Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK - a nested case-control analysis

AIMS To assess incidence rates (IRs) of and identify risk factors for incident severe hypoglycaemia in patients with type 2 diabetes newly treated with antidiabetic drugs. METHODS Using the UK-based General Practice Research Database, we performed a retrospective cohort study between 1994 and 2011 and a nested case-control analysis. Ten controls from the population at risk were matched to each case with a recorded severe hypoglycaemia during follow-up on general practice, years of history in the database and calendar time. Using multivariate conditional logistic regression analyses, we adjusted for potential confounders. RESULTS Of 130,761 patients with newly treated type 2 diabetes (mean age 61.7 ± 13.0 years), 690 (0.5%) had an incident episode of severe hypoglycaemia recorded [estimated IR 11.97 (95% confidence interval, CI, 11.11-12.90) per 10,000 person-years (PYs)]. The IR was markedly higher in insulin users [49.64 (95% CI, 44.08-55.89) per 10,000 PYs] than in patients not using insulin [8.03 (95% CI, 7.30-8.84) per 10,000 PYs]. Based on results of the nested case-control analysis increasing age [≥ 75 vs. 20-59 years; adjusted odds ratio (OR), 2.27; 95% CI, 1.65-3.12], cognitive impairment/dementia (adjusted OR, 2.00; 95% CI, 1.37-2.91), renal failure (adjusted OR, 1.34; 95% CI, 1.04-1.71), current use of sulphonylureas (adjusted OR, 4.45; 95% CI, 3.53-5.60) and current insulin use (adjusted OR, 11.83; 95% CI, 9.00-15.54) were all associated with an increased risk of severe hypoglycaemia. CONCLUSIONS Severe hypoglycaemia was recorded in 12 cases per 10,000 PYs. Risk factors for severe hypoglycaemia included increasing age, renal failure, cognitive impairment/dementia, and current use of insulin or sulphonylureas.

Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: a population-based case-control study

OBJECTIVE The aim of this study was to explore the risk of incident gout in patients with type 2 diabetes mellitus (T2DM) in association with diabetes duration, diabetes severity and antidiabetic drug treatment. METHODS We conducted a case-control study in patients with T2DM using the UK-based Clinical Practice Research Datalink (CPRD). We identified case patients aged ≥18 years with an incident diagnosis of gout between 1990 and 2012. We matched to each case patient one gout-free control patient. We used conditional logistic regression analysis to calculate adjusted ORs (adj. ORs) with 95% CIs and adjusted our analyses for important potential confounders. RESULTS The study encompassed 7536 T2DM cases with a first-time diagnosis of gout. Compared to a diabetes duration <1 year, prolonged diabetes duration (1-3, 3-6, 7-9 and ≥10 years) was associated with decreased adj. ORs of 0.91 (95% CI 0.79 to 1.04), 0.76 (95% CI 0.67 to 0.86), 0.70 (95% CI 0.61 to 0.86), and 0.58 (95% CI 0.51 to 0.66), respectively. Compared to a reference A1C level of <7%, the risk estimates of increasing A1C levels (7.0-7.9, 8.0-8.9 and ≥9%) steadily decreased with adj. ORs of 0.79 (95% CI 0.72 to 0.86), 0.63 (95% CI 0.55 to 0.72), and 0.46 (95% CI 0.40 to 0.53), respectively. Neither use of insulin, metformin, nor sulfonylureas was associated with an altered risk of incident gout. CONCLUSIONS Increased A1C levels, but not use of antidiabetic drugs, was associated with a decreased risk of incident gout among patients with T2DM.

Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study.

OBJECTIVE Vitamin D (D₃) status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, few placebo-controlled intervention data are available. We aimed to assess the effect of large doses of parenteral D3 on glycosylated haemoglobin (HbA(₁c)) and estimates of insulin action (homeostasis model assessment insulin resistance: HOMA-IR) in patients with stable T2DM. MATERIALS AND METHODS We performed a prospective, randomised, double-blind, placebo-controlled pilot study at a single university care setting in Switzerland. Fifty-five patients of both genders with T2DM of more than 10 years were enrolled and randomised to either 300,000 IU D₃ or placebo, intramuscularly. The primary endpoint was the intergroup difference in HbA(₁c) levels. Secondary endpoints were: changes in insulin sensitivity, albuminuria, calcium/phosphate metabolism, activity of the renin-aldosterone axis and changes in 24-hour ambulatory blood pressure values. RESULTS After 6 months of D₃ supply, there was a significant intergroup difference in the change in HbA(₁c) levels (relative change [mean ± standard deviation] +2.9% ± 1.5% in the D₃ group vs +6.9% ± 2.1% the in placebo group, p = 0.041) as HOMA-IR decreased by 12.8% ± 5.6% in the D₃ group and increased by 10% ± 5.4% in the placebo group (intergroup difference, p = 0.032). Twenty-four-hour urinary albumin excretion decreased in the D₃ group from 200 ± 41 to 126 ± 39, p = 0.021). There was no significant intergroup difference for the other secondary endpoints. CONCLUSIONS D₃ improved insulin sensitivity (based on HOMA-IR) and affected the course of HbA(₁c) positively compared with placebo in patients with T2DM.

