S. Quéré

Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.

Purpose: The real-life LUMIERE study on patients with wet age-related macular degeneration treated with intravitreal ranibizumab in 2006 to 2009 showed that failure to follow recommendations was associated with lower efficacy than had been observed in the development phase. The TWIN Study reviewed the situation in 2010 to 2011. Methods: Retrospective, descriptive purely observational study of data acquired after 12 months of treatment with intravitreal ranibizumab. Results: In 881 patients (68% women, mean age, 79 years) treated by 21 ophthalmologists, the mean gain in visual acuity was +4.3 ± 15.4 letters (up from 3.2 ± 14.8 in 2006–2009; NS). Significant improvements were documented in the mean interval between diagnosis and treatment initiation (down from 12.6 ± 26.4–7.7 ± 10.9 days; P < 0.001), and in the percentage of patients who received a full course of induction treatment (56.6 vs. 39.6%; P < 0.001). After induction, hardly any patients were monitored every month as recommended, although retreatment was more assiduous (5.6 ± 2.3 vs. 5.1 ± 2.1 injections; P < 0.001). Conclusion: Despite improvements in key parameters, the effectiveness of intravitreal ranibizumab is still compromised by poor compliance with the guidelines, especially the frequency of postinduction monitoring that is now the most important determinant of successful treatment.

Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial

Immediate or early use of proliferation signal inhibitor (PSI)/mammalian target of rapamycin (mTOR) inhibitor therapy can avoid high exposure to calcineurin inhibitors but concerns exist relating to the risk of delayed graft function (DGF) and impaired wound healing with the mTOR sirolimus. CALLISTO was a 12‐month, prospective, multicenter, open‐label study. Deceased‐donor kidney transplant patients at protocol‐specified risk of DGF were randomized to start everolimus on day 1 (immediate everolimus, IE; n = 65) or week 5 (delayed everolimus, DE; n = 74). Incidence of the primary endpoint (biopsy‐proven acute rejection, BPAR; graft loss, death, DGF, wound healing complications related to transplant surgery or loss to follow‐up) was 64.6% and 66.2% in the IE and DE groups, respectively, at month 12 (P = 0.860). The overall incidence of BPAR was 20.1%. Median estimated glomerular filtration rate was 48 ml/min/1.73 m2 and 49 ml/min/1.73 m2 in the IE and DE groups, respectively, at month 12. DGF and wound healing complications were similar between groups. Adverse events led to study drug discontinuation in 17 IE patients (26.2%) and 28 DE patients (37.8%) (NS). In conclusion, introduction of everolimus immediately or early posttransplant in DGF‐risk patients is associated with good efficacy, renal function and safety profile. There seems no benefit in delaying initiation of everolimus.

Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: Results from the randomized Optima study

AIM To compare continuous glucose monitoring (CGM) profiles on vildagliptin versus sitagliptin in addition to metformin, in patients with inadequately controlled type 2 diabetes mellitus (HbA(1c) 6.5-8.0%). METHODS A multicenter, prospective, randomised, open-label study with blinded endpoint analysis. CGM data acquired over three days--firstly on metformin alone and then 8 weeks after the addition of either vildagliptin (n=14) or sitagliptin (n=16)--were blinded and analyzed centrally. RESULTS In comparable populations with a mean baseline HbA1c of 7.1%, 24-hour glucose variability--measured by mean amplitude of glucose excursions and standard deviation of mean glucose concentration--showed similar improvement on both drugs versus metformin alone. In contrast, a series of predefined parameters reflecting daily glycaemic control--mean 24-hour blood glucose concentration, and the times spent in the optimal glycaemic range (70-140 mg/dL) and above the hyperglycaemic thresholds of 140 and 180 mg/dL together with the corresponding AUC values--were significantly improved from baseline only in the vildagliptin arm. In addition, overall hyperglycaemia (AUC[24 h] > 100 mg/dL) significantly dropped from baseline on vildagliptin [-37%] but not on sitagliptin [-9%], while postprandial hyperglycaemia (AUC[0-4 h] × 3) was significantly reduced on both, and basal hyperglycaemia (overall--postprandial hyperglycaemia was reduced only on vildagliptin [-41%; P = 0.04]). CONCLUSIONS The addition of a DPP-4 inhibitor significantly reduced glycaemic variability with no difference between the two drugs. However, vildagliptin induced better circadian glycaemic control than sitagliptin with a significant decrease on overall hyperglycemia, mainly driven by reduction on basal hyperglycaemia.

Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.

Markers of epithelial‐mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open‐label, 12‐month trial, de novo kidney transplant patients received cyclosporine, enteric‐coated mycophenolate sodium (EC‐MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT− based on month 3 biopsy, then randomized to start everolimus with half‐dose EC‐MPS (720 mg/day) and cyclosporine withdrawal (CNI‐free) or continue cyclosporine with standard EC‐MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3–12) in EMT+ patients. 194 patients were randomized (96 CNI‐free, 98 CNI); 153 (69 CNI‐free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI‐free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy‐proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI‐free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI‐free protocol, in which everolimus exposure was relatively low and administered with half‐dose EC‐MPS, CNI‐free patients were overwhelmingly under‐immunosuppressed and experienced an increased risk of BPAR.

