Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure

Microvascular and cardiovascular outcomes according to renal function in patients treated with once-weekly exenatide: Insights from the EXSCEL trial

OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI 20.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70-1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74-0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58-0.93]; P for interaction 5 0.035) and CV death (HR 1.08 [95% CI 0.85-1.38]; P for interaction 5 0.031). CONCLUSIONS EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity

Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members

SGLT2 (for “Sodium GLucose coTransporter” protein 2) is the major protein responsible for glucose reabsorption in the kidney and its inhibition has been the focus of drug discovery efforts to treat type 2 diabetes. In order to better clarify the human tissue distribution of expression of SGLT2 and related members of this cotransporter class, we performed TaqMan™ (Applied Biosystems, Foster City, CA, USA) quantitative polymerase chain reaction (PCR) analysis of SGLT2 and other sodium/glucose transporter genes on RNAs from 72 normal tissues from three different individuals. We consistently observe that SGLT2 is highly kidney specific while SGLT5 is highly kidney abundant; SGLT1, sodium-dependent amino acid transporter (SAAT1), and SGLT4 are highly abundant in small intestine and skeletal muscle; SGLT6 is expressed in the central nervous system; and sodium myoinositol cotransporter is ubiquitously expressed across all human tissues

Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances

Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: Results of the study to evaluate early kidney disease

Abnormalities of mineral metabolism occur early in chronic kidney disease. Quantification of the prevalence of these abnormalities has not been described using current assays nor in large unselected populations. This outpatient cohort cross-sectional study was conducted in 153 centers, (71% primary care practices). Blood for parathyroid hormone (PTH), vitamin D metabolites, creatinine, calcium (Ca), and phosphorus (P) were drawn between June and October 2004. Low 1,25-dihydroxyvitamin D (1,25 OH2 D3) was defined as <22pg/ml. The 1814 patients had a mean age of 71.1 years old; 48% had diabetes mellitus (DM). Low 1,25 OH2 D3 was evident at all estimated glomerular filtration rate (eGFR) levels: 13% in those with eGFR >80ml/min, >60% in those with eGFR <30ml/min. High PTH (>65pm/dl) occurred in 12% with eGFR >80ml/min. Serum Ca and P were normal until eGFR was <40ml/min. Significant differences in the mean and median values of 1,25 OH2 D3, PTH, but not 25(OH)D3 levels, were seen across deciles of eGFR (P<0.001). Multivariate analysis revealed that DM, increased urinary albumin/creatinine ratio and lower eGFR predicted lower values of 1,25 OH2 D3. A high prevalence of mineral metabolite abnormalities occurs in a large unreferred US cohort. Low 1,25 OH2 D3 and elevated PTH are common at higher eGFR than previously described. As bone, cardiovascular disease, and mineral metabolite are correlated; further studies are necessary to determine the importance of these findings relative to outcomes

Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: Results of the IMPROVE trial

Microalbuminuria independently predicts increased cardiovascular risk in hypertensive patients, especially in those with concomitant diabetes or established cardiovascular disease. Drugs that target the renin–angiotensin–aldosterone system reduce microalbuminuria regardless of diabetic status. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events was a multicenter, randomized, double-blind, placebo-controlled paralleled group study in which hypertensive patients with microalbuminuria and increased cardiovascular risk were randomized to 20 weeks treatment with ramipril plus irbesartan or to ramipril plus placebo. Patients discontinued or tapered previous antihypertensive therapy during a 14-day placebo lead-in period. Change in albumin excretion rate from baseline to week 20 was the primary end point. Adjusted week 20 baseline geometric ratios for ramipril plus irbesartan and ramipril plus placebo were not significantly different. Although differences in blood pressure reductions were observed between the two treatments, these changes did not affect microalbuminuria. More patients on dual therapy achieved target blood pressure goals at week 20 than with monotherapy. The incidence of adverse effects and treatment-related adverse effects was similar in both groups. Our results suggest that patients with cardiovascular risk and relatively low albumin excretion rates in early-stage disease may only require monotherapy with renin–angiotensin–aldosterone blocking agents