FGF21 Agonists: An Emerging Therapeutic for Metabolic Dysfunction-Associated Steatohepatitis and Beyond.

The worldwide epidemics of obesity, hypertriglyceridemia, dyslipidemia, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) / metabolic dysfunction-associated steatohepatitis (MASH) represents a major economic burden on healthcare systems. At-risk MASH patients, defined as MASH with moderate or significant fibrosis are at higher risk of comorbidity / mortality with a significant risk of cardiovascular diseases and/or major adverse liver outcomes. Despite a high unmet medical need, there is no approved therapy to date. Several drug candidates have reached the phase 3 development stage and could lead to several potential conditional drug approvals in the coming years. Within the armamentarium of future treatment options, FGF21 analogs exhibit an interesting positioning thanks to their pleiotropic effects in addition to their significant effect on both MASH resolution and fibrosis improvement. In this review, we summarize preclinical and clinical data from FGF21 analogs for MASH and explore additional potential therapeutic indications.

Hyperinsulinemia, an overlooked clue and potential way forward in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease is closely associated with other features of the metabolic syndrome such as type 2 diabetes. The progression of the disease may lead to liver fibrosis, which is the main predictor of major adverse liver outcomes. Insulin resistance plays a major role in the pathogenesis of the disease. A component of fasting hyperinsulinemia is a failure of the liver to adjust the peripheral level of insulin due to reduced clearance. The associated fasting hyperinsulinemia has been independently associated as a predictor of major adverse liver outcomes and major adverse cardiovascular events. In this review, we discuss the potential mechanism and entanglement between liver fibrosis and hyperinsulinemia, and we hypothesize that the measure of fasting insulin could become a hepatic functional test within the armamentarium of noninvasive tests for the assessment of Metabolic dysfunction-associated steatotic liver disease.

Clinical Trial Landscape in NASH.

Nonalcoholic fatty liver disease consists of a spectrum starting from nonalcoholic fatty liver disease that may progress to nonalcoholic steatohepatitis (NASH), which can lead to fibrosis, cirrhosis, hepatocellular carcinoma, or even liver failure. The prevalence of NASH has increased in parallel with the rising rate of obesity and type 2 diabetes. Given the high prevalence and deadly complications of NASH, there have been significant efforts to develop effective treatments. Phase 2A studies have assessed various mechanisms of action across the spectrum of the disease, while phase 3 studies have focused mainly on NASH and fibrosis stage 2 and higher, as these patients have a higher risk of disease morbidity and mortality. The primary efficacy endpoints also vary, by using noninvasive tests in early-phase trials while relying on liver histological endpoints in phase 3 studies as required by regulatory agencies. Despite initial disappointment due to the failure of several drugs, recent phase 2 and 3 studies have shown promising results, with the first Food and Drug Administration-approved drug for NASH expected to be approved in 2023. In this review, we discuss the various drugs under development for NASH, their mechanisms of action, and the results of their clinical trials. We also highlight the potential challenges in developing pharmacological therapies for NASH.

Challenges and opportunities in NASH drug development.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD-NASH trials and potential mitigating strategies to move the field forward.

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1).

BACKGROUND & AIMS: Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH. METHODS: Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed. RESULTS: One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to -25% LFC, p = 0.008-0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure. IMPACT AND IMPLICATIONS: Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease. CONCLUSIONS: PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein. IMPACT AND IMPLICATIONS: Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease.

Efficacy and safety of imeglimin add-on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): A randomized, double-blind, placebo-controlled phase 3 trial with a 36-week open-label extension period.

