetic patients in the USA, where obesity (body mass index ≥ 30) is pretty much the rule, their results offer a tantalizing view of the future where rational drug selection will be based on specific patient parameters. I look forward to other investigators reporting similar analyses from other databases. This study also begs an additional interpretation. If a patient with diabetes fails to respond well to a given drug, most clinicians will add another agent. Perhaps the first drug should be discontinued when starting a different agent and this report raises the prospect of using simple measurements to guide medication adjustments. It is often assumed that poor treatment results are due to non-compliance, but we must consider the possibility that the drug was a poor choice to begin with. The results by Nagasaka et al . indicate that some patients will not respond to treatment. For example, the study volunteers assigned to pioglitazone therapy failed to respond if they had either a low HOMA-R or a low HOMAβ and would benefit from switching to a different drug rather than receiving an additional agent. Estimating HOMA-R and HOMAβ is a simple matter using fasting plasma glucose and insulin levels and only requires the additional measurement of insulin. This may be a small price to pay in exchange for better initial drug selection. We need more studies before recommending such an approach, but the current report indicates the potential benefit.

Evaluation of a Self-Administered Oral Glucose Tolerance Test

OBJECTIVE To assess the feasibility of using a disposable, self-administered, capillary blood sampling oral glucose tolerance test (OGTT) device in a community setting. RESEARCH DESIGN AND METHODS Eighteen healthy and 12 type 2 diabetic volunteers underwent six 75-g OGTTs using a prototype device in the following three settings: unaided at home (twice); unaided but observed in clinic (twice); and performed by a nurse with simultaneous laboratory glucose assays of 0- and 120-min venous plasma samples (twice). The device displayed no results. A detachable data recorder returned to the clinic provided plasma-equivalent 0- and 120-min glucose values and key parameters, including test date, start and end times, and time taken to consume the glucose drink. RESULTS The device was universally popular with participants and was perceived as easy to use, and the ability to test at home was well liked. Device failures meant that 0- and 120-min glucose values were obtained for only 141 (78%) of the 180 OGTTs performed, independent of setting. Device glucose measurements showed a mean bias compared with laboratory-measured values of +0.9 at 5.0 mmol/L increasing to +4.4 at 15.0 mmol/L. Paired device glucose values were equally reproducible across settings, with repeat testing showing no training effect regardless of setting order. CONCLUSIONS Self-administered OGTTs can be performed successfully by untrained individuals in a community setting. With improved device reliability and appropriate calibration, this novel technology could be used in routine practice to screen people who might need a formal OGTT to confirm the presence of impaired glucose tolerance or diabetes.

Baseline Characteristics and Temporal Differences in Acarbose Cardiovascular Evaluation (ACE) Trial Participants

; The ACE trial is examining whether acarbose, an insulin-sparing postprandial glucose-lowering agent, can reduce cardiovascular (CV) events in patients who have coronary heart disease (CHD) and impaired glucose tolerance (IGT), with prevention of type 2 diabetes (T2D) as a secondary outcome. This update report evaluates the impact of the protocol-driven 4-week CV risk management optimization strategy during the run-in period, lists participant baseline characteristics, and examines whether temporal differences occurred during the 7-year recruitment period.