Cinacalcet-induced hypocalcemia in a cohort of European haemodialysis patients: predictors, therapeutic approaches and outcomes

BACKGROUND: Calcimimetic treatment of secondary hyperparathyroidism in chronic dialysis patients is often followed by hypocalcemia. METHODS: We investigated the frequency, predictors, consequences and therapeutic responses following cinacalcet-induced hypocalcemia in an incident European hemodialysis cohort of 1068 patients with a cinacalcet prescription. RESULTS: Of 905 normocalcemic patients initiating cinacalcet, 67% developed hypocalcemia within 12 months: 68% mild, 23% moderate, 9% severe. Compared to persistently normocalcemic patients, those with severe hypocalcemia were more often diabetic, overweight, had cardiovascular disease, shorter dialysis vintage, used a catheter dialysis access, had fewer active vitamin-D sterols, and exhibited higher CRP and iPTH and lower calcium levels. Multivariate predictors of hypocalcemia included a catheter for vascular access, low albumin and high iPTH. Generally, no therapeutic intervention to prevent hypocalcemia was taken prior to cinacalcet initiation. After the hypocalcemic event, the most common clinical response was no change of the dialysis or medical regimen. Following the hypocalcemic event, iPTH remained low even in those with severe hypocalcemia. The number of deaths and cardiovascular events did not differ between patients with and without hypocalcemia within six months following cinacalcet initiation. CONCLUSION: Two-thirds of cinacalcet initiated patients experienced hypocalcaemia with 9% being severe. Hypocalcemia was mostly asymptomatic, transient (with and without targeted intervention to correct it) and not associated with an increase in cardiovascular events or deaths

Maternal effects on anogenital distance in a wild marmot population

Peer reviewedPublisher PD

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

International audienceAIMS: The aim of this study was to assess the efficacy and safety of imeglimin monotherapy compared to placebo for 24 weeks in Japanese patients with type 2 diabetes mellitus (T2DM).MATERIAL 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 T2DM either treatment-na�ve or previously treated with one oral anti-diabetes agent were eligible for participation. Patients were randomly assigned (1:1:1:1) to receive orally imeglimin 500 mg or imeglimin 1000 mg or imeglimin 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 that received at least one dose of study drug. This trial is registered at JAPIC (JapicCTI-153086).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 < 0.0001 for all). Treatment-emergent adverse events (TEAE) were reported for 68.0%, 62.2%, 73.3% and 68.0% of patients receiving imeglimin 500 mg, imeglimin 1000 mg, imeglimin 1500 mg and placebo, respectively. A small increase in gastrointestinal adverse effects (e.g. diarrhea) occurred with the 1500 mg dose level. Hypoglycemia was balanced between groups.CONCLUSIONS: Imeglimin as monotherapy in Japanese patients with T2DM was well tolerated and significantly improved glycemic control with no significant increase in hypoglycemic events versus placebo. Given the marginal increase in efficacy with the 1500 mg vs. 1000 mg dose (along with the potential for gastrointestinal tolerability issues), a dose of 1000 mg BID was selected for subsequent Phase III studies

Recovery of plasma volume after 1 week of exposure at 4,350 m

Ecole Nationale de Ski et D'Alpinisme, BP 24, 74401 Chamonix, France. [email protected] Plasma volume (PV) decreases at high altitude, but is rapidly restored upon return to sea-level (RSL). The aim of this study was (1) to describe PV recovery upon RSL with concomitant changes in major fluid regulating hormones, and (2) to test the hypothesis that PV recovery is promoted by the administration of a plasma expander. Ten male subjects were evaluated at rest and during submaximal exercise at sea-level (SL), after 7 days at 4,350 m (H7), and on RSL, on day 1 (RSL1, rest only) and day 2 (RSL2). PV (measured by carbon monoxide rebreathing), plasma renin (Ren), aldosterone (Aldo), atrial natriuretic factor (ANF) and arginine vasopressin (AVP) were measured at rest and during exercise. The subjects were divided into two groups 1 h before RSL, one group receiving PV expansion (475+/-219 ml) to ensure normovolemia (PVX, n=6), the others serving as controls (Control, n=4). PV decreased by 13.6% in H7 ( n=10), but was restored in RSL2, regardless of PVX. Ren, Aldo and AVP, which were similar in both groups, were reduced in H7, but were higher in RSL2 (rest or exercise). ANF was modified neither by hypoxia nor by PVX. Total water intake was reduced in H7, but remained normal in RSL in both groups, whereas water output dropped in RSL. PVX increased urine flow rate in RSL1 compared with subjects not given PVX. The present results suggest that PV recovery during early RSL is mainly due to a decreased diuresis, promoted at least in part by changes in fluid regulating hormones. However, neither PV recovery, nor hormonal responses were altered with PVX-induced normovolemia upon RSL