AIMS: To evaluate the efficacy and safety of imeglimin for up to 52 weeks as combination therapy with insulin in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: This double-blind, randomized, parallel-group phase 3 trial was performed at 35 sites in Japan. Eligible patients were individuals aged ≥20 years with type 2 diabetes and inadequate glycaemic control with insulin. Patients were randomly assigned (1:1) to either imeglimin (1000 mg twice daily) or matched placebo, in combination with insulin, for 16 weeks. In a subsequent 36-week, open-label extension period, all patients received imeglimin 1000 mg twice daily. The primary endpoint was change in mean glycated haemoglobin (HbA1c) from baseline to week 16. RESULTS: In all, 108 and 107 patients were randomly assigned to treatment with imeglimin 1000 mg twice daily or placebo, respectively. Compared with placebo, the adjusted mean difference in change from baseline HbA1c at Week 16 was -0.60% (95% confidence interval [CI] -0.80 to -0.40; P < 0.0001). This decrease was sustained up to 52 weeks with a mean decrease of -0.64% (95% CI -0.82 to -0.46) versus baseline. The incidence of patients experiencing adverse events and serious adverse events was similar in the two treatment groups. The number of patients experiencing hypoglycaemia was similar in the two treatment groups. In patients receiving imeglimin, all hypoglycaemic events were mild in severity; no episodes required assistance. CONCLUSIONS: Imeglimin significantly improved HbA1c in Japanese patients with insufficiently controlled type 2 diabetes by insulin and had a similar safety profile to placebo. The efficacy of imeglimin on top of insulin was sustained for 52 weeks. Imeglimin represents a potential new treatment option for this population as add-on to insulin therapy.

Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52-week, open-label, multicentre phase 3 trial.

AIM: To evaluate the safety and efficacy of imeglimin for 52 weeks as monotherapy or combination therapy with existing antidiabetic agents in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: TIMES 2 was a phase 3, pivotal, open-label trial including patients with type 2 diabetes inadequately controlled despite diet/exercise or despite treatment with a single agent from one of several available classes of antidiabetic drugs along with diet/exercise. All patients received imeglimin 1000 mg twice-daily orally for 52 weeks as monotherapy or combination therapy. The primary endpoint was safety (adverse events, laboratory results, ECG). The secondary endpoints were changes from baseline in HbA1c and fasting plasma glucose at week 52. RESULTS: A total of 714 patients received the following treatments: imeglimin monotherapy (n = 134), combination with an α-glucosidase inhibitor (n = 64), biguanide (n = 64), dipeptidyl peptidase-4 inhibitor (DPP4-I; n = 63), glinide (n = 64), glucagon-like peptide-1 receptor agonist (GLP1-RA; n = 70), sodium-glucose co-transporter-2 inhibitor (n = 63), sulphonylurea (n = 127), or thiazolidinedione (n = 65). The percentage of patients experiencing at least one treatment emergent adverse event (TEAE) was 75.5%. Most of these events were mild or moderate in intensity. Serious TEAEs, none of them related to the study drug, occurred in 5.6% of all patients. No clinically significant changes in ECG, vital signs, physical examination, or laboratory tests were noted in any groups. At week 52, HbA1c decreased by 0.46% with imeglimin monotherapy, by 0.56%-0.92% with imeglimin as oral combination therapy, and by 0.12% with injectable GLP1-RA combination therapy. The greatest net HbA1c reduction (0.92%) occurred in patients receiving a DPP4-I in combination with imeglimin. CONCLUSIONS: Imeglimin provides well-tolerated, long-term safety and efficacy in both monotherapy and oral combination therapy in Japanese patients with type 2 diabetes.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

BACKGROUND: AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877. FINDINGS: Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. INTERPRETATION: PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. FUNDING: Poxel.

Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of imeglimin, the first in a new class of oral antidiabetic agent, in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, parallel-group, placebo-controlled phase 3 trial in 30 sites in Japan. Eligible participants were individuals aged ≥20 years with type 2 diabetes treated with diet and exercise, stable for ≥12 weeks prior to screening, and whose HbA1c was 7.0-10.0% (53-86 mmol/mol). Patients were randomly assigned (1:1) to either oral imeglimin (1,000 mg twice daily) or matched placebo for 24 weeks. Investigators, participants, and the sponsor of the study remained blinded throughout the trial. The primary end point was the change in mean HbA1c from baseline to week 24, and the key secondary end point was the percentage of responders (according to two definitions) at week 24. RESULTS: Between 26 December 2017 and 1 February 2019, 106 and 107 patients were randomly assigned to treatment with imeglimin and placebo, respectively. Compared with placebo, the adjusted mean difference in change from baseline HbA1c at week 24 was -0.87% (95% CI -1.04 to -0.69 [-9.5 mmol/mol; 95% CI -11.4 to -7.5]; P < 0.0001). Forty-seven (44.3%) patients reported ≥1 adverse event in the imeglimin group versus 48 adverse events (44.9%) in the placebo group. CONCLUSIONS: Imeglimin significantly improved HbA1c in Japanese patients with type 2 diabetes compared with placebo and had a similar safety profile to placebo. Imeglimin represents a potential new treatment option for this population.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.

Efficacy and safety of imeglimin in Japanese patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial.

AIM: To assess the efficacy and safety of imeglimin monotherapy compared with placebo for 24 weeks in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In this 24-week, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2b clinical trial, Japanese adults (age ≥ 20 years) with T2D either treatment-naïve or previously treated with one oral antidiabetes agent were eligible for participation. Patients were randomly assigned (1:1:1:1) to receive orally imeglimin 500, 1000 or 1500 mg, or placebo twice-daily over a 24-week period. The primary endpoint was the placebo-adjusted change at week 24 in HbA1c. Safety outcomes were assessed in all patients who received at least one dose of study drug. RESULTS: A total of 299 patients were randomized to receive double-blind treatment with orally twice-daily placebo (n = 75), imeglimin 500 mg (n = 75), 1000 mg (n = 74) or 1500 mg (n = 75). At week 24, imeglimin significantly decreased HbA1c (difference vs. placebo: imeglimin 500 mg -0.52% [95% CI: -0.77%, -0.27%], imeglimin 1000 mg -0.94% [95% CI: -1.19%, -0.68%], imeglimin 1500 mg -1.00% [95% CI: -1.26%, -0.75%]; P < .0001 for all). Treatment-emergent adverse events were reported for 68.0%, 62.2%, 73.3% and 68.0% of patients receiving imeglimin 500, 1000 or 1500 mg and placebo, respectively. A small increase in gastrointestinal adverse effects (e.g. diarrhoea) occurred with the 1500 mg dose level. Hypoglycaemia was balanced among groups. CONCLUSIONS: Imeglimin as monotherapy in Japanese patients with T2D was well tolerated and significantly improved glycaemic control with no significant increase in hypoglycaemic events versus placebo. Given the marginal increase in efficacy with the 1500 versus 1000 mg dose (along with the potential for gastrointestinal tolerability issues), a dose of 1000 mg twice-daily was selected for subsequent phase 3 studies.

Pharmacokinetics of Imeglimin in Subjects with Moderate Hepatic Impairment.

BACKGROUND: Imeglimin is a novel oral antidiabetic drug used to treat type 2 diabetes, targeting the mitochondrial bioenergetics. Imeglimin is mainly excreted unchanged by the kidneys and is a substrate of organic cation transporters, which are expressed in the kidney and the liver. OBJECTIVE: The aim of this study was to assess the effect of hepatic impairment on the pharmacokinetics of imeglimin. METHODS: An open-label, single-dose, parallel-group study was carried out in seven subjects with normal hepatic function and seven subjects with moderate hepatic impairment who received a single dose of imeglimin 1000 mg. Blood and urine samples were collected up to 48 h after imeglimin administration. Pharmacokinetics were determined using non-compartmental methods. RESULTS: Imeglimin maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with moderate hepatic impairment was 1.3-fold (90% confidence interval [CI] 1.05-1.60) and 1.5-fold (90% CI 1.19-1.82) higher than in subjects with normal hepatic function, but was not considered as clinically meaningful. Higher plasma exposure and amount of imeglimin renally excreted in moderate hepatic impaired subjects, associated with an unchanged elimination rate, suggests that this increase could be linked to a higher oral absorption and/or lower hepatic uptake in this population. CONCLUSIONS: Imeglimin was safe and well tolerated in all subjects. CLINICAL TRIAL REGISTRATION: EudraCT 2018-001950-83.

Lack of Drug-Drug Interaction Between Cimetidine, a Renal Transporter Inhibitor, and Imeglimin, a Novel Oral Antidiabetic Drug, in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Imeglimin is a novel oral antidiabetic drug to treat type 2 diabetes, targeting the mitochondrial bioenergetics. In vitro, imeglimin was shown to be a substrate of human multidrug and toxic extrusion transporters MATE1 and MATE2-K and organic cation transporters OCT1 and OCT2. The objective of the study was to assess the potential drug-drug interaction between imeglimin and cimetidine, a reference inhibitor of these transporters. METHODS: A phase 1 study was carried out in 16 subjects who received a single dose of 1500 mg imeglimin alone on day 1 followed by a 6-day treatment (day 5 to day 10) with cimetidine 400 mg twice daily. On day 8, a single dose of imeglimin was co-administered with cimetidine. Blood and urine samples were collected up to 72 h after each imeglimin administration. Pharmacokinetic parameters were determined using non-compartmental methods. RESULTS: Imeglimin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.3-fold [90% CI (1.12-1.62) and (1.10-1.46) for Cmax and AUC0-last, respectively] higher when imeglimin was co-administered with cimetidine but this increase was not considered clinically relevant. This increase could be mainly explained by a reduction in renal elimination, mediated through the cimetidine inhibition of renal MATE1 transporter. Imeglimin taken alone or with cimetidine was safe and well tolerated in all subjects. CONCLUSIONS: No clinically significant drug-drug interaction exists between imeglimin and cimetidine, a reference inhibitor of MATE1, MATE2-K, OCT1 and OCT2 transporters. CLINICAL TRIAL REGISTRATION: EudraCT 2018-001103-36.

Absence of QTc prolongation in a thorough QT study with imeglimin, a first in class oral agent for type 2 diabetes mellitus.

PURPOSE: Imeglimin is the first in a new class of oral antidiabetic agents, the glimins, currently in development to improve glycemic control in patients with type 2 diabetes mellitus. A thorough QT study was conducted to establish electrophysiological effects of therapeutic and supratherapeutic doses of imeglimin on cardiac repolarization. METHODS: In this randomized, double-blind, four-period, placebo and active controlled crossover study, healthy subjects were administered a single dose of imeglimin 2250 mg, imeglimin 6000 mg, moxifloxacin 400 mg, and placebo. 12-Lead Holter ECGs were recorded from 1 h before dosing until at least 24 h after each dose. This study was performed at a single-center inpatient clinical pharmacology unit. RESULTS: The upper bound of the two-sided 90% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTc intervals (ΔΔQTcF) did not exceed the regulatory threshold of 10 ms in any of the imeglimin dose groups. There were no QTcF values above 500 ms nor changes from pre-dose in QTcF above 60 ms in the imeglimin groups. Imeglimin did not exert a relevant effect on heart rate and PR or QRS intervals. Assay sensitivity was demonstrated by the effect of moxifloxacin 400 mg, with a lower bound two-sided 90% confidence interval for ΔΔQTcF of 10.6 ms. CONCLUSION: This thorough QT study demonstrated that therapeutic and supratherapeutic exposures of imeglimin did not induce a QT/QTc prolongation with a strong confidence as evidenced by the assay sensitivity. TRIAL REGISTRATION NUMBER/DATE: NCT02924337/ October 5, 2016.

Signification of distal urinary acidification defects in hypocitraturic patients.

BACKGROUND AND OBJECTIVES: Hypocitraturia has been associated with metabolic acidosis and mineral disorders. The aim of this study was to investigate the occurrence of urinary acidification defects underlying hypocitraturia. MATERIALS AND METHODS: This retrospective observational study included 67 patients (32 men), aged 40.7±15.1 years with hypocitraturia (<1.67 mmol/24-h) and nephrolithiasis, nephrocalcinosis, and/or bone demineralization, referred to our center from 2000 to 2015. We aimed to assess renal distal acidification capacity, prevalence and mechanisms of urinary acidification defects. Patients with low baseline plasma HCO3- (<22 mmol/L) were studied by bicarbonate loading or furosemide/fludrocortisone tests. Patients with normal baseline plasma HCO3- had an ammonium-chloride challenge test. A normal response was a decrease in urinary pH <5.3 and an increase in urinary NH4+ ≥33 µmol/min and defined idiopathic hypocitraturia. RESULTS: Eleven patients (16.4%) had low HCO3- and overt distal acidification defect. Three had a mutation in the gene encoding AE1, 4 had Gougerot-Sjögren syndrome and no cause was found in the remaining 4 cases. Fifty-six patients (83.6%) had normal HCO3-; of those, 33 (58.9%) had idiopathic hypocitraturia. Among the 23 (41%) remaining patients, 12 were unable to increase urinary NH4+ excretion (among them, 8 were able to decrease urinary pH and 4 were not) whereas 11 were able to increase urinary NH4+ excretion but unable to decrease urinary pH. These 11 patients had higher fasting urinary calcium, reflecting bone resorption, than the other 12 patients: median 0.41 [0.24-0.47] vs. 0.22 [0.08-0.37] mmol/mmol creatinine (P = 0.04). CONCLUSIONS: Patients with hypocitraturia and normal plasma HCO3- frequently show a latent acidification defect that can be further dissected into one of several subtypes based on urinary pH and NH4+ response to the acid load. Those patients with impaired urine acidification capacity but preserved NH4+ excretion exhibit particularly high calciuria and should be identified to optimize nephrolithiasis prevention.

