Primary‐care observational database study of the efficacy of GLP‐1 receptor agonists and insulin in the UK

Aims

We investigated use and efficacy of glucagon‐like peptide‐1 (GLP‐1) receptor agonists in UK practice.

Methods

People starting a GLP‐1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose‐lowering agents were identified from The Health Information Network observational primary care database (2007–2011). Mean change in HbA_1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics.

Results

Baseline characteristics of GLP‐1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA_1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP‐1 receptor agonist cohort was younger, had shorter diabetes duration and follow‐up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose‐lowering agents. Lower HbA_1c reduction on GLP‐1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference ?1.4 (95% CI ?4.1, 1.2) mmol/mol], except in the highest HbA_1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference ?17.8 (?28.6, ?7.0) mmol/mol]. GLP‐1 receptor agonist users lost weight [?4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6‐month target reduction for GLP‐1 receptor agonists of 11 mmol/mol (1.0%) HbA_1c and 3% weight was reached by 24.9% of those continuing treatment.

Conclusions

Those starting GLP‐1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA_1c reduction unless baseline HbA_1c is very high. The UK 6‐month GLP‐1 receptor agonist target is usually not reached.

     

Diagnostic value of glycated haemoglobin (HbA1c) for the early detection of diabetes in high‐risk subjects

Objective The aim of this study was to assess the validity of fasting plasma glucose (FPG) and/or glycated haemoglobin (HbA_1c) as screening tests for the early detection of diabetes in high‐risk subjects. Methods A total of 392 subjects (149 male and 243 female) with risk factors for diabetes were included. All subjects underwent a 75‐g oral glucose tolerance test and HbA_1c measurement. Receiver operating characteristic curve analysis was used to examine the sensitivity and specificity of FPG and HbA_1c for detecting diabetes, which was defined as a FPG ≥ 7.0 mmol/l or a post‐challenge 2‐h plasma glucose ≥ 11.1 mmol/l. Results The prevalence of newly diagnosed diabetes was 22.4% (n = 88). The current guideline of FPG ≥ 7.0 mmol/l for diabetes screening detected only 55.7% of diabetic subjects. The optimal cut‐off points of HbA_1c and FPG for the diagnosis of diabetes were 6.1% (sensitivity 81.8%, specificity 84.9%) and 6.1 mmol/l (sensitivity 85.2%, specificity 88.5%), respectively. The screening model using FPG ≥ 6.1 mmol/l and/or HbA_1c ≥ 6.1% had sensitivities of 71.6–95.5% and specificities of 77.6–95.7% for detecting undiagnosed diabetes. Conclusions The current American Diabetes Association diagnostic criteria, based only on FPG, are relatively insensitive in the detection of diabetes in high‐risk subjects. The simultaneous measurement of FPG and HbA_1c might be a more sensitive screening tool for identifying high‐risk individuals with diabetes at an early stage.     

Accuracy of glycated haemoglobin in screening for pre‐diabetes in Asian Indians—a community survey: the Chandigarh Urban Diabetes Study (CUDS)

Aim To compare American Diabetes Association and International Expert Committee recommended cut‐off values of HbA_1c for detecting the presence of pre‐diabetes against plasma glucose values obtained from oral glucose tolerance tests in Asian Indians. Methods A cross‐sectional randomly sampled population survey involving 2368 adults, aged ≥ 20 years. HbA_1c was measured on a Bio‐Rad 10 system in 1972 subjects. Results Of the 1972 subjects studied, 329 were detected to have pre‐diabetes based on isolated impaired fasting glucose in 125 subjects (6.3%), isolated impaired glucose tolerance in 141 subjects (7.1%) and the presence of both in 63 subjects (3.2%). The HbA_1c cut‐off of 34 mmol/mol (5.7%), as recommended by the American Diabetes Association for detecting the presence of pre‐diabetes, showed sensitivity of 62%, specificity 77%, with a positive predictive value of 34.7%, a negative predictive value of 89.5% and accuracy of 67.8%; whereas the HbA_1c cut‐off recommended by the International Expert Committee of 42 mmol/mol (6%) had a sensitivity of 36%, specificity of 90%, positive predictive value of 42.7%, negative predictive of 85.4% and an accuracy of 77%. However, both these HbA_1c cut‐offs underdiagnosed the presence of pre‐diabetes in 38 and 64% of these subjects, respectively. Conclusions The American Diabetes Association and the International Expert Committee recommended HbA_1c cut‐off values and oral glucose tolerance tests identify different pre‐diabetes cohorts. Long‐term prospective studies are required to define the usefulness of one over the other.     