How are patients with type 2 diabetes and renal disease monitored and managed? Insights from the observational OREDIA study.

Background and aim Chronic kidney disease (CKD) is frequent in type 2 diabetes mellitus (T2DM), and therapeutic management of diabetes is more challenging in patients with renal impairment (RI). The place of metformin is of particular interest since most scientific societies now recommend using half the dosage in moderate RI and abstaining from use in severe RI, while the classic contraindication with RI has not been removed from the label. This study aimed to assess the therapeutic management, in particular the use of metformin, of T2DM patients with CKD in real life. Methods This was a French cross-sectional observational study: 3,704 patients with T2DM diagnosed for over 1 year and pharmacologically treated were recruited in two cohorts (two-thirds were considered to have renal disease [CKD patients] and one-third were not [non-CKD patients]) by 968 physicians (81% general practitioners) in 2012. Results CKD versus non-CKD patients were significantly older with longer diabetes history, more diabetic complications, and less strict glycemic control (mean glycated hemoglobin [HbA1c] 7.5% versus 7.1%; 25% of CKD patients had HbA1c ≥8% versus 15% of non-CKD patients). Fifteen percent of CKD patients had severe RI, and 66% moderate RI. Therapeutic management of T2DM was clearly distinct in CKD, with less use of metformin (62% versus 86%) but at similar mean daily doses (~2 g/d). Of patients with severe RI, 33% were still treated with metformin, at similar doses. For other oral anti-diabetics, a distinct pattern of use was seen across renal function (RF): use of sulfonylureas (32%, 31%, and 20% in normal RF, moderate RI, and severe RI, respectively) and DPP4-i (dipeptidyl peptidase-4 inhibitors) (41%, 36%, and 25%, respectively) decreased with RF, while that of glinides increased (8%, 14%, and 18%, respectively). CKD patients were more frequently treated with insulin (40% versus 16% of non-CKD patients), and use of insulin increased with deterioration of RF (19%, 39%, and 61% of patients with normal RF, moderate RI, and severe RI, respectively). Treatment was modified at the end of the study-visit in 34% of CKD patients, primarily to stop or reduce metformin. However, metformin was stopped in only 40% of the severe RI patients. Conclusion Despite a fairly good detection of CKD in patients with T2DM, RI was insufficiently taken into account for adjusting anti-diabetic treatment.

Efficacy of morning and evening dosing of amlodipine/valsartan combination in hypertensive patients uncontrolled by 5 mg of amlodipine.

ObjectivesThis study compared the effects of morning and evening dosing of amlodipine/valsartan combination on 24-h blood pressure (BP) in patients uncontrolled by amlodipine (5 mg). MethodsThis was a multicenter study that used a prospective, randomized, open-label, blinded endpoint design. Patients with essential hypertension, whos ambulatory BP was uncontrolled after 4 weeks on amlodipine (5 mg) were randomized to receive amlodipine/valsartan (5/160 mg) for 8 weeks in the morning or evening (n=231, 232, respectively), with optional uptitration up to 10/160 mg after 4 weeks if the office BP was uncontrolled. A 30-h ambulatory BP measurement was taken at randomization and at the end of the study. ResultsMorning and evening dosing with amlodipine/valsartan had equivalent effects on systolic BP (mean 24 h, daytime, night-time, and 24–30 h) and diastolic BP (mean 24 h, daytime, night-time, and 24–30 h). There was a small difference in the night-time diastolic BP (−4.92 vs.−6.20 mmHg; P=0.02) and a slight but nonsignificant trend for higher BP reduction during daytime for morning intake and during night-time for evening intake. BP control rates based on 24-h ambulatory BP measurement values (<120/80 mmHg) were similar between morning and evening dosing (47 vs. 45%). ConclusionThese results indicate that, in patients with BP uncontrolled by amlodipine (5 mg), morning and evening treatment with amlodipine/valsartan combination have similar effects on circadian BP, especially when 24-h mean values are considered.

Physical activity in patients with type 2 diabetes and hypertension – insights into motivations and barriers from the MOBILE study

