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Henry R.R.,Center for Metabolic Research | Henry R.R.,University of California at San Diego | Thakkar P.,Janssen Research and Development LLC | Tong C.,Janssen Research and Development LLC | And 2 more authors.
Diabetes Care | Year: 2015

OBJECTIVE This study assessed the efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This 18-week, double-blind, phase 2 study randomized 351 patients (HbA1c 7.0- 9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA1c reduction from baseline of ≥0.4% (≥4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA1c, body weight, and insulin dose, aswell as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTS More patients had both HbA1c reduction ≥0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P < 0.001). Both canagliflozin doses provided reductions in HbA1c, body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7-6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9-1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seenwith canagliflozin 100 and 300 mg versus placebo. CONCLUSIONS Canagliflozin provided reductions in HbA1c, body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin. © 2015 by the American Diabetes Association. Source


Henry R.R.,Center for Metabolic Research | Henry R.R.,University of California at San Diego | Staels B.,University of Lille Nord de France | Fonseca V.A.,Tulane University | And 7 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

Aim: To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. Methods: Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100mg sitagliptin alone; 15, 30 or 45mg pioglitazone alone, or 100mg sitagliptin plus 15, 30 or 45mg pioglitazone for 54weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30mg with pioglitazone 45mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15mg with pioglitazone monotherapy at the two higher doses. Results: Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. Conclusions: Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated. © 2013 John Wiley & Sons Ltd. Source


Mudaliar S.,Center for Metabolic Research | Mudaliar S.,University of California at San Diego
International Journal of Clinical Practice | Year: 2013

The progressive deterioration of glycaemic control in individuals with type 2 diabetes mellitus (T2DM) results from insulin resistance combined with the ongoing loss of β-cell function. Although it had been suggested that most β-cell dysfunction occurs after the development of T2DM, studies have documented a substantial early loss of β-cell function, particularly during the prediabetic state. In patients diagnosed with T2DM, β-cell function continues to decline despite treatment with commonly prescribed antihyperglycaemic medications, and ultimately exogenous insulin administration is required to maintain optimal glycaemic control. Thus, interventions to address the early decline in β-cell function could potentially alter the course of T2DM, preventing or delaying its onset and decreasing the incidence of complications. Original research and review articles on this topic were identified in a PubMed search from January 2000 through August 2012. Data from prospective studies and clinical trials suggest that lifestyle modifications and certain antihyperglycaemic medications, including thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors and insulin, may preserve or enhance β-cell function. The implication of current data is that early initiation of lifestyle modifications and antihyperglycaemic agents that preserve β-cell function might reverse or delay progression to T2DM in those with prediabetes. Moreover, improved β-cell function may confer more durable glucose control and perhaps reduce/delay the incidence of diabetic complications. Long-term studies are needed to validate this hypothesis. © Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Source


Peters A.L.,University of Southern California | Henry R.R.,Center for Metabolic Research | Henry R.R.,University of California at San Diego | Thakkar P.,Janssen Research and Development LLC | And 2 more authors.
Diabetes Care | Year: 2016

Objective To assess the incidence of serious adverse events (AEs) of diabetic ketoacidosis (DKA) with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as an add-on to insulin in adults with type 1 diabetes. Research Design and Methods In this 18-week, randomized, double-blind, phase 2 study, patients (N = 351;HbA1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion received canagliflozin 100 or 300 mg or placebo once daily. The incidence of ketone-related AEs, defined as any event from a prespecified list of preferred terms (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, urine ketone body present), including serious AEs of DKA, was assessed based on AE reports. Results At week 18, the incidence of any ketone-related AE with canagliflozin 100 and 300 mg was 5.1% (n = 6 of 117) and 9.4% (n = 11 of 117), respectively; no patients in the placebo group experienced a ketone-related AE. The incidence of serious AEs of DKA was 4.3% (n = 5 of 117) with canagliflozin 100 mg and 6.0% (n = 7 of 117) with canagliflozin 300 mg; all serious events occurred in the presence of circumstances that are known to potentially precipitate DKA (e.g., infection, insulin pump failure). Among the 12 patients with a serious AE of DKA, blood glucose levels ranged from 9.4 to >44.4 mmol/L (170 to >800 mg/dL). Baseline characteristics were generally similar in patients with and without a ketone-related AE. Conclusions Canagliflozin was associated with an increased incidence of serious AEs of DKA in patients with type 1 diabetes inadequately controlled with insulin. Mitigation strategies are needed for use in future clinical trials to reduce the risk of DKA with canagliflozin treatment in patients with type 1 diabetes. © 2016 by the American Diabetes Association. Source


Henry R.R.,University of California at San Diego | Henry R.R.,Center for Metabolic Research | Logan D.,Medpace Clinical Pharmacology Unit | Alessi T.,Intarcia Therapeutics | Baron M.A.,Intarcia Therapeutics
Clinical Therapeutics | Year: 2013

Background: Exenatide, a glucagon-like peptide-1 receptor agonist administered by self-injection, decreases plasma glucose, glycosylated hemoglobin (HbA1c), and weight in patients with type 2 diabetes. ITCA 650 is an investigational new drug that provides continuous subcutaneous delivery of exenatide. Objective: This randomized, open-label, multicenter, 28-day study evaluated the tolerability, pharmacodynamics, and pharmacokinetics of ITCA 650 in patients with type 2 diabetes. Methods: The study enrolled patients with type 2 diabetes who were receiving a stable regimen of diet and exercise alone or a stable dose of metformin monotherapy, thiazolidinedione monotherapy, or metformin plus thiazolidinedione combination therapy. Patients were randomized to receive 10, 20, 40, or 80 μg/d of ITCA 650 placed subcutaneously for 28 days. Plasma glucose, HbA1c, insulin, and weight were measured at regular intervals throughout the study. Exenatide levels and anti-exenatide antibodies were also assessed. Results: Forty-four patients were randomized to treatment. From baseline to end point, significant (P < 0.05) decreases in fasting plasma glucose levels, 2-hour postprandial glucose levels, and glucose AUC curve were seen in all treatment groups. HbA1c levels also decreased significantly (P < 0.001) in all 4 treatment groups. Weight was significantly (P < 0.05) lowered in the 40- and 80-μg/d groups. Detectable levels of exenatide were noted within 12 to 24 hours of ITCA 650 placement, reached steady state by 24 hours, and then remained relatively steady during a plateau period until device removal on day 29. Exenatide levels declined to undetectable levels within 24 hours after removal of the ITCA 650. The most common adverse events were nausea, decreased appetite, and vomiting; these were transient and mostly mild or moderate in severity. Mild local adverse events related to the healing process were common at the placement site but abated after 1 week. Twelve patients developed anti-exenatide antibodies; however, the pharmacokinetics of ITCA 650 were not altered compared with those who did not develop antibodies. Conclusions: ITCA 650 provided continuous and controlled subcutaneous delivery of exenatide for 28 days that was generally well tolerated and produced significant reductions in plasma glucose, HbA1c, and weight. Further studies are warranted to characterize the long-term tolerability and efficacy of ITCA 650 for the treