Absolute Reduction In HbA1c Research Articles

Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators.

We investigated the association of early achieved HbA1c level and magnitude of HbA1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin. This was a population-based cohort study including all metformin initiators with HbA1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA1c achieved (<6.5% or higher) and by magnitude of HbA1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors. We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA1c achieved compared with a target HbA1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA1c change (Δ = 0). A large initial HbA1c reduction and achievement of low HbA1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.

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 unclear1. 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=6.6x10-14) greater metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients

ObjectivesTo develop a nomogram for estimating the glycated haemoglobin (HbA1c) response to different dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes.DesignA systematic review and meta-analysis of randomised controlled trials (RCTs)...

Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients

Saroglitazar is a dual PPAR α/γ agonist approved in India for the management of diabetic dyslipidemia. AimsThe objective of this study was to evaluate the safety and efficacy of saroglitazar 4 mg once daily in clinical practice. MethodsThis was an observational, multicenter, single-arm study. Patients with type 2 diabetes (with on-going antidiabetic medication), age above 18 years, and triglycerides ≥200 mg/dL were included. ResultsA total 2804 patients with a mean duration of diabetes 6.29 yrs were included in this analysis. The baseline demographic profile was: mean age of 53 yrs, mean body weight 72.3 kg and mean BMI of 27 kg/m2. 62.5% patients were male and 57.8% were reported to be on statin therapy at baseline. All 2804 patients were on antidiabetic medications with 15.4% patients on monotherapy and rest were on two or more than two antidiabetic medications at baseline. The baseline triglycerides and HbA1C values were 312.3 mg/dL and 8.3% respectively. At 3 months follow-up, use of saroglitazar 4 mg led to significant reduction in TG (35.8%), LDL-C (16.4%), total cholesterol (19%) and non-HDL-C (23.4%). Addition of saroglitazar to baseline antidiabetic medications showed a significant 0.9% absolute reduction in HbA1c with significant improvement in fasting and post prandial plasma glucose. No serious adverse events, alteration in liver or renal enzymes and edema or weight gain were reported. ConclusionSaroglitazar is a potential therapeutic option in type 2 diabetic patients with high TG levels, not controlled by statins, for comprehensive control of lipid and glycemic parameters with acceptable safety profile.

Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis

SummaryBackgroundMetformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method.MethodsIn this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture.Findings5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1–68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect.InterpretationGlycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.FundingWellcome Trust.

Carbohydrate counting and insulin dose adjustment group sessions for type 1 diabetes: a pilot of their effectiveness at a primary care diabetes centre

AbstractIt is recommended that a structured group education programme such as DAFNE (Dose Adjustment For Normal Eating) is offered to all adults with type 1 diabetes. Such programmes teach the skills of carbohydrate counting and insulin dose adjustment with the aim of improving glycaemic control (HbA1c) without increasing the risk of hypoglycaemia.South West Essex Community Services adult diabetes service was finding that individuals were not accessing the DAFNE programme for various reasons. A diabetes specialist dietitian and nurse decided to pilot the delivery of two 3‐hour group sessions to teach some of the basic carbohydrate counting and insulin dose adjustment skills.Changes in HbA1c pre‐ and post‐intervention were reported for 68 subjects. The four different intervention arms compared were: those who attended just the carbohydrate counting session (n=14), those who attended both sessions (n=24), those who had attended one or both sessions and then went on to attend DAFNE (n=10), and those who had received no carbohydrate counting education (n=20).Those who had attended one or both of the 3‐hour sessions had a mean and absolute reduction in HbA1c compared with the group that had not received any education, although this was not statistically significant. The group that had attended one or both of the 3‐hour sessions and DAFNE did achieve a statistically significant reduction in HbA1c compared with the group that had not received any education.Despite several identified limitations to the pilot, it was felt that the delivery of the two 3‐hour carbohydrate counting and insulin dose adjustment sessions demonstrated some clinically (if not statistically) significant improvement in HbA1c. Copyright © 2013 John Wiley &amp; Sons.

An observational study of acarbose treatment in patients with type 2 diabetes from the Middle East and Morocco

BackgroundThe prevalence of type 2 diabetes is increasing dramatically in the Middle East and North Africa region. However, there are few trials that have determined the effect of antidiabetic treatment in an observational setting in these countries.MethodsThis was a noninterventional study performed in Morocco in 2006–2007 and in the Middle East in 2005–2006 to observe the efficacy and safety of acarbose in patients with pretreated or untreated type 2 diabetes. Glycemic parameters (fasting blood glucose, one-hour postprandial blood glucose, and HbA1c) were recorded within a 3-month period. The observation period included an initial visit at the start of acarbose therapy and up to three follow-ups.ResultsAcarbose was effective in reducing glycemic parameters in patients from Morocco (n = 1082) and the Middle East (n = 1737). The mean one-hour postprandial blood glucose decreased by 35.5% to 165.4 ± 47.9 mg/dL in the Middle East and by 35.5% to 179.0 ± 49.9 mg/dL in Morocco. Mean fasting blood glucose decreased by 30.8% to 126.6 ± 34.2 mg/dL (Middle East) and by 34.5% to 150.6 ± 47.1 mg/dL (Morocco). The absolute reduction in HbA1c was 1.3% in the Middle East (final value 7.4%) and 1.0% in Morocco (final value 7.5%). Overall, 107 patients (Middle East) and 26 patients (Morocco) experienced minor drug-related adverse events, which were mainly gastrointestinal. The tolerability of acarbose was rated as very good/good by 80.8% in the Middle East and by 68.6% in Morocco.ConclusionThis study illustrates the efficacy and safety of acarbose in the treatment of type 2 diabetic patients in an observational setting.

Efficacy of saxagliptin as an add-on to oral monotherapy in the phase 3 clinical development program: Predictive factors of the treatment response in type 2 diabetes

Saxagliptin, a dipeptidyl peptidase-4 inhibitor, has been the focus of a large clinical development programme, including Phase 3 randomized vs placebo-controlled clinical trials as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control using initial monotherapy (metformin, glibenclamide, thiazolidinedione). This clinical programme has shown saxagliptin to be effective in the control of fasting and postprandial glycemic parameters, in addition to a good overall safety profile. The present paper aims at reviewing the overall short-term and long-term efficacy of saxagliptin in its Phase 3 development program and tries to pinpoint some factors that may be more predictive of treatment response in clinical practice. In individual and pooled analyses of the three pivotal add-on to monotherapy trials, saxagliptin (5mg once daily) led to significant reductions in HbA1c from baseline to 24 weeks. Additional analyses showed that reductions in HbA1c were maintained in the long-term, notably for 102 weeks, in combination with metformin. Data have also shown that the absolute reduction in HbA1c seen with saxagliptine from baseline to Week 24 was numerically greater with an elevated baseline HbA1c. In these recently published pooled analyses, clinically pertinent reductions in HbA1c were also obtained with saxagliptin across a wide range of subgroups of T2D patients when examined either by specific baseline demographic characteristics or by β-cell function indices such as the HOMA-β.