Associations of HbA1c and educational level with risk of cardiovascular events in 32 871 drug‐treated patients with Type 2 diabetes: a cohort study in primary care

Aims

To explore the association of HbA_1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes.

Methods

A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose‐lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA_1c levels and educational level with risks of cardiovascular events and all‐cause mortality were analysed.

Results

The associations of HbA_1c with risk of all‐cause and cardiovascular mortality were J‐shaped, with the lowest risk observed for cardiovascular mortality at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. The lowest risk observed for all‐cause mortality was at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2–2.1), P = 0.0008] at the lowest HbA_1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8–1.6), P = 0.3873].

Conclusions

Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA_1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315)     

Socio‐economic status and HbA1c in type 2 diabetes: A systematic review and meta‐analysis

Up until now, differences in HbA_1c levels by socio‐economic status (SES) have been identified, but not yet quantified in people with type 2 diabetes. The aim of this study was therefore to assess the difference in HbA_1c levels between people with type 2 diabetes of different SES in a systematic review and meta‐analysis. A systematic literature search was conducted in MEDLINE, Embase, Ebsco, and the Cochrane Library until January 14, 2018. Included studies described adults with type 2 diabetes in whom the association between SES and HbA_1c levels was studied. Studies were rated for methodological quality and data were synthesized quantitatively (meta‐analysis) and qualitatively (levels of evidence), stratified for type of SES variable, i.e., education, income, deprivation, and employment. Fifty‐one studies were included: 15 high, 27 moderate, and 9 of low methodological quality. Strong evidence was provided that people of low SES have higher HbA_1c levels than people of high SES, for deprivation, education, and employment status. The pooled mean difference in HbA_1c levels between people of low and high SES was 0.26% (95% CI, 0.09‐0.43) or 3.12 mmol/mol (95% CI, 1.21‐5.04) for education and 0.20% (95% CI, ?0.05 to 0.46) or 2.36 mmol/mol (95%CI, ?0.61 to 5.33) for income. In conclusion, our systematic review and meta‐analysis showed that there was an inverse association between SES and HbA_1c levels in people with type 2 diabetes. Future research should focus on finding SES‐sensitive strategies to reduce HbA_1c levels in people with type 2 diabetes.     

Diabetes distress,but not depressive symptoms,is associated with glycaemic control among Japanese patients with Type 2 diabetes: Diabetes Distress and Care Registry at Tenri (DDCRT 1)

Aims To investigate the association between glycaemic control, diabetes distress and depressive symptoms among Japanese patients with Type 2 diabetes. Methods Cross‐sectional data from 3305 patients with Type 2 diabetes were obtained from a baseline assessment of a diabetes registry at a general hospital in Japan. The Centre for Epidemiologic Studies Depression scale and Problem Areas in Diabetes scale were used to measure depressive symptoms and diabetes‐related distress, respectively. Modified Poisson regression analysis was used to estimate the relative risks for poor glycaemic control across the quartiles of Centre for Epidemiologic Studies Depression scale and Problem Areas in Diabetes scale scores. Results The average age of the participants was 64.9 years and the average HbA_1c level was 58.1 mmol/mol (7.5%). Clinically significant levels of depressive symptoms (Centre for Epidemiologic Studies Depression scale scores ≥ 16) were reported by 27.8% of participants. These scores significantly correlated with Problem Areas in Diabetes scale scores (r = 0.4354, P < 0.0001). Diabetes distress, but not depressive symptoms, was significantly associated with higher HbA_1c levels. The relative risks for poor glycaemic control (HbA_1c≥ 64 mmol/mol; 8.0%), when adjusted for age, sex, BMI, type of diabetes therapy and duration of diabetes, was 67% higher among patients with Problem Areas in Diabetes scale scores in the highest quartile (≥ 26.25) compared with those in the lowest quartile (0–3.75). Conclusion A significant association between glycaemic control and diabetes‐related distress, but not depressive symptoms, was observed in Japanese patients with Type 2 diabetes.     

