Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes.

AIMS: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. METHODS: CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. RESULTS: Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. CONCLUSIONS: In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.

Effects of blood pressure lowering on cardiovascular risk according to baseline body-mass index: a meta-analysis of randomised trials.

BACKGROUND: The cardiovascular benefits of blood pressure lowering in obese people compared with people of normal weight might depend on choice of drug. We compared the effects of blood pressure-lowering regimens on cardiovascular risk in groups of patients categorised by baseline body-mass index (BMI). METHODS: We used individual patient data from trials included in the Blood Pressure Lowering Treatment Trialists' Collaboration to compare the effects of different classes of blood pressure-lowering regimens for the primary outcome of total major cardiovascular events (stroke, coronary heart disease, heart failure, and cardiovascular death). We used meta-analyses and meta-regressions to assess interactions between treatment and BMI when fitted as either a categorical variable (<25 kg/m(2), 25 to <30 kg/m(2), and ≥30 kg/m(2)) or a continuous variable. FINDINGS: Analyses were based on 135,715 individuals from 22 trials who had 14,353 major cardiovascular events. None of the six primary comparisons showed evidence that protection varied by drug class across the three BMI groups (all p for trend >0·20). When analysed as a continuous variable, angiotensin-converting-enzyme inhibitors gave slightly greater protection for each 5 kg/m(2) higher BMI than did calcium antagonists (hazard ratio 0·93, 95% CI 0·89-0·98; p=0·004) or diuretics (0·93, 0·89-0·98; p=0·002). The meta-regressions showed no relation between BMI category and the risk reduction for a given fall in systolic blood pressure. By contrast with a previous report, we noted no relation between BMI and the efficacy of calcium antagonists compared with diuretics. INTERPRETATION: We found little evidence that selection of a particular class of blood pressure-lowering drug will lead to substantially different outcomes for individuals who are obese compared with those who are lean. FUNDING: None.

Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials.

OBJECTIVE: To define the cardiovascular effects of lowering blood pressure in people with chronic kidney disease. DESIGN: Collaborative prospective meta-analysis of randomised trials. DATA SOURCES AND ELIGIBILITY: Participating randomised trials of drugs to lower blood pressure compared with placebo or each other or that compare different blood pressure targets, with at least 1000 patient years of follow-up per arm. MAIN OUTCOME MEASURES: Major cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death) in composite and individually and all cause death. PARTICIPANTS: 26 trials (152,290 participants), including 30,295 individuals with reduced estimated glomerular filtration rate (eGFR), which was defined as eGFR <60 mL/min/1.73 m(2). DATA EXTRACTION: Individual participant data were available for 23 trials, with summary data from another three. Meta-analysis according to baseline kidney function was performed. Pooled hazard ratios per 5 mm Hg lower blood pressure were estimated with a random effects model. RESULTS: Compared with placebo, blood pressure lowering regimens reduced the risk of major cardiovascular events by about a sixth per 5 mm Hg reduction in systolic blood pressure in individuals with (hazard ratio 0.83, 95% confidence interval 0.76 to 0.90) and without reduced eGFR (0.83, 0.79 to 0.88), with no evidence for any difference in effect (P=1.00 for homogeneity). The results were similar irrespective of whether blood pressure was reduced by regimens based on angiotensin converting enzyme inhibitors, calcium antagonists, or diuretics/ß blockers. There was no evidence that the effects of different drug classes on major cardiovascular events varied between patients with different eGFR (all P>0.60 for homogeneity). CONCLUSIONS: Blood pressure lowering is an effective strategy for preventing cardiovascular events among people with moderately reduced eGFR. There is little evidence from these overviews to support the preferential choice of particular drug classes for the prevention of cardiovascular events in chronic kidney disease.

Is doubling of serum creatinine a valid clinical 'hard' endpoint in clinical nephrology trials?

The composite of end stage renal disease (ESRD), doubling of serum creatinine and (renal) death, is a frequently used endpoint in randomized clinical trials in nephrology. Doubling of serum creatinine is a well-accepted part of this endpoint because a doubling of serum creatinine reflects a large sustained change in glomerular filtration rate (GFR) and predicts the development of ESRD. Although doubling of serum creatinine is frequently used, the validity of using this outcome as part of a composite endpoint is hampered by various factors. Firstly, serum creatinine may reflect changes in muscle mass unrelated to true GFR changes. Secondly, changes in serum creatinine may reflect hemodynamic changes in renal perfusion and not a structural effect on renal function. Finally, doubling of serum creatinine is an arbitrary choice and different proportional changes may represent a better indicator for ESRD. In this minireview, each of these factors will be discussed and recommendations are made for interpretation of clinical trials using doubling of serum creatinine as a composite endpoint in nephrology trials.

Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.

