Inhibition of the renin-angiotensin system in normotensive type 2 diabetes: effects and mechanisms of action

The majority of clinical trials, investigating the effects of angiotensin-receptor antagonists on the diabetic kidney, have focused on hypertensive patients, thereby leaving the possibility that reduction of the systemic blood pressure explains for (most of ) the renoprotective eff ects1-5. Therefore, we studied the effects of the angiotensin-receptor antagonist losartan on urinary albumin excretion, renal function and blood pressure in normotensive patients with type 2 diabetes mellitus and microalbuminuria. The significant reduction in urinary albumin excretion rate by 35%, which we observed after 10 weeks of losartan treatment, is quantitatively comparable to the antiproteinuric effects of losartan in hypertensive diabetic patients1,2,4,6,7. In our normotensive patients, this reduction could not be explained by changes in systemic blood pressure or creatinine clearance, suggesting the involvement of other losartan-mediated mechanisms. First, antagonising the intrarenal angiotensin II leads to favorable intraglomerular haemodynamics, like reduction in arteriolar resistance and intraglomerular pressure, thereby increasing renal plasma flow, reducing the filtration fraction and thus urinary albumin excretion8,9. These changes mainly account for the early rapid component of albuminuria reduction, which parallels the time-course of changes in renal haemodynamics and is thought to be maximal within the first weeks of treatment10,11. Our results of the order of magnitude of the antiproteinuric effect after 5 respectively 10 weeks of losartan treatment, as well as the fact that urinary albumin excretion returned to pretreatment levels in the 5-week placebo washout period, are in concordance with these observations and thus probably result mostly from renal haemodynamic factors. Secondly, losartan treatment probably results in slower, non-haemodynamic renal changes as well, contributing to the well-established long-term renoprotective effects of angiotensin II antagonists in patients with diabetes mellitus3-5. These changes possibly involve improvement of endothelial function and reduction of the chronic low-grade infl ammatory state12,13. However, we have no data on this in our patient population to support this assumption in our studies. Furthermore, the interference of losartan with various growth factor systems is thought to reduce the production of extracellular matrix proteins, finally resulting in slowing down the progression of glomerulosclerosis and tubulointerstitial fi brosis14

Normotensive women with type 2 diabetes and microalbuminuria are at high risk for macrovascular disease

OBJECTIVE - The excess risk of macrovascular disease and death associated with diabetes seems higher in women than in men. The pathogenesis for this risk difference has not been fully elucidated. We investigated whether female sex was associated with macrovascular disease and death, independently of known risk factors related to type 2 diabetes, nephropathy, or retinopathy in normotensive patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS - We conducted a prospective, prolonged follow-up study of a subgroup of 67 diabetic patients (46 men and 21 women) without established cardiovascular disease who participated in a larger clinical trial. Data were collected on current and past health, medication use, blood pressure, renal function, and HbA1c during the follow-up period of 4.7 ± 0.8 (means ± SE) years. The end point was a composite of death, cardiovascular disease, cerebrovascular events, and peripheral artery disease. RESULTS - Of the women, eight (38.1%) met the end point compared with six (13.4%) of the men (P = 0.02 for difference in event-free survival). The hazard ratio of women relative to men was 3.19 (95% CI 1.11-9.21), which further increased after adjusting for age, systolic blood pressure, BMI, smoking, total-to-HDL cholesterol ratio, urinary albumin excretion, and retinopathy. CONCLUSIONS - In our study population of normotensive patients with type 2 diabetes and microalbuminuria, female sex was associated with increased risk of fatal and nonfatal cardiovascular disease, independent of the classical cardiovascular risk factors, the severity of nephropathy or presence of retinopathy, or health care utilization

Occurrence and predictors of persistent impaired glucose tolerance after acute ischemic stroke or transient ischemic attack

Background Impaired glucose tolerance is often present in patients with a transient ischemic attack (TIA) or ischemic stroke and doubles the risk of recurrent stroke. This impaired glucose tolerance can be transient, reflecting an acute stress response, or persistent, representing undiagnosed impaired glucose metabolism possibly requiring treatment. We aimed to assess the occurrence of persistent impaired glucose tolerance after a stroke or TIA and to develop a prediction model to identify patients at risk of persistent impaired glucose tolerance. Methods Patients admitted to the str

Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke (MAAS): study protocol for a randomized controlled trial

Background: Impaired glucose tolerance is present in one third of patients with a TIA or ischemic stroke and is associated with a two-fold risk of recurrent stroke. Metformin improves glucose tolerance, but often leads to side effects. The aim of this study is to explore the feasibility, safety, and effects on glucose metabolism of metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will also assess whether a slow increase in metformin dose and better support and information on this treatment will reduce the incidence of side effects in these patients. Methods/Design: The Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke trial (MAAS trial) is a phase II, multicenter, randomized, controlled, open-label trial with blinded outcome assessment. Non-diabetic patients (n = 100) with a recent (<6 months) TIA, amaurosis fugax or minor ischemic stroke (modified Rankin scale ≤ 3) and impaired glucose tolerance, defined as 2-hour post-load glucose levels between 7.8 and 11.0 mmol/L after repeated standard oral glucose tolerance test, will be included. Patients with renal or liver impairment, heart failure, chronic hypoxic lung disease stage III-IV, history of lactate acidosis or diabetic ketoacidosis, pregnancy or breastfeeding, pancreatitis and use of digoxin will be excluded. The patients will be randomly assigned in a 1:1:2 ratio to metformin, sitagliptin or "no treatment." Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased during a 6-week period to a twice daily dose of 1000 mg. Patients allocated to sitagliptin will be treated with a daily fixed dose of 100 mg. The study has been registered as NTR 3196 in The Netherlands Trial Register. Primary outcomes include percentage still on treatment, percentage of (serious) adverse events, and the baseline adjusted difference in 2-hour post-load glucose levels at 6 months. Discussion: This study will give more information about the feasibility and safety of metformin and sitagliptin as well as the effect on 2-hour post-load glucose levels at 6 months in patients with TIA or ischemic stroke and impaired glucose tolerance

Prediction of Persistent Impaired Glucose Tolerance in Patients with Minor Ischemic Stroke or Transient Ischemic Attack

Background: Impaired glucose tolerance (IGT) in patients with ischemic stroke can return to normal, reflecting an acute stress response, or persist. Persistent IGT is associated with an increased risk of recurrent stroke, other cardiovascular diseases and unfavorable outcome after stroke. We aim to validate our previously developed model to identify patients at risk of persistent IGT in an independent data set, and, if necessary, update the model. Methods: The validation data set consisted of 239 nondiabetic patients with a minor ischemic stroke or TIA and IGT in the acute phase (2-hour post-load glucose levels between 7.8 and 11.0 mmol/l). The outcome was persistent versus normalized IGT, based on repeated oral glucose tolerance test after a median of 46 days. The discriminative ability of the original model was assessed with the area under the ROC curve (AUC). The updated model was internally validated with bootstrap resampling and cross-validated in the development population of the original model. Results: One-hundred eighteen of 239 (49%) patients had persistent IGT. The original model, with the predictors age, current smoking, statin use, triglyceride, hypertension, history of cardiovascular diseases, body mass index (BMI), fasting plasma glucose performed poorly (AUC .60). The newly developed model included only BMI, hypertension, statin use, atrial fibrillation, 2-hour post-load glucose levels, HbA1c, large artery atherosclerosis, and predicted persistent IGT more accurately (internally validated AUC 0.66, externally validated AUC .71). Conclusions: This prediction model with simple clinical variables can be used to predict persistent IGT in patients with IGT directly after minor stroke or TIA, and may be useful to optimize secondary prevention by early identification of patients with disturbed glucose metabolism

Use of monomeric and oligomeric flavanols in the dietary management of patients with type 2 diabetes mellitus and microalb

__Background:__ Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications. Monomeric and oligomeric flavanols (MOF) isolated from grape seeds (Vitis vinifera) have been linked to improved endothelial function and vascular health. The aim of this study is to determine the effect of a daily supplementation of 200 mg MOF on renal endothelial function of patients with T2D and microalbuminuria. __Methods/design:__ For this double-blind, placebo-controlled, randomized, multicenter trial 96 individuals (ages 40-85 years) with T2D and microalbuminuria will be recruited. Participants will be randomly assigned to the intervention group, receiving 200 mg of MOF daily for 3 months, or to the control group, receiving a placebo. The primary endpoint is the evolution over time in albumin excretion rate (AER) until 3 months of intervention as compared with placebo. Secondary endpoints are the evolution over time in established plasma markers of renal endothelial function-asymmetric dimethylarginine (ADMA), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and von Willebrand Factor (vWF)-until 3 months of intervention as compared with placebo. Mixed modeling will be applied for the statistical analysis of the data. __Discussion:__ We hypothesize that T2D patients with microalbuminuria have a medically determined requirement for MOF and that fulfilling this requirement will result in a decrease in AER and related endothelial biomarkers. If confirmed, this may lead to new insights in the dietary management of patients with T2D

Safety, feasibility and efficacy of metformin and sitagliptin in patients with a TIA or minor ischaemic stroke and impaired glucose tolerance

Introduction Impaired glucose tolerance (IGT) is highly prevalent after stroke and is associated with recurrent stroke and unfavourable outcome. Objectives We aimed to assess the feasibility, safety and effects on glucose metabolism of metformin or sitagliptin in patients with transient ischaemic attack (TIA) or minor ischaemic stroke and IGT. Design We performed a multicentre, randomised, controlled, open-label phase II trial with blinded outcome assessment. Interventions Patients were randomised in a 2:1:1 ratio to 'no medication', sitagliptin or metformin. Primary and secondary outcome measures Primary outcome measures were baseline adjusted differences of 2-hour postload glucose; secondary outcome measures fasting glucose, glycosylated haemoglobin 1c (HbA1c) levels, tolerability and safety of metformin and sitagliptin at 6 months. Patients on metformin or sitagliptin were contacted by telephone for recording of possible adverse events and to support continuation of treatment at 2 weeks, 6 weeks and 3 months after inclusion. These events were not analysed as outcome measures. Results Fifty-three patients were randomised to control group, 26 to metformin and 22 to sitagliptin. We found no significant differences in 2-hour postload glucose between patients on antidiabetic drugs and controls ((-0.04 mmol/L (95% CI-0.53 to 0.45)). Patients in the treatment arms had reduced fasting glucose: ((-0.21 mmol/L (95% CI-0.36 to-0.06)) and HbA1c levels ((-1.16 mmol/mol (95% CI-1.84 to-0.49)). Thirteen patients (50%) on metformin and 7 (32%) on sitagliptin experienced side effects. Sixteen patients (61%) in the metformin and 13 (59%) in the sitagliptin group were still on treatment after 6 months. Conclusions Metformin and sitagliptin were both effective in reducing fasting glucose and HbA1c levels in patients with recent TIA or minor ischaemic stroke and IGT. However, the reduction of glucose levels and sample size was relatively small. The clinical relevance, therefore, needs to be tempered. A phase III trial is needed to investigate whether medical treatment, compared with lifestyle intervention or a combination of both, not only improves glucose metabolism in IGT, but also leads to reduction of recurrent TIA or ischaemic stroke in these patients. Trial registration number NL3048.</p