Presence of retinopathy and incident kidney and cardiovascular events in type 2 diabetes with normoalbuminuria – A post-hoc analysis of the PRIORITY randomized clinical trial

AimsBaseline diabetic retinopathy (DR) and risk of development of microalbuminuria, kidney function decline, and cardiovascular events (CVEs) in type 2 diabetes.MethodsPost-hoc analysis of the PRIORITY study including 1758 persons with type 2 diabetes and normoalbuminuria followed for a median of 2.5 (IQR: 2.0–3.0) years. DR diagnosis included non-proliferative and proliferative abnormalities, macular oedema, or prior laser treatment. Cox models were fitted to investigate baseline DR presence with development of persistent microalbuminuria (urinary albumin-creatinine ratio > 30 mg/g); chronic kidney disease (CKD) G3 (eGFR <60 ml/min/1.73m²); and CVE. Models were adjusted for relevant risk factors.ResultsAt baseline, 304 (17.3 %) had DR. Compared to persons without DR, they were older (mean ± SD: 62.7 ± 7.7 vs 61.4 ± 8.3 years, p = 0.019), had longer diabetes duration (17.9 ± 8.4 vs. 10.6 ± 7.0 years, p < 0.001), and higher HbA_1c (62 ± 13 vs. 56 ± 12 mmol/mol, p < 0.001). The adjusted hazard ratios of DR at baseline for development of microalbuminuria (n = 197), CKD (n = 166), and CVE (n = 64) were: 1.50 (95%CI: 1.07, 2.11), 0.87 (95%CI: 0.56, 1.34), and 2.61 (95%CI: 1.44, 4.72), compared to without DR.ConclusionsPresence of DR in normoalbuminuric type 2 diabetes was associated with an increased risk of developing microalbuminuria and CVE, but not with kidney function decline.     

Empagliflozin in women with type 2 diabetes and cardiovascular disease – an analysis of EMPA-REG OUTCOME®

Aims/hypothesis

The global epidemic of type 2 diabetes affects women and men equally; however, the relative impact on the cardiovascular (CV) system appears greater for women than men when compared with peers without diabetes. Furthermore, women are often under-represented in CV outcome trials, resulting in less certainty about the impact of CV prevention therapies across the sexes. The EMPA-REG OUTCOME® trial, which included 28.5% women, found that empagliflozin, given in addition to standard of care, reduced the risk of CV death by 38%, heart failure (HF) hospitalisation by 35% and a composite endpoint for incident or worsening nephropathy by 39%. Here we report a secondary analysis of the trial to determine the relative effects of empagliflozin in women vs men.

Methods

The population studied were individuals with type 2 diabetes (HbA_1c 53–86 mmol/mol [7–10%] and eGFR >30 ml min^?1 [1.73 m]^?2), with established atherosclerotic CV disease. Individuals were randomised to receive empagliflozin 10 mg or 25 mg, or placebo once daily in addition to standard of care, and followed. The trial continued until ≥691 individuals had experienced an adjudicated event included in the primary outcome. All CV outcome events, including HF hospitalisations and deaths were prospectively adjudicated by blinded clinical events committees.

Results

At baseline, the demographic profile of the 2004 women (age ± standard deviation 63.6?±?8.8 years) compared with the 5016 men (age 63.0?±?8.6 years) in the trial was largely similar, with the exception that LDL-cholesterol was numerically higher in women (2.5?±?1.0 vs 2.1?±?0.9 mmol/l), consistent with lower rates of lipid-lowering therapies (75.4% vs 83.2%). Women were also less likely to have smoked (31.5% vs 69.9%). The annualised incidence rate for women in the placebo group was numerically lower than in men for CV death (1.58% vs 2.19%), numerically higher for HF hospitalisation (1.75% vs 1.33%) and similar for renal events (7.22% vs 7.75%). We did not detect any effect modification by sex within the statistical power restrictions of the analysis for CV death, HF hospitalisation and incident or worsening nephropathy (interaction p values 0.32, 0.20 and 0.85, respectively). Compared with placebo, empagliflozin increased the rates of genital infections in both women (2.5% vs 10.0%) and men (1.5% vs 2.6%).

Conclusions/interpretation

CV death, HF hospitalisation and incident or worsening nephropathy rate reductions induced by empagliflozin were not different between women and men.

     

Effect of dapagliflozin on cardiac function in people with type 2 diabetes and albuminuria – A double blind randomized placebo-controlled crossover trial

AimsSodium glucose transport inhibitors (SGLT2i) can reduce risk of heart failure (HF) and cardiovascular death in people with type 2 diabetes (T2D) and existing cardiovascular disease. Our aim was to examine the effect of the SGLT2i dapagliflozin on cardiac function in people with T2D and albuminuria.MethodsA secondary analysis of a double-blind, randomized, cross-over study of 12 weeks treatment with dapagliflozin 10 mg versus placebo. Myocardial function was assessed by echocardiography and biomarkers of cardiac risk were measured. An exploratory diastolic composite of echocardiographic variables was computed.ResultsOf the 36 participants completing the study 89% were male, mean age 64 ± 8 years, diabetes duration 16.4 ± 4.7 years and HbA_1c 73 ± 15 mmol/mol (8.9 ± 1.4%), 30.6% had former cardiovascular events and 32% had macroalbuminuria. Mean left ventricular ejection fraction (LVEF) was 55.4% after placebo and 54.3% after dapagliflozin (p = 0.15), global longitudinal strain −16.1 vs. −15.9, (p = 0.64), E/e′ 7.6 vs. 7.6 (p = 0.082), and tissue Doppler velocity e′ 10.0 vs. 10.6 (p = 0.05). The composite score showed diastolic function improvement of 19.8% (p = 0.021). No other significant changes were observed.ConclusionsDapagliflozin may have minor effects on diastolic function in people with T2D, albuminuria and preserved LVEF.     

Vitamin D and nifedipine in the treatment of Chinese patients with grades I–II essential hypertension: A randomized placebo-controlled trial

Objectives

Low vitamin D status has been shown to be associated with hypertension. We planned to research the effect of vitamin D and nifedipine in the treatment of patients with essential hypertension.

Methods

Patients with grades I–II essential hypertension were enrolled in this single-center, double-blind, placebo-controlled trial in Beijing. All patients received a conventional antihypertensive drug (nifedipine, 30 mg/d). One hundred and twenty-six patients were randomly assigned to receive vitamin D (n = 63, 2000 IU/d) or a placebo (n = 63) as an add-on to nifedipine, by the method of permutated block randomization. Ambulatory blood pressure monitoring was performed at baseline (month 0), at month 3 and at month 6.

Results

In vitamin D supplementation group, there was a significant increase in mean 25-hydroxyvitamin D levels from baseline (19.4 ± 11.6 ng/ml) to 6 months (34.1 ± 12.2 ng/ml; p < 0.001). At 6 months, the primary end points, a difference in the fall of 24-h mean blood pressure, between the groups was −6.2 mm Hg (95% CI −11.2; −1.1) for systolic blood pressure (p < 0.001) and −4.2 mm Hg (95% CI −8.8; −0.3) for diastolic blood pressure (p < 0.001) under intention to treat analysis. In patients with vitamin D <30 ng/ml at baseline (n = 113), 24-h mean blood pressure decreased by 7.1/5.7 mm Hg (p < 0.001). Safety and tolerability were similar among the two groups.

Conclusions

Vitamin D supplementation can reduce blood pressure in patients with hypertension, it can be an adjuvant therapy for patients with grades I–II essential hypertension.Clinical Trial Registration: This study was registered in the Chinese Clinical Trial Registry, it is available in Website: http://www.chictr.org/cn/; Registration number: ChiCTR-ONC-13003840.     