The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus

Objective: To compare the effects of a 4-month strength training (ST) versus aerobic endurance training (ET) program on metabolic control, muscle strength, and cardiovascular endurance in subjects with type 2 diabetes mellitus (T2D). Design: Randomized controlled trial. Setting: Large public tertiary hospital. Participants: Twenty-two T21) participants (I I men, I I women; mean age +/- standard error, 56.2 +/- 1.1 y; diabetes duration, 8.8 +/- 3.5y) were randomized into a 4-month ST program and 17 T2D participants (9 men, 8 women; mean age, 57.9 +/- 1.4y; diabetes duration, 9.2 +/- 1.7y) into a 4-month ET program. Interventions: ST (up to 6 sets per muscle group per week) and ET (with an intensity of maximal oxygen consumption of 60% and a volume beginning at 15min and advancing to a maximum of 30min 3X/wk) for 4 months. Main Outcome Measures: Laboratory tests included determinations of blood glucose, glycosylated hemoglobin (Hb A(1c)), insulin, and lipid assays. Results: A significant decline in Hb A, was only observed in the ST group (8.3% +/- 1.7% to 7.1% +/- 0.2%, P=.001). Blood glucose (204 +/- 16mg/dL to 147 +/- 8mg/dL, P <.001) and insulin resistance (9.11 +/- 1.51 to 7.15 +/- 1.15, P=.04) improved significantly in the ST group, whereas no significant changes were observed in the ET group. Baseline levels of total cholesterol (207 +/- 8mg/dL to 184 +/- 7mg/dL, P <.001), low-density lipoprotein cholesterol (120 +/- 8mg/dL to 106 +/- 8mg/dL, P=.001), and triglyceride levels (229 +/- 25mg/dL to 150 +/- 15mg/dL, P=.001) were significantly reduced and high-density lipoprotein cholesterol (43 +/- 3mg/dL to 48 +/- 2mg/dL, P=.004) was significantly increased in the ST group; in contrast, no such changes were seen in the ET group. Conclusions: ST was more effective than ET in improving glycemic control. With the added advantage of an improved lipid profile, we conclude that ST may play an important role in the treatment of T2D.

Diastolic dysfunction is a manifestation of ventricular-vascular interaction in patients with type 2 diabetes mellitus

Vascular disease is accelerated in patients with Type 2 diabetes mellitus (T2DM). Since the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on left ventricular (LV) morphology and function in patients with T2DM. Conventional echocardiography and tissue Doppler imaging were performed in 172 T2DM patients (95 men; aged 55±11y) with preserved ejection fraction (62±5%). Patients were stratified into groups based on LV geometric pattern (normal [n = 79], concentric remodeling [n = 33], concentric hypertrophy [n = 29], eccentric hypertrophy [n = 31]). Total arterial compliance (TAC) was recorded by simultaneous radial tonometry and aortic outflow pulsed wave Doppler. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences between the LV geometric groups in demographic or clinical parameters. The concentric hypertrophy group had significantly increased carotid artery diameter (6.0±0.7mm versus 6.5±0.7mm; p < 0.05) and stiffness (1912±1203 dynes/cm2mm versus 2976±2695 dynes/cm2mm×10−6; p < 0.05) compared to those with normal geometry. However, TAC did not differ between groups. LV diastolic function, as determined by the ratio of diastolic mitral inflow velocity to mitral annulus tissue velocity (E/E_), was significantly associated with carotid artery relative wall thickness and intima media thickness (p < 0.05). Moreover, E/E_ was independently predicted by carotid artery relative wall thickness (β = 22.9; p = 0.007). We conclude that structural characteristics of the carotid artery are associated with abnormal LV structure and function in patients with T2DM. The LV functional irregularities may be a downstream consequence of amplified pressure wave reflections effecting sub-optimal ventricular-vascular interaction.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in South Asian males with type 2 diabetes mellitus

South Asians have a higher risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) than white Caucasians, for a given BMI. Premature biological ageing, assessed by reduction in telomere length (TL), may be mediated by factors resulting from altered metabolic profiles associated with obesity. We hypothesise that ethnicity and metabolic status represent detrimental factors contributing to premature biological ageing. Therefore we assessed TL in two South Asian, age and BMI-matched cohorts [T2DM (n = 142) versus non-T2DM (n = 76)] to determine the effects of BMI, gender, lipid and CVD profile on biological ageing. Genomic DNA was obtained from the UKADS cohort; biochemical and anthropometric data was collected and TL was measured by quantitative real-time PCR. Our findings indicated a gender-specific effect with reduced TL in T2DM men compared with non-T2DM men (P = 0.006). Additionally, in T2DM men, TL was inversely correlated with triglycerides and total cholesterol (r = -0.419, P <0.01; r = -0.443, P <0.01). In summary, TL was reduced amongst South Asian T2DM men and correlated with triglycerides and total cholesterol. This study highlights enhanced biological ageing among South Asian, T2DM men, which appears to be tracked by changes in lipids and BMI, suggesting that raised lipids and BMI may directly contribute to premature ageing.

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background - Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods - We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results - The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion - Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

New drugs for type 2 diabetes mellitus:what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulforylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women. Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagonlike peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on P cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety. In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.