Area‐under‐the‐HbA1c‐curve above the normal range and the prediction of microvascular outcomes: an analysis of data from the Diabetes Control and Complications Trial

Aims In the Diabetes Control and Complications Trial, mean updated HbA_1c accounted for most of the differential risk of microvascular complications between intensive and conventional insulin therapy. We hypothesized, however, that a more precise measure of chronic hyperglycaemic exposure may be the incremental area‐under‐the‐HbA_1c‐curve above the Diabetes Control and Complications Trial‐standardized normal range for HbA_1c (iAUC_HbA1c>norm). Methods Using the Principal Diabetes Control and Complications Trial data set, we compared the following three measures of chronic glycaemic exposure for their capacity to predict retinopathy, nephropathy and neuropathy during the Diabetes Control and Complications Trial: mean updated HbA_1c, iAUC_HbA1c>norm, and total area‐under‐the‐HbA_1c‐curve (tAUC_HbA1c). For each outcome, models using each of these three glycaemic measures were compared in the following three ways: hazard or odds ratio, χ² statistic, and Akaike information criterion. Results The three glycaemic measures did not differ in their prediction of neuropathy. iAUC_HbA1c>norm was modestly superior to mean updated HbA_1c for predicting nephropathy (χ²P = 0.017, Akaike P = 0.032). In contrast, for predicting retinopathy, both iAUC_HbA1c>norm (χ²P = 0.0005, Akaike P = 0.0005) and tAUC_HbA1c (χ²P = 0.004, Akaike P = 0.004) were significantly better than mean updated HbA_1c. Varying its HbA_1c threshold incrementally between 37 and 53 mmol/mol (5.5–7.0%), inclusive, did not improve the prediction of retinopathy by iAUC_{HbA1c>threshold} beyond that of tAUC_HbA1c,consistent with the concept of a continuous relationship between glycaemia and retinopathy, with no glycaemic threshold. Conclusions Both iAUC_HbA1c>norm and tAUC_HbA1c were superior to mean updated HbA_1c for predicting retinopathy. Optimal assessment of chronic glycaemic exposure as a determinant of retinopathic risk may require consideration of both the degree of hyperglycaemia and its duration.     

A randomized non‐inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with Type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin

Aims To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non‐inferior to adding exenatide twice daily to sitagliptin and metformin. Methods Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice‐daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice‐daily exenatide plus sitagliptin and metformin (ADD, n = 128). Results Non‐inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA_1c from baseline to week 20, was not shown {between‐treatment difference in least‐squares mean [95% CI 3 mmol/mol (0.30%)] [0.8–5.8 (0.07–0.53)]}. A greater reduction (P = 0.012) in HbA_1c [least‐squares mean (se )] was experienced by patients in the ADD group {?7 mmol/mol [?0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {?4 mmol/mol [?0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA_1c target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self‐monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. Conclusions Non‐inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti‐hyperglycaemic medication.     

Differences in HbA1C at the time of diabetes diagnosis in the adult population of Ontario,Canada

AimsTo determine the proportion of adults with HbA_1c ≥ 8.0% (64 mmol/mol) at diabetes diagnosis, as an indicator of delayed diagnosis or less intensive screening.MethodsWe conducted a cross-sectional population-level study using clinical, administrative and immigration data from Ontario, Canada. We identified all individuals diagnosed with diabetes between June 2012 and June 2015, and determined the HbA_1c between 60 days prior to and 30 days after diagnosis. Individuals were stratified based on many sociodemographic, clinical and primary care characteristics, and the proportion with HbA_1c ≥ 8.0% (64 mmol/mol) was determined.ResultsMean HbA_1c at diabetes diagnosis in the population was 7.3 ± 1.9% (56 ± 21 mmol/mol), and 21.1% had HbA_1c ≥ 8.0% (64 mmol/mol) at diagnosis. Factors for which there were important differences in the proportion with HbA_1c ≥ 8.0% (64 mmol/mol) included age, sex, ethnicity, comorbidities, frequency of primary care and primary care rostering.ConclusionsIn a real-world population-level setting, more than one-fifth of individuals diagnosed with diabetes have HbA_1c levels ≥8.0% (64 mmol/mol), suggesting a delay in diagnosis due to inadequate screening. Differences were found based on age, sex and clinical factors, but not based on socioeconomic or immigration factors.     