Background Although physical activity (PA) is key in the management of type 2 diabetes (T2DM) and hypertension, it is difficult to implement in practice. Methods Cross-sectional, observational study. Participating physicians were asked to recruit two active and four inactive patients, screened with the Ricci-Gagnon (RG) self-questionnaire (active if score ≥16). Patients subsequently completed the International Physical Activity Questionnaire. The objective was to assess the achievement of individualized glycated hemoglobin and blood pressure goals (<140/90 mmHg) in the active vs inactive cohort, to explore the correlates for meeting both targets by multivariate analysis, and to examine the barriers and motivations to engage in PA. Results About 1,766 patients were analyzed. Active (n=628) vs inactive (n=1,138) patients were more often male, younger, less obese, had shorter durations of diabetes, fewer complications and other health issues, such as osteoarticular disorders (P<0.001 for all). Their diabetes and hypertension control was better and obtained despite a lower treatment burden. The biggest difference in PA between the active vs inactive patients was the percentage who declared engaging in regular leisure-type PA (97.9% vs 9.6%), also reflected in the percentage with vigorous activities in International Physical Activity Questionnaire (59.5% vs 9.6%). Target control was achieved by 33% of active and 19% of inactive patients (P<0.001). Active patients, those with fewer barriers to PA, with lower treatment burden, and with an active physician, were more likely to reach targets. The physician’s role emerged in the motivations (reassurance on health issues, training on hypoglycemia risk, and prescription/monitoring of the PA by the physician). A negative self-image was the highest ranked barrier for the inactive patients, followed by lack of support and medical concerns. Conclusion Physicians should consider PA prescription as seriously as any drug prescription, and take into account motivations and barriers to PA to tailor advice to patients’ specific needs and reduce their perceived constraints.

Conversion from everolimus with low-exposure cyclosporine to everolimus with mycophenolate sodium maintenance therapy in kidney transplant recipients: a randomized, open-label multicenter study.

BACKGROUND Data in kidney transplant recipients regarding elimination of calcineurin inhibitor (CNI) therapy from a de novo regimen based on low CNI exposure and an mTOR inhibitor are sparse, and restricted to CNI elimination within the first six months post-transplant. MATERIAL/METHODS In a 12-month, randomized, multicenter, open-label study, kidney transplant patients who had received everolimus, low-exposure cyclosporine and corticosteroids from transplantation to month 12 (with proteinuria <1 g/24 h at month 12) were randomized to convert from cyclosporine to mycophenolate sodium 720 mg/day with increased everolimus exposure (6-10 ng/mL [CNI-free group], n=15) or continue unchanged (everolimus 3-8 ng/mL [CNI group], n=15). RESULTS Median (range) baseline mGFR was 54 (21-87) mL/min and 37 (range 18-69) mL/min (p=0.053) in the CNI-free and CNI groups, respectively, compared to 56 (18-126) mL/min and 32 (12-63) mL/min at month 12 (p=0.007). The between-group difference in change in mGFR from baseline to month 12 post-conversion (the primary endpoint) was -14.4 mL/min (95% CI -29.3 to 0.6 mL/min, p=0.059 [least squares mean]). Changes in serum creatinine and estimated GFR to month 12 were significantly in favor of CNI-free patients. One CNI patient experienced biopsy-proven acute rejection. Study drug was discontinued due to adverse events in one CNI-free patient (7%) and three CNI-treated patients (20.0%). CONCLUSIONS Elimination of CNI from a de novo regimen of everolimus with low-exposure CNI at one year post-transplant maintained efficacy and led to a non-significant but clinically relevant improvement in renal function, although patients numbers were low (n=30). Findings from this small study require confirmation in a larger controlled trial.

Glycemic control according to glomerular filtration rate in patients with type 2 diabetes and overt nephropathy: A prospective observational study

BACKGROUND AND OBJECTIVE Type 2 diabetes (T2D) and chronic kidney disease (CKD) are closely linked. This study aimed to describe and analyze the relations between renal function and glycemic control in T2D patients with overt nephropathy. PATIENTS AND METHODS Data were collected from a French observational prospective multicenter study. Patients included were adults with T2D, clinical proteinuria and an estimated glomerular filtration rate (eGFR) over 15 mL/min/1.73 m(2). Baseline data and glycemic control after a one-year follow-up are presented here. RESULTS Data from 986 adult patients were analyzed. Mean age was 70 years. Mean eGFR was 42 mL/min/1.73 m(2), 66% of patients had proteinuria above 1g/day. HbA1c was higher in patients with lower eGFR in a model adjusted to age, gender, body mass index, hemoglobin level and erythropoietin use. Statistical significance was lost when stepwise multivariate analysis took into account the type of pharmacological treatment used to treat hyperglycemia.The type of antidiabetic agents differed across eGFR strata. Below 60 mL/min/1.73 m(2), the use of metformin declined while the use of insulin increased.After one year of follow up, 35% of patients had persistently poor or worsened glycemic control (HbA1c>8%). The only covariate independently associated with this characteristic was the duration of insulin therapy. CONCLUSION In patients with T2D and overt nephropathy, the observed correlation of low eGFR with high HbA1c was not predicted by eGFR. Our data rather underscore a different use of antidiabetic treatments in patients with advanced renal dysfunction, and the difficulty to improve glycemic control in patients with long standing insulin therapy.

Three-Year Outcomes in Kidney Transplant Patients Randomized to Steroid-Free Immunosuppression or Steroid Withdrawal, with Enteric-Coated Mycophenolate Sodium and Cyclosporine: The Infinity Study

In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8–31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1–25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6–36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.