Sickle-cell disease and malaria: evaluation of seasonal intermittent preventive treatment with sulfadoxine-pyrimethamine in Senegalese patients—a randomized placebo-controlled trial

Sickle-cell disease (SCD) patients are at high risk of developing malaria which is a major contributor to morbidity and mortality in this disease. In Senegal, malaria transmission is high during rainy season, between July and October, and it was noted that sickle-cell crisis are frequent during this period. Then we carried out a double-blind randomized controlled trial to compare the impact of monthly sulfadoxine-pyrimethamine (SP) during the high-transmission season versus placebo on malaria incidence and morbidity of sickle-cell anemia. Sixty (60) SCD patients were randomized either to receive three intermittent preventive treatment (ITP) with SP or placebo using the random permutation table with nine elements. The drug was administrated as follows: sulfadoxine 25 mg/kg and pyrimethamine 1.25 mg/kg and this treatment was given once during the following months: September, October, and November. Overall four episodes of malaria disease were diagnosed, all these cases in the placebo arm. Thus, overall prevalence was 6.6% and there was no other case of malaria in the SP arm during the study period. Parasitological diagnosis confirmed the presence of Plasmodium falciparum in all four cases. No patient death was encountered during the study. SP treatment was well tolerated as only one patient (1.6%) in the SP arm reported pruritis. A significant reduction of patients' complaints (p = 002) and blood requirements (p = 0.001) was noted in the SP group; whereas, no impact was observed on vaso-occlusive crisis and hospitalization occurrence. Malaria prophylaxis by monthly intake of SP during the transmission period of the parasite reduced the prevalence of malaria and was safe in SCD patients leaving in malaria endemic area.     

Toe–brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria

Aims/hypothesis

The study aimed to evaluate toe–brachial index (TBI) and ankle–brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria.

Methods

This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement.

Results

Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and all-cause mortality (1.37 [1.09, 1.57]) unadjusted and after adjustment for traditional risk factors (CVD 1.44 [1.23, 1.59] and all-cause mortality 1.39 [1.07, 1.60]). After additional adjustment for NT-proBNP and coronary artery calcification, lower TBI remained a determinant of CVD (p = 0.023). When TBI was added to traditional risk factors, the AUC increased significantly for CVD, by 0.063 (95% CI 0.012, 0.115) from 0.743 (p = 0.016), but not for all-cause mortality; adding ABI did not improve the AUC significantly. The rIDI for TBI was 46.7% (p < 0.001) for CVD and 46.0% (p = 0.002) for all-cause mortality; for ABI, the rIDI was 51.8% (p = 0.004) for CVD and 53.6% (p = 0.031) for all-cause mortality.

Conclusions/interpretation

Reduced TBI and ABI were associated with increased risk of CVD and all-cause mortality, independent of traditional risk factors in type 2 diabetes, and improved prognostic accuracy.

     

Benefits of satins in elderly subjects without established cardiovascular disease： A meta- analysis

To assess whether statins reduce all-cause mortality and CV events in elderly people without established CV disease.     

Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial

Aim: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase‐4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment‐naive or who had received one oral antidiabetes drug (OAD). Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run‐in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2‐week placebo run‐in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo‐corrected change in HbA1c from baseline of ?0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by ?1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2‐h postprandial glucose of ?3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment‐%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third‐party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of β‐cell function. The safety profile of linagliptin was comparable with that of placebo.     

The LEADER trial in type 2 diabetes: Were the characteristics and outcomes of the participants representative?

AimsTo compare the characteristics and outcomes of people with type 2 diabetes recruited to the LEADER trial to those of participants in the contemporaneous community-based Fremantle Diabetes Study Phase II (FDS2) who fulfilled LEADER entry criteria.MethodsBaseline characteristics of LEADER and LEADER-eligible FDS2 participants were compared using bivariate methods. Incidence rates of the primary (nonfatal myocardial infarction, nonfatal stroke, cardiovascular disease (CVD) death) and other outcomes in the LEADER placebo group were compared with those in LEADER-eligible FDS2 participants during 3.8 years after entry, the median LEADER follow-up.ResultsOf 1551 FDS2 type 2 participants, 323 (20.8%) were LEADER-eligible. Compared with the LEADER sample, they were an average 6 years older, and were less likely to be male, obese and to have prior CVD. There were 3.9 and 2.9 primary outcomes/100 patient-years in LEADER placebo-treated and FDS2 LEADER-eligible patients, respectively. Incidence rates for first myocardial infarction and stroke were 1.9 and 2.1 events/100 patient-years and 1.1 and 1.0 events/100 patient-years, respectively. FDS2 LEADER-eligible patients had a lower CVD death rate of 0.8 versus 1.6/100 patient-years in the LEADER placebo group, but their non-CVD mortality was greater (2.1 versus 1.0/100 patient-years).ConclusionsThese data suggest recruitment bias in type 2 diabetes CVD outcome trials.     

A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial

STUDY OBJECTIVES: Skeletal muscle weakness commonly occurs in patients with COPD. Long-term use of systemic glucocorticosteroids further contributes to muscle weakness. Anabolic steroids could be an additional mode of intervention to improve outcome of pulmonary rehabilitation by increasing physiologic functioning, possibly mediated by increasing erythropoietic function. PATIENTS AND METHODS: We randomly assigned 63 male patients with COPD to receive on days 1, 15, 29, and 43 a deep IM injection of 50 mg of nandrolone decanoate (ND) [Deca-Durabolin; N.V. Organon; Oss, The Netherlands] in 1 mL of arachis oil, or 1 mL of arachis oil alone (placebo) in a double-blind design. All patients participated in a standardized pulmonary rehabilitation program. Outcome measures were body composition by deuterium and bromide dilution, respiratory and peripheral muscle function, incremental exercise testing, and health status by the St. George's Respiratory Questionnaire. RESULTS: Treatment with ND relative to placebo resulted in higher increases in fat-free mass (FFM; mean, 1.7 kg [SD, 2.5] vs 0.3 kg [SD, 1.9]; p = 0.015) owing to a rise in intracellular mass (mean, 1.8 kg [SD, 3.1] vs - 0.5 kg [SD, 3.1]; p = 0.002). Muscle function, exercise capacity, and health status improved in both groups to the same extent. Only after ND were increases in erythropoietic parameters seen (erythropoietin: mean, 2.08 U/L [SD, 5.56], p = 0.067; hemoglobin: mean, 0.29 mmol/L [SD, 0.73], p = 0.055). In the total group, the changes in maximal inspiratory mouth pressure (PImax) and peak workload were positively correlated with the change in hemoglobin (r = 0.30, p = 0.032, and r = 0.34, p = 0.016, respectively), whereas the change in isokinetic leg work was correlated with the change in erythropoietin (r = 0.38, p = 0.013). In the patients receiving maintenance treatment with low-dose oral glucocorticosteroids (31 of 63 patients; mean, 7.5 mg/24 h [SD, 2.4]), greater improvements in PImax (mean, 6.0 cm H(2)O [SD, 8.82] vs - 2.18 cm H(2)O [SD, 11.08], p = 0.046), and peak workload (mean, 20.47 W [SD, 19.82] vs 4.80 W [SD, 7.74], p = 0.023) were seen after 8 weeks of treatment with ND vs placebo. CONCLUSIONS: In conclusion, a short-term course of ND had an overall positive effect relative to placebo on FFM without expanding extracellular water in patients with COPD. In the total group, the improvements in muscle function and exercise capacity were associated with improvements in erythropoietic parameters. The use of low-dose oral glucocorticosteroids as maintenance medication significantly impaired the response to pulmonary rehabilitation with respect to respiratory muscle function and exercise capacity, which could be restored by ND treatment.     