Assessing the economic value of maintained improvements in Type 1 diabetes management,in terms of HbA1c,weight and hypoglycaemic event incidence

Aims

Insulin therapy is indicated for people with Type 1 diabetes mellitus; however, treatment‐related weight gain and hypoglycaemia represent barriers to optimal glycaemic management. This study assessed the health economic value of maintained reductions in HbA_1c, BMI and hypoglycaemia incidence among the UK Type 1 diabetes population.

Methods

The Cardiff Type 1 Diabetes Model was used to estimate lifetime costs, life‐years and quality‐adjusted life‐years (QALYs) for individuals with Type 1 diabetes at different baseline HbA_1c, BMI and hypoglycaemic event rates. Results were discounted at 3.5%, and the net monetary benefit associated with improving Type 1 diabetes management was derived at £20 000/QALY gained. Per‐person outputs were inflated to national levels using UK Type 1 diabetes prevalence estimates.

Results

Modelled subjects with an HbA_1c of 86 mmol/mol (10.0%) were associated with discounted lifetime per‐person costs of £23 795; £12 649 of which may be avoided by maintaining an HbA_1c of 42 mmol/mol (6.0%). Combined with estimated QALY gains of 2.80, an HbA_1c of 42 mmol/mol (6.0%) vs. 86 mmol/mol (10.0%) was associated with a £68 621 per‐person net monetary benefit. Over 1 year, unit reductions in BMI produced £120 per‐person net monetary benefit, and up to £197 for the avoidance of one non‐severe hypoglyceamic event.

Conclusions

Maintained reductions in HbA_1c significantly alleviate the burden associated with Type 1 diabetes in the UK. Given the influence of weight and hypoglycaemia on health economic outcomes, they must also be key considerations when assessing the value of Type 1 diabetes technologies in clinical practice.     

The effect of biopsy‐positive silent coeliac disease and treatment with a gluten‐free diet on growth and glycaemic control in children with Type 1 diabetes

Objective To determine the effect of coeliac disease and treatment with a gluten‐free diet on growth and glycaemic control in asymptomatic children with Type 1 diabetes. Methods Data were compared in children with coeliac disease diagnosed by annual antibody screening and jejunal biopsy and treated with a gluten‐free diet (n = 49) against individuals who were antibody negative (n = 49) matched for age, sex and duration of diabetes. Results No differences in growth were observed. In the years prior to diagnosis of coeliac disease, mean glycated haemoglobin (HbA_1c) was lower in cases compared with control subjects [8.3 ± 1.1% vs. 8.7 ± 0.9%, P = 0.02 (mean ± sd )]. In cases, HbA_1c deteriorated 12 months from the start of a gluten‐free diet to levels similar to control subjects (8.9 ± 1.5% vs. 8.8 ± 1.5%, P‐value for analysis of variance = 0.9). In regression analysis, the diagnosis of coeliac disease and start of a gluten‐free diet was associated with a rise in HbA_1c in the first year of treatment [odds ratio 1.56 (95% confidence intervals 1.16–2.10), P = 0.003] after adjusting for insulin dose and regimen and other variables. Conclusions In children with Type 1 diabetes, lower HbA_1c prior to diagnosis of silent coeliac disease rises following treatment with a gluten‐free diet to levels similar to those without coeliac disease. Although unproven, these observations may relate to abnormalities at the small bowel mucosa before the appearance of circulating coeliac antibodies.     