Copeptin is increased in resistant hypertension.

OBJECTIVES: The participation of vasopressin in the mechanisms of resistant hypertension is unclear. We compared plasma copeptin concentration, a surrogate marker for vasopressin secretion, between patients with resistant hypertension and those with controlled blood pressure (CBP), in a post hoc analysis of the Prise en charge de l'Hypertension Artérielle RESistante au traitement trial. METHODS: After 4-week treatment with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day, and amlodipine 5 mg/day (baseline), 166 patients were classified as having resistant hypertension (n = 140) or CBP (n = 26) by ambulatory BP monitoring. Patients with resistant hypertension were then randomized for 12 weeks of sequential nephron blockade (n = 74) or sequential renin-angiotensin system blockade (n = 66). Plasma copeptin concentration was measured at baseline and week 12 by immunoassay. RESULTS: Baseline plasma copeptin concentration was positively associated with male sex, plasma osmolality, BP, and negatively with glomerular filtration rate. It was higher in the resistant hypertension than in the CBP group [geometric mean 5.7 (confidence interval 95% 5.1-6.4) vs. 2.9 (2.3-3.9) fmol/ml, adjusted P < 0.0001). The relationship between plasma copeptin concentration and urinary osmolality was similar in the two groups. At 12 weeks, plasma copeptin concentration in patients whose BP was controlled by sequential nephron blockade or sequential renin-angiotensin system blockade [6.8 (5.6-8.2) and 4.3 (3.0-5.9) fmol/ml, respectively) remained significantly higher than in patients with CBP at baseline (P < 0.0001 vs. both). CONCLUSION: In patients with resistant hypertension, plasma copeptin concentrations were approximately two-fold higher than those of patients with CBP, after adjustment for plasma osmolality. This difference was not accounted for by renal resistance to vasopressin, suggesting a primary reset of osmostat.

Observations of a large Dent disease cohort.

Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.

[Vaccines against Herpes zoster: Effectiveness, safety, and cost/benefit ratio]. / Les vaccins contre le zona: efficacité, sécurité, et rapport coût/bénéfices.

CONTEXT: A vaccination against herpes zoster and its complication is available in France since June 2015. Its exact benefit for public health is still controversial and its level of protection is not optimal. All those reasons seem to suggest a low acceptation rate from general practitioners. OBJECTIVE: To evaluate the effectiveness, the safety, and the cost/benefit ratio of the vaccination against herpes zoster in people aged 50 year or over. DOCUMENTARY SOURCE: Systematic review in Medline and PubMed with research by key words: "herpes zoster vaccine", "zoster vaccine" and "post herpetic neuralgia vaccine". SELECTION OF STUDIES: Randomized and observational studies published in English and French language have been selected by two readers. RESULTS: On 1886 articles identified, 62 studies were included in this systematic review of which 21 randomized trials, 21 observational studies, and 17 medico-economic studies concerned the unadjuvanted vaccine. Considered studies showed an effectiveness of 50% against herpes zoster and 60% on post-herpetic neuralgia incidence of the unadjuvanted vaccine. Five randomized controlled studies were identified for the adjuvanted vaccine. The overall effectiveness of this vaccine was > 90% whatever the age of subjects including those over age 70 and 80. The medico-economic studies conducted in many countries have shown that vaccine policies were beneficial in individuals aged 60 years or over. LIMITATION OF THE WORK: Most of data of effectiveness, and tolerance result from 2 large controlled studies only (SPS and ZEST) for the unadjuvanted vaccine and only one for the adjuvanted vaccine. CONCLUSION: Despite controversy and few uncertainties, the vaccine significantly reduces herpes zoster and its complication incidence. In terms of public health objectives, it reduces the burden of the disease and has a positive medico-economic impact. Preliminary data concerning the adjuvanted vaccine, whilst very promising, are still too limited. Up to now, no group of people with particularly high risk of herpes zoster-related complication who will beneficiate the most of the vaccination has been identified yet and only an age criteria has been considered for the recommendation.