Can peer educators influence healthy eating in people with diabetes? Results of a randomized controlled trial

Aims To assess whether the Expert Patient Programme (EPP), adapted for people with Type 2 diabetes, can be used to promote healthy eating to improve glycaemic control. Methods Adults with Type 2 diabetes (n = 317) were randomized to receive either a diabetes‐specific EPP (n = 162) or individual one‐off appointments with a dietitian (control group) (n = 155). The diabetes‐specific EPP followed the standard National Health Service programme although all participants in the group had diabetes only, rather than a mix of chronic conditions. Participants attended a group session for 2 h once per week for 6 weeks. In addition, a final seventh‐week 2‐h session was included that was specific to issues concerning diabetes. Outcomes were assessed at baseline, 6 and 12 months. Results There were no statistically significant differences between the control and the intervention group in any of the clinical outcomes measured. There was no significant difference between the groups in any dietary outcome. There was a higher starch intake in the EPP group, although this did not reach statistical significance (effect size for starch adjusted for baseline values 8.8 g; 95% CI ?1.3 to 18.9). There was some loss of participants between baseline measurement and randomization, although this did not appear to have had an important impact on baseline balance. Conclusions In this study of people with Type 2 diabetes, the EPP approach was not effective in changing measures of diabetes control or diet.     

Chronic kidney disease categories and renal–cardiovascular outcomes in type 2 diabetes without prevalent cardiovascular disease: a prospective cohort study (JDDM25)

Aims/hypothesis

In type 2 diabetic patients at low risk for cardiovascular disease (CVD), the relationship between the clinical course of nephropathy by stage of chronic kidney disease (CKD) and onset of CVD remains unclear. Clarification of this relationship is important for clinical decision-making for both low- and high-risk diabetic patients.

Methods

This 4?year prospective study enrolled 2,954 type 2 diabetic patients with no prevalent CVD, and serum creatinine <176.8?μmol/l. The risk for CVD onset (non-fatal and fatal CVD and stroke, and peripheral arterial disease) was assessed according to CKD stage categorised by urinary albumin-to-creatinine ratio (ACR; mg/mmol) and estimated GFR (eGFR; ml?min^?1 1.73?m^?2). Association of progression from ‘no CKD’ stage (ACR <3.5?mg/mmol and eGFR ≥90?ml?min^?1 1.73?m^?2) with risk for CVD onset was also evaluated.

Results

During follow-up (median 3.8?years), 89 CVD events occurred. Compared with patients with ‘no CKD’ as reference, those with ACR?≥?35.0?mg/mmol with co-existing eGFR 60–89?ml?min^?1 1.73?m^?2 or <60?ml?min^?1 1.73?m^?2 showed increased risk for CVD onset, whereas those with eGFR ≥90?ml?min^?1 1.73?m^?2 did not. Those with ACR <3.5?mg/mmol and eGFR <60?ml?min^?1 1.73?m^?2 did not show any increased risk. Among patients with ‘no CKD’ stage at baseline, those who progressed to ACR ≥3.5?mg/mmol during follow-up showed an increased risk compared with those who did not, whereas those who progressed to eGFR <90?ml?min^?1 1.73?m^?2 did not have increased risk.

Conclusions/interpretation

The risk for CVD was associated with progression of albuminuria stage rather than eGFR stage in type 2 diabetic patients at relatively low risk for CVD.     

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial

AimsThe coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk.MethodsODYSSEY DM–INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening ≥ 70 mg/dL (1.81 mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24 weeks of alirocumab 75 mg every 2 weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C ≥ 70 mg/dL at week 8 underwent a blinded dose increase to 150 mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety.ResultsThis is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017.ConclusionThe ODYSSEY DM–INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.     

Incident and recurrent hypoglycaemia with linagliptin and glimepiride over a median of 6 years in the CAROLINA cardiovascular outcome trial

Aim

The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA.

Materials and methods

Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored.

Results

Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [−0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (−1.54 kg, [−1.80, −1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation.

Conclusions

Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.