A decrease in serum 1,5‐anhydroglucitol levels is associated with the presence of a first‐degree family history of diabetes in a Chinese population with normal glucose tolerance

Aim

This study aimed to investigate alterations in HbA_1c, glycated albumin (GA) and 1,5‐anhydroglucitol (1,5‐AG) in Chinese first‐degree relatives of individuals with diabetes (FDR) in pursuit of an index for early screening of glucose metabolism disturbance.

Methods

A total of 467 participants (age range: 20–78 years) with normal weight and normal glucose tolerance, as determined by a 75‐g oral glucose tolerance test, were enrolled. HbA_1c was measured using high‐performance liquid chromatography. Serum GA and 1,5‐AG levels were determined by enzymatic methods. Serum insulin levels were measured using an electrochemiluminescence immunoassay.

Results

The study population included 208 FDR and 259 non‐FDR. Serum 1,5‐AG levels were lower in FDR than that in non‐FDR (20.4 ± 7.5 vs 23.8 ± 8.3 μg/ml, P < 0.001), but HbA_1c and GA levels did not differ between them (P = 0.835 and 0.469, respectively). Logistic regression analysis revealed an independent relationship between a first‐degree family history of diabetes and reduced serum 1,5‐AG levels (odds ratio = 0.944, P < 0.001). Multiple regression analysis showed that a first‐degree family history of diabetes (β = –3.041, P < 0.001) and insulinogenic index (β = 0.081, P = 0.001) were independently associated with serum 1,5‐AG levels.

Conclusion

In a Chinese population with normal glucose tolerance, serum 1,5‐AG levels were lower among FDR, and serum 1,5‐AG levels were independently associated with FDR status. For FDR, serum 1,5‐AG levels were more sensitive than HbA_1c or GA levels to early‐phase abnormality in glucose metabolism.     

A long‐term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized,double‐blind,parallel‐group comparison trial

Aims This study compared the effects of pioglitazone and gliclazide on metabolic control in drug‐naïve patients with Type 2 diabetes mellitus. Methods A total of 1270 patients with Type 2 diabetes were randomized in a parallel‐group, double‐dummy, double‐blind study. Patients with poorly controlled Type 2 diabetes (HbA_1c 7.5–11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA_1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C‐peptide and pro‐insulin levels were measured. Results Mean HbA_1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: ?1.4%; gliclazide: ?1.4%; (90% CI: ?0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference ?0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: ?0.7 to ?0.1)]. Improvements in high‐density lipoprotein cholesterol (HDL‐C) and total cholesterol/HDL‐C were greater with pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide. Conclusions Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA_1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.     

Improved glycaemic control and treatment satisfaction with a simple wearable 3‐day insulin delivery device among people with Type 2 diabetes

Aim

To evaluate the PAQ^® (CeQur SA, Horw, Switzerland), a wearable 3‐day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes.

Method

Adults with Type 2 diabetes with HbA_1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single‐arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA_1c, seven‐point self‐monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects.

Results

A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m², Type 2 diabetes duration 17 ± 8 years, HbA_1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA_1c –16 ± 9 mmol/mol (95% CI –20, –12) or –1.5 ± 0.9% (95% CI –1.8, –1.1) P<0.0001], and at all seven self‐monitored blood glucose readings time points (P ≤0.03). Total daily insulin dose increased by 12.1 ± 19.5 U (95% CI 3.9, 20.4; P=0.0058), the number of meal time boluses increased by 0.9 ± 1.5/day (95% CI 0.3, 1.5; P=0.0081) and body weight remained stable. Six participants had mild to moderate catheter site reactions and one mild skin irritation occurred. No participant experienced severe hypoglycaemia.

Conclusions

Adults with Type 2 diabetes were safely transitioned from insulin injections to the PAQ and had significantly improved glycaemic control and treatment satisfaction with insulin therapy. (ClinicalTrials.gov identifiers: NCT02158078 & NCT02419859)     

Modelling incremental benefits on complications rates when targeting lower HbA1c levels in people with Type 2 diabetes and cardiovascular disease

Aim

Glucose‐lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA_1c reductions might reduce risk is unclear.

Methods

Participant‐level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes‐specific simulation model to quantify the likely impact of different HbA_1c decrements on complication rates. Ten‐year micro‐ and macrovascular rates were estimated with HbA_1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA_1c decrement.

Results

Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd ) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL‐cholesterol 2.3 (0.9) mmol/l, HDL‐cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1–15.6) years. Ten‐year cumulative relative risk reductions for modelled HbA_1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes‐related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single‐eye blindness.

Conclusions

These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA_1c reductions in Type 2 diabetes.     

Translating HbA<Subscript>1c</Subscript> measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis

This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA_1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA_1c measurements are applicable to pregnant women with diabetes.

Methods

CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA_1c measure. In total, 688 average glucose–HbA_1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA_1c.

Results

There was a strong association between HbA_1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA_1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA_1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA_1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week.

Conclusions/interpretation

The HbA_1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care.

     

Cognitive behavioural therapy (CBT) compared with blood glucose awareness training (BGAT) in poorly controlled Type 1 diabetic patients: long‐term effects on HbA1c moderated by depression. A randomized controlled trial

Objective To test the effectiveness at 6 and 12 months’ follow‐up of group cognitive behavioural therapy (CBT) compared with blood glucose awareness training (BGAT) in poorly controlled Type 1 diabetic patients and to explore the moderating effect of baseline depression. Research design and methods Adults with Type 1 diabetes (n = 86) with glycated haemoglobin (HbA_1c) ≥ 8% were randomized to CBT or BGAT. Primary outcome was HbA_1c control. Secondary outcomes were: self‐care, diabetes‐related distress (Problem Areas in Diabetes scale; PAID), diabetes self‐efficacy (Confidence in Diabetes Self‐care scale; CIDS) and depressive symptoms (Centre for Epidemiological Studies – Depression scale; CES‐D). Measurements were scheduled before CBT and BGAT, and at 3, 6 and 12 months after. Differential effects were analysed for the subgroup of patients reporting low vs. high baseline levels of depression. Results Neither CBT nor BGAT had a significant impact on HbA_1c at 6 and 12 months’ follow‐up. Both interventions resulted in lower depressive symptoms (CES‐D 15.7–13.3, P = 0.01) up to 12 months, but only CBT was effective in lowering HbA_1c in patients with high baseline depression scores (HbA_1c 9.5–8.8%) up to 1 year of follow‐up (P = 0.03). Conclusions Our findings suggest that group CBT can effectively help Type 1 diabetic patients with co‐morbid depression achieve and maintain better glycaemic outcomes.     

Taspoglutide,a once‐weekly glucagon‐like peptide 1 analogue,vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open‐label randomized trial

Aims To compare the efficacy and safety of once‐weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. Methods This open‐label, parallel‐group, multi‐centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA_1c after 24 weeks. Results After 24 weeks, least‐square mean changes from baseline in HbA_1c in patients receiving taspoglutide 10 mg [?8 mmol/mol (se 1)] [?0.77% (se 0.05)] or taspoglutide 20 mg [?11 mmol/mol (se 1)] [?0.98% (se 0.05)] were non‐inferior to insulin glargine [?9 mmol/mol (se 1)] [?0.84% (se 0.05)]; treatment difference of 0.07% (95% CI ?0.06 to 0.21) and ?0.14% (95% CI ?0.28 to ?0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Conclusions Compared with insulin glargine, taspoglutide provided non‐inferior HbA_1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.     

Long‐term glycaemic effects of pioglitazone compared with placebo as add‐on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18)

