Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.

clinicaltrials.gov Identifier: NCT01915498.

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis-and intravascular volume reduction-related adverse events (AEs) were evaluated using pooled data from four placebo-controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI] .1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were À6.0 mm Hg (À9.1 to À2.9) and À7.4 mm Hg (À10.4 to À4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg (À1.6 to 4.5) and À1.6 mm Hg (À4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis-related AEs (eg, pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction. J Clin Hypertens (Greenwich). 2014;16:875-882. ª

Background/Aims: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m². The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m²). Methods: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. Results are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m²) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m²). Results: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA_1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA_1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA_1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis. Conclusion: In subjectswith T2DM and stage 3 CKD, canagliflozin reduced HbA_1c, body weight, and blood pressure, and was generally well tolerated.

In patients with T2DM, canagliflozin was generally associated with small mean percent changes in serum electrolytes. Infrequent episodes of potassium elevation occurred with canagliflozin 300 mg, but occurred more often in patients with reduced eGFR.

Canagliflozin improved glycemic control, reduced BP and was generally well tolerated in people with type 2 diabetes across a range of ages, BMIs and renal functions.

No abstract

7015 Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS), with manifestations akin to retinoic acid syndrome seen during acute promyelocytic leukemia Tx. Methods: A phase 1 dose-escalation/expansion study (N = 239) (NCT01915498) included 109 pts with relapsed/refractory AML who received enasidenib 100 mg /day. An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential IDH-DS cases. The DSRC identified and agreed on signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. Of the 109 pts, the DSRC identified and retrospectively reviewed 27 cases (8 investigator reported IDH-DS cases and 19 cases suggestive of IDH-DS) to determine consistency with IDH-DS. Results: The DSRC found 13 of the 27 cases to be consistent with IDH-DS (11.9% of 109 pts). Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in > 2 pts were dyspnea (n = 10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4 cases and hydroxyurea was used for cytoreduction. Enasidenib was interrupted for 9 pts (median 7 days) but dose reductions or discontinuation were not required. Six of 13 pts had clinical responses (2 complete remission [CR], 2 CR with incomplete hematologic recovery, 1 partial remission, 1 morphologic leukemia-free state), 6 had stable disease and 1 had progressive disease. Conclusions: Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective management strategies, should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in m IDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, differentiation. Clinical trial information: NCT01915498.