OBJECTIVE: To quantify the relative risk reductions achieved with different regimens to lower blood pressure in younger and older adults. DESIGN: Meta-analyses and meta-regression analyses used to compare the effects on the primary outcome between two age groups (<65 v > or =65 years). Evidence for an interaction between age and the effects of treatment sought by fitting age as a continuous variable and estimating overall effects across trials. PRIMARY OUTCOME: total major cardiovascular events. RESULTS: 31 trials, with 190 606 participants, were included. The meta-analyses showed no clear difference between age groups in the effects of lowering blood pressure or any difference between the effects of the drug classes on major cardiovascular events (all P> or =0.24). Neither was there any significant interaction between age and treatment when age was fitted as a continuous variable (all P>0.09). The meta-regressions also showed no difference in effects between the two age groups for the outcome of major cardiovascular events (<65 v > or =65; P=0.38). CONCLUSIONS: Reduction of blood pressure produces benefits in younger (<65 years) and older (> or =65 years) adults, with no strong evidence that protection against major vascular events afforded by different drug classes varies substantially with age.

Lower blood pressure and risk of recurrent stroke in patients with chronic kidney disease: PROGRESS trial.

Recent epidemiological studies have shown a J-shaped association between the risk of stroke and systolic blood pressure (SBP) levels in people with chronic kidney disease (CKD). The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, placebo-controlled trial demonstrating that perindopril-based blood pressure (BP) lowering reduced the risk of stroke in 6105 participants with prior cerebrovascular disease. We estimated the effects of therapy on the risk of recurrent stroke in 1757 of these participants with stage 3 or greater CKD according to baseline BP and the relationship between achieved follow-up BP and the risk of stroke. Active therapy produced comparable and significant reductions in the risk of stroke across all baseline SBP levels. The age- and gender-adjusted incidence of stroke increased significantly in a log-linear relationship for achieved SBP levels and strokes per 1000 person-years. This association persisted after adjusting for potential confounding factors. We found that perindopril-based BP lowering effectively prevented recurrent stroke in people with CKD, across a wide range of BP levels, without evidence of an increased risk of stroke in people with low BP levels.

High prevalence of chronic kidney disease in Thailand.

We describe the prevalence of stage III and IV chronic kidney disease in Thailand from a representative sample of individuals aged 35 years and above using a stratified, multistage, cluster-sampling method. Population estimates were calculated by applying sampling weights from the 2000 Thai census. Glomerular filtration rates were estimated from serum creatinine using the Cockroft-Gault and the simplified Modification of Diet in Renal Disease (MDRD) formulae. The prevalence of stage III disease among individuals aged 35 years and above was estimated to be about 20% using the Cockroft-Gault formula and about 13% from the MDRD formula. Stage IV disease was present in about 0.9 and 0.6% of this population using the respective formulae. The highest prevalence rates were observed in less well-developed rural areas and the lowest in developed urban areas. The prevalence of chronic kidney disease was significantly higher than that reported in individuals over 40 years old from the United States for both stage III and IV disease and higher than the reported incidence in Taiwan and Australia. This high prevalence of chronic kidney disease in Thailand has obvious implications for the health of its citizens and for the allocation of health-care resources.

Sirolimus: a single center experience in combination with calcineurin inhibitors.

A retrospective survey was performed to establish patient and graft outcome for all 41 patients at our centre receiving sirolimus (SRL) in combination with calcineurin inhibition (CNI) as primary therapy for the 6 years prior to March 2002. Patient mortality [12%; n = 5 (TTP, lymphoma, mucormycosis, and small bowel perforation] was significantly higher at 3 months compared with those not receiving SRL, but not thereafter. 12.8% had delayed graft function and 33% had one or more episodes of rejection in the first 6 months. Mean GFR at 12 months was significantly lower (47.3 mL/min) in the SRL group compared with those not receiving SRL (51.3 mL/min). Twenty-two patients had a 12-month protocol biopsy; CNI toxicity was present in 36%. SRL was associated with significant hyperlipidaemia (serum cholesterol, 5.2 +/- 1.4 at baseline vs 7.3 +/- 1.7 mmol/L at 3 months, P <.001; triglycerides, 2.3 +/- 1.4 at baseline vs 2.7 +/- 1.1 mmol/L at 3 months, P <.05). Mild thrombocytopenia occurred in 23% but was not associated with haemorrhagic events. LDH increased by 62%, remaining elevated out to 2 years post engraftment. Seven patients developed insulin requiring diabetes mellitus, similar to the rate observed in our general transplant population.Thus, in this early experience, SRL in combination with CNI was associated with significant mortality and morbidity including CNI toxicity, presumably a reflection of a heavy burden of immunosuppression. However, 1-year graft survival on SRL was similar to the mean Australia-wide graft survival regardless of immunosuppression. The future use of SRL may center around CNI sparing and avoidance type protocols.

Gizzerosine-induced histopathological lesions in broiler chicks.

1. The aim of this study was to investigate pathomorphological changes in broiler chicks fed with different doses of gizzerosine, a substance produced during the heat treatments of fish meal. 2. The experiment was carried out in Ross broiler chicks which were divided into three groups: group A received 100% of non-medicated commercial mash for broiler chicks. During an experimental 5-d period, 50% of commercial mash was replaced with unheated fish meal (0.65 ppm gizzerosine) in group B and in group C with heated fish meal (1.15 ppm gizzerosine). Fourteen chicks from each group were killed every day. Samples of gastrointestinal and lymphoid organs, lung, pancreas, liver, brain and kidney tissue were sampled for histopathological analysis. Organs were embedded in paraffin and stained with hematoxylin-eosin stain and using periodic acid-Schiff reagent (PAS) and Sudan III (frozen sections). 3. Necropsy did not reveal notable differences between treated groups. There were no significant histopathological changes in immunocompetent organs nor in the lungs, the pancreas, the kidney or the brain. Sharply demarcated multiple vacuoles were observed in the myocardium in group C toward the end of the experiment. In group C, the prevalent changes in the gizzard and the proventriculus were slight to severe cuticle erosions and oedema of the lamina propria with or without multiple vacuoles, respectively, towards the end of the experiment. The most prominent changes toward the end of the experiment were dispersed cell vacuolisation in duodenal, jejunual, ileal and caecal lamina propria in group C. 4. In conclusion, it should be emphasised that extra-gizzard gizzerosine-induced lesions are probably not mediated by H2-receptor stimulation, but could be a consequence of cellular hypoxia.

Pharmacological intervention in renal fibrosis and vascular sclerosis.

Progressive renal disease is associated with the development of fibrosing lesions not only in the glomerulus, but also in the interstitial and vascular compartments of the kidney. A growing body of work suggests that the mechanisms involved in this process are to a large extent shared by the glomerular mesangial cell, tubulointerstitial fibroblast and vascular smooth muscle cell. In this review we consider evidence that treatment strategies focused on any one of these cells are likely to be of universal benefit in the abrogation of the ongoing scarring that accompanies progressive renal disease, while at the same time reducing the progressive vascular sclerosis so often ultimately responsible for the excessive mortality seen in patients with renal failure.

Effects of dopaminergic drugs on inflammatory bowel disease induced with 2,4-dinitrofluorbenzene in BALB/c mice.

The aim of the study was to demonstrate the effects of dopaminergic drugs on 2,4-dinitrofluorbenzene (DNFB) induced experimental inflammatory bowel disease (IBD) in previously sensitized BALB/c mice. The number and extent of ulcerations and erosions, the intensity of haemorrhages, oedema, and accumulation of neutrophils and eosinophils within colonic lamina propria and submucosa were scored and statistically evaluated. The 180 BALB/c mice, were allocated into three equal groups. The mice in the first experimental group were treated with domperidone (DP), a peripheral dopamine (DA) antagonist. The mice from the second experimental group were treated with bromocriptine (BC), a dopamine agonist. The mice from the control group were treated with an equivalent volume of normal saline in the same manner. Ten animals from each group were killed on days 1, 2, 3, 5 and 10, subsequent to the challenge enema of DNFB solution. Gross and microscopic examination of the colon was performed. Treatment with BC resulted in clinical improvement and decreased mortality rate by 2 of 60 (3%), while domperidone treatment increased mortality rate to 12 of 60 (20%) compared with the controls [4 of 60 (6%)]. The analysis of the microscopic lesions indicated that the beneficial effects of BC were the result of maintenance of vascular integrity.

Treatment of renovascular disease with percutaneous stent insertion: long-term outcomes.

Renal artery stenosis is a common, progressive cause of hypertension and renal impairment, and is frequently treated with percutaneous transluminal dilatation and stenting. The outcome of this procedure is still being evaluated. The records of 198 consecutive patients who had stents inserted at the Royal Melbourne Hospital were analysed retrospectively, and adequate follow-up information on 148 (75%), in whom a total of 182 renal arteries had been treated was obtained. Technical success was achieved in 144 patients (97%). Complications occurred in 19 patients (13.3%), with major complications occurring in 10 (7.0%) and one death occurring in relation to the procedure. A fall in average systolic blood pressure of 13.2 mmHg (12.1-14.3 mmHg) was seen and a fall in diastolic blood pressure of 10.1 mmHg (9.3-10.9 mmHg), without an increase in the number of antihypertensive drugs used. Renal function remained stable in the majority of patients, particularly those who had minimal baseline renal impairment. Restenosis was common after 6 months, occurring eventually in 29% of screened patients, but was not shown to affect clinical outcomes. Insertion of renal artery stents is a safe and effective treatment for renal artery stenosis.