Aims To assess the long‐term glycaemic effects, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of ≥ 90 days or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients receiving metformin or sulphonylurea monotherapy at baseline in the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive). Methods In PROactive, patients with Type 2 diabetes and macrovascular disease were randomized to pioglitazone (force titrated to 45 mg/day) or placebo, in addition to other existing glucose‐lowering therapies. In a post‐hoc analysis, we categorized patients not receiving insulin at baseline and treated by oral monotherapy into two main cohorts: add‐on to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow‐up averaged 34.5 months. Results There were significantly greater reductions in glycated haemoglobin (HbA_1c) with pioglitazone than with placebo and more pioglitazone‐treated patients achieved HbA_1c targets, irrespective of the baseline oral glucose‐lowering regimen and despite a decrease in the use of other glucose‐lowering agents. Approximately twice as many in the placebo groups progressed to permanent insulin use than in the pioglitazone groups across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea monotherapy. The overall safety of both dual therapies was good. Conclusions Intensifying an existing oral monotherapy regimen to a dual oral regimen by adding pioglitazone resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The efficacy and safety of adding pioglitazone to either metformin monotherapy or sulphonylurea monotherapy were good.     

Impact of type 1 diabetes on maternal long-term risk of hospitalisation and mortality: a nationwide combined clinical and register-based cohort study (The EPICOM study)

Aims/hypothesis

The aims of this study were to examine long-term mortality and morbidity rates in mothers with type 1 diabetes, both overall and according to the level of albuminuria prior to pregnancy, the presence of hypertension, pre-eclampsia and periconceptional HbA_1c.

Methods

This study was a part of the EPICOM (Environmental Versus Genetic and Epigenetic Influences on Growth, Metabolism and Cognitive Function in Offspring of Mothers with Type 1 Diabetes) study, which is a prospective follow-up study focusing on pregnancies complicated by maternal type 1 diabetes. We carried out a nationwide combined clinical and register-based cohort study of mortality rates and hospital admissions in mothers with diabetes (n?=?986) who gave birth between 1992 and 2000. Control mothers (n?=?91,441) were women from the background population, matched according to age and year of childbirth. Age at follow-up was 32–66 years.

Results

Mortality rate was increased threefold in mothers with diabetes compared with control mothers (HR 3.41 [95% CI 2.42, 4.81]; p?<?0.0001), and was also increased with pre-gestational kidney dysfunction (normoalbuminuria, HR 2.17 [95% CI 1.28, 3.68]; microalbuminuria, HR 3.36 [95% CI 0.82, 13.8]; macroalbuminuria, HR 12.9 [95% CI 5.45, 30.7]). Moreover, the presence of hypertension prior to or at any time during pregnancy and of pre-eclampsia also increased mortality rate (hypertension, HR 4.34 [95% CI 2.13, 8.84]; pre-eclampsia, HR 5.55 [95% CI 2.71, 11.4]). Mortality rate also increased with higher levels of HbA_1c in early pregnancy (HbA_1c ≤75 mmol/mol [≤9%], HR 2.15 [95% CI 1.31, 3.53]; HbA_1c >75 mmol/mol [>9%], HR 6.10 [95% CI 2.67, 14.0]). However, in mothers with diabetes and HbA_1c <64 mmol/mol (<8%) in the first trimester and normal pre-gestational urinary albumin excretion rate (n?=?517), mortality rate was comparable with that of control mothers. Among mothers with diabetes, mortality rate was associated with HbA_1c level: per 11 mmol/mol (1 percentage point) increase in HbA_1c, HR was 1.52 (95% CI 1.19, 1.94; p?=?0.001). In mothers with diabetes, the overall incidence of hospital admissions was more than double (incidence rate ratio [IRR] 2.69 [95% CI 2.59, 2.80]; p?<?0.0001) that of control mothers, as were admissions with various diagnoses from 14 out of 19 ICD-10 chapters. Among mothers with diabetes, the IRR for hospital admissions increased with the level of HbA_1c: per 11 mmol/mol (1 percentage point) increase in HbA_1c, HR was 1.07 (95% CI 1.04, 1.10; p?<?0.0001).

Conclusions/interpretation

Overall, mothers with type 1 diabetes have a two- to threefold increase in mortality and morbidity rates. HbA_1c levels, level of albuminuria around the time of conception, and the presence of hypertension and pre-eclampsia are important risk factors for mortality/morbidity in this cohort. However, it is reassuring that mothers with type 1 diabetes without kidney complications and with HbA_1c <64 mmol/mol (<8%) in early pregnancy have a similar survival potential during the period where they are raising their children to that of control mothers from the background population.