Combined Aerobic and Resistance Exercise for Patients With Type 2 Diabetes

TYPE 2 DIABETES MELLITUS IS A MAJOR RISK FACTOR FOR excess morbidity and mortality. The excess vascular risk in type 2 diabetes is attributable both to hyperglycemia and to other metabolic disturbances associated with abdominal obesity, insulin resistance, and compensatory hyperinsulinemia. Sedentary lifestyle is also a major cardiovascular risk factor, and regular exercise attenuates the vascular risks associated with type 2 diabetes. Aerobic exercise refers to activities such as walking or jogging with continuous, repetitive movement of large muscle groups for at least 10 minutes at a time, whereas resistance exercise refers to activities such as weight lifting that use muscular strength to move a weight or work against a resistance load. Aerobic exercise for individuals with diabetes has been recommended for many decades, but the American Diabetes Association only began recommending resistance exercise in 2006. In this issue of JAMA, Church and colleagues report the results of the Health Benefits of Aerobic and Resistance Training in Individuals with Diabetes (HART-D) trial. This study provides important evidence on the effects of aerobic and resistance training on improving hemoglobin A1c (HbA1c) levels. In this trial, 262 previously sedentary patients with type 2 diabetes were randomized to a sedentary control group or to 1 of 3 exercise groups: aerobic exercise, resistance training, or a combination of both. Patients in the combined group performed smaller amounts of aerobic and resistance exercise than those in groups performing just one type of exercise so that the total amount of time devoted to exercise each week was similar among the 3 groups. The aerobic group performed 12 kcal/kg of body weight per week of aerobic exercise, equivalent to walking briskly at 4 mph for about 50 minutes per session 3 times a week. The resistance training group performed 2 to 3 sets of 10 to 12 repetitions of 9 exercises 3 times a week. The combined group performed 10 kcal/kg of body weight per week of aerobic exercise (equivalent to 42 minutes 3 times a week of walking at 4 mph, 83% of the amount done by the aerobic group) plus 1 set each of 9 exercises 2 times a week (less than a third of the resistance training volume performed by the resistance training group). No efforts were made to minimize changes in diet or medications. Only the combined training group achieved statistically significant reduction in absolute reduction in HbA1c in the HART-D trial compared with the control group (0.34%). The aerobic group had an absolute reduction of 0.24%; the resistance group, 0.16%. All groups had modest and similar decreases in waist circumference compared with the control group. In addition to the greatest HbA1c reduction, the combined training group also had the most decreases, and the least increases, in use of hypoglycemic medication. The findings of the HART-D trial are important for several reasons. First, the study duration was 9 months, making it longer than most exercise intervention trials involving patients with diabetes. Second, the study population was relatively large in number (n=262) and ethnically diverse, with almost 44% of participants being African American, and had a relatively high proportion of female participants (63%). Third, the total time spent exercising was roughly the same in the combined training group as in the other 2 singleexercise groups. Therefore, any difference between the combined exercise group and the other exercise groups can be confidently attributed to the combination of 2 types of exercise rather than the amount of time spent exercising. The HbA1c changes achieved in the HART-D trial were modest, perhaps because there was no effort to minimize medication changes. Participants whose HbA1c level did not improve with exercise were more likely to have their hypoglycemic therapy intensified, thus attenuating the difference in HbA1c that could be achieved between groups. It is likely that intergroup HbA1c differences in HART-D may have been greater if medication changes had been discouraged. The results are encouraging in that a significant incremental improvement in glycemic control was made in the HART-D combination group over and above that achieved through ongoing efforts by physicians and patients in both groups to optimize glycemic control with medications. Another possibility is that the higher proportion of women and

Lower Baseline Glycemia Reduces Apparent Oral Agent Glucose-Lowering Efficacy

Perusal of advertisements for oral hypoglycemic agents in this and many other medical journals shows an emphasis on the absolute reduction in HbA1c (A1C). Evidence linking reduction in A1C in diabetic patients to prevention of macrovascular events is weak. However, epidemiological evidence suggests that the risk for cardiovascular disease in this group may actually begin at A1C concentrations well within the normal range (1). This association has led a number of professional organizations to recommend that A1C levels be brought to levels <6.5% (2). An important question to be asked is whether the reduction in A1C differs at lower versus higher baseline levels of A1C. Expectations for the degree of reduction to be attained with a given agent may be excessively optimistic when a person’s initial A1C is already <7.5–8.0%. Some of the deliberations of policy advisory groups are available. The European Agency for the Evaluation of Medicinal Products has published guidelines for diabetes product evaluation suggesting that the change in A1C be utilized as “primary analysis” of drug efficacy, although allowing the baseline A1C to be included as a covariate (3). A meeting of the Center for Drug Evaluation and Research Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration concluded that A1C should be the primary outcome variable for diabetes drugs and suggested an absolute decrease of 0.7% as the minimal acceptable level for approval (4). This may prevent acceptance of agents that are as effective as existing treatments at A1C levels …

The effects of orlistat in patients with diabetes: improvement in glycaemic control and weight loss

ABSTRACTObjective: In addition to direct weight reduction, there may be other benefits of obesity treatment including improved insulin sensitivity. The purpose of this study was to characterise concomitant diabetes drug use and the related costs in patients with diabetes treated with orlistat (Xenical) in the first 6 months of treatment.* Xenical is a trade name of Roche Pharmaceuticals, Basle, SwitzerlandMethods: One hundred overweight patients with diabetes and a body mass index (BMI) ≥ 28 kg/m2 were enrolled in a structured UK hospital-based weight management clinic and treated with orlistat plus behavioural interventions. Among other measures, weight, glucose control (HbA1c) and drug treatments were recorded. Subjects were followed-up for a maximum of 24 months at intervals of 1–3 months, with a maximum treatment period of 24 months.Results: The majority of subjects (91%) had type 2 diabetes. They had a mean age of 55 years and 55% were women. For patients followed up at 6 months, their mean BMI at baseline was 39.5 kg/m2 with a mean HbA1c of 7.6%. The mean weight loss at 6 months was 7.1 kg ( p < 0.001). Despite a significant average absolute HbA1c reduction of 0.62% ( p < 0.001), the most notable gains were made by those with the highest baseline HbA1c values (a mean relative reduction of 20% for those above the 75th percentile). There were 50 patients treated with insulin at baseline and 47 at 6 months. Of those treated with insulin, the mean dose was 130 units at baseline and 90 units at 6 months ( p < 0.001). Twenty patients (44.4%) initially treated with oral hypoglycaemic agents alone reduced their dose after 6 months (not significant). Despite marked improvement in insulin sensitivity (baseline mean, 1.24 units/kg; 6 month mean, 0.90 units/kg [p < 0.001]) there was no correlation with BMI change. The average cost of diabetes treatment at baseline was £1.16 per day and £0.83 at 6 months ( p < 0.001). Age was the only independent predictor for insulin dose reduction.Conclusions: Orlistat appears to reduce the need for concomitant diabetes medication irrespective of weight loss, a reduction that is likely to represent a large cost offset for orlistat treatment.

Pro-Active Call Center Treatment Support (PACCTS) to Improve Glucose Control in Type 2 Diabetes

To determine whether Pro-Active Call Center Treatment Support (PACCTS), using trained nonmedical telephonists supported by specially designed software and a diabetes nurse, can effectively improve glycemic control in type 2 diabetes. A randomized controlled implementation trial of 1-year duration was conducted in Salford, U.K. The trial comprised 591 randomly selected individuals with type 2 diabetes. By random allocation, 197 individuals were assigned to the usual care (control) group and 394 to the PACCTS (intervention) group. Lifestyle advice and drug treatment in both groups followed local guidelines. PACCTS patients were telephoned according to a protocol with the frequency of calls proportional to the last HbA(1c) level. The primary outcome was absolute reduction in HbA(1c), and the secondary outcome was the proportion of patients reducing HbA(1c) by at least 1%. A total of 332 patients (84%) in the PACCTS group and 176 patients (89%) in the control group completed the study. Final HbA(1c) values were available in 374 patients (95%) in the PACCTS group and 180 patients (92%) in the usual care group. Compared with usual care, HbA(1c) improved by 0.31% (95% CI 0.11-0.52, P = 0.003) overall in the PACCTS patients. For patients with baseline HbA(1c) >7%, the improvement increased to 0.49% (0.21-0.77, P < 0.001), whereas in patients with baseline HbA(1c) <7% there was no change. The difference in the proportions of patients achieving a >/=1% reduction in HbA(1c) significantly favored the PACCTS intervention: 10% (4-16, P < 0.001) overall and 15% (7-24, P < 0.001) for patients with baseline HbA(1c) >7%. In an urban Caucasian trial population with blood glucose HbA(1c) >7%, PACCTS facilitated significant improvement in glycemic control. Further research should extend the validity of findings to rural communities and other ethnic groups, as well as to smoking and lipid and blood pressure control.

Benefits of monitoring blood glucose by collection of blood on filter paper strips

AbstractBackgroundThe accuracy of blood glucose meters has been questioned and the quality control remains rudimentary. Collection of blood spots on filter paper strips allows laboratory estimations whilst maintaining the convenience of blood collection in the patient's own home.MethodPatients provide blood spots on specially prepared filter paper strips and post them to the laboratory for analysis.ResultsIn 12 months, eight of 19 pregnant diabetic patients had their meter changed because of inconsistency between meter readings and filter paper results. In six consecutive cases of discrepancy between HbA1c and home monitoring, filter paper glucose all proved higher than home monitoring results. This led to a change of meter in three cases, and of insulin regime in all cases, resulting in a mean absolute reduction in HbA1c of 1.92 % (SD 0.9, p &lt; 0.01).Over the past two years, nine patients without diabetes have been investigated for hypoglycaemia by self‐collection of blood spots when symptomatic. In eight cases hypoglycaemia was excluded, but was confirmed in the remaining case, and an insulinoma was subsequently diagnosed and excised.ConclusionMonitoring of blood glucose levels using filter strips proved a useful tool in pregnancy management, in evaluating discrepancies between HbA1c and home monitoring results, and investigating unexpected hypoglycaemia in non‐diabetic patients. Copyright © 2002 John Wiley &amp; Sons, Ltd.