All-Cause and Cardiovascular Mortality Among Insulin-Naïve People With Type 2 Diabetes Treated With Insulin Detemir or Glargine: A Cohort Study in the UK.

Introduction: Uncontrolled type 2 diabetes (T2D) is associated with an increased risk of micro- and macrovascular complications and mortality. The impact of basal insulins on the risks of mortality and cardiovascular mortality in people with T2D has not been thoroughly investigated in real-world settings. The aim of the present real-word study was to investigate differences in mortality among insulin-naïve people with T2D who initiated insulin detemir (detemir) and insulin glargine (glargine).

A comprehensive approach to benefit-risk assessment in drug development.

Major regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit-risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data-driven benefit-risk assessment method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval phase.

Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial.

Background: Autoregulation of GFR, i.e. maintenance of relative constancy of GFR despite variations in mean arterial pressure (MAP) >80 mmHg, is impaired in diabetic kidney disease; furthermore, some antihypertensive drugs may jeopardize autoregulation.

Expression, localization, and function of the thioredoxin system in diabetic nephropathy.

Excessive reactive oxygen species play a key role in the pathogenesis of diabetic nephropathy, but to what extent these result from increased generation, impaired antioxidant systems, or both is incompletely understood. Here, we report the expression, localization, and activity of the antioxidant thioredoxin and its endogenous inhibitor thioredoxin interacting protein (TxnIP) in vivo and in vitro. In normal human and rat kidneys, expression of TxnIP mRNA and protein was most abundant in the glomeruli and distal nephron (distal convoluted tubule and collecting ducts).

Impact of diabetic nephropathy and angiotensin II receptor blockade on urinary polypeptide patterns.

Background: New insights into the pathogenesis and treatment of diabetic renal disease may emerge from recent advances in proteomics using high-throughput mass spectrometry (MS) of urine.

Methods: Using a combination of online capillary electrophoresis (CE) and MS we evaluated urinary polypeptide patterns in four groups of type 2 diabetic patients matched for age, gender, and diabetes duration, including 20 normoalbuminuric patients with and 20 without diabetic retinopathy, 20 microalbuminuric patients with diabetic retinopathy, and 18 macroalbuminuric patients with diabetic retinopathy. Furthermore, changes in urinary polypeptide patterns during treatment with the angiotensin II receptor blocker (ARB) candesartan were evaluated in the macroalbuminuric patients in a randomized double-blinded, cross-over trial where each patient received treatment with placebo, candesartan 8, 16, and 32 mg daily each for 2 months.

Progression of nephropathy in type 2 diabetic patients.

Background: Nephropathy in type 2 diabetes is the single most common cause of end-stage renal disease (ESRD), but the decline in kidney function varies considerably between individuals, and determinants of renal function loss, early in the course of renal disease, have not been clearly identified.

Methods: In a prospective observational study, we followed 227 (60 female) Caucasian type 2 diabetic patients with nephropathy for 6.5 (range 3 to 17) years from a baseline glomerular filtration rate (GFR) of 83 (SD30) mL/min/1.

Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular end points.

The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The increased RAAS activity plays an important role in the hemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies have demonstrated that albuminuria is not only a marker of glomerular lesions, but also a progression promoter, and finally a powerful predictor of the long-term beneficial effect of blood pressure-lowering therapy.

Comparative effects of Irbesartan on ambulatory and office blood pressure: a substudy of ambulatory blood pressure from the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study.

Objective: Irbesartan was renoprotective independently of its blood pressure-lowering effect in the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA2) study. However, blood pressure was evaluated by trough office blood pressure (OBP), which may underestimate reductions in 24-h ambulatory blood pressure (ABP). In the present study, we evaluated 24-h blood pressure patterns in a subpopulation of the IRMA2 trial.

Autoregulation of glomerular filtration rate in patients with type 2 diabetes during isradipine therapy.

Objective: Calcium-channel blockade impairs renal autoregulation in animals. Impaired renal autoregulation leads to transmission of the systemic blood pressure (BP) into the glomerulus, resulting in capillary hypertension. Information on the impact of calcium antagonist treatment on renal autoregulation in humans is lacking.

Optimal dose of candesartan for renoprotection in type 2 diabetic patients with nephropathy: a double-blind randomized cross-over study.

Objective: We evaluated the optimal dose of the angiotensin II receptor antagonist candesartan cilexetil for renoprotection as reflected by short-term changes in albuminuria in hypertensive type 2 diabetic patients with nephropathy.

Research Design And Methods: A total of 23 hypertensive patients with type 2 diabetes and nephropathy were enrolled in this double-blind randomized cross-over trial with four treatment periods, each lasting 2 months. Each patient received placebo and candesartan: 8, 16, and 32 mg daily in random order.

Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study.

Objective: Many patients with diabetic nephropathy (DN) have levels of albuminuria > 1 g/day and blood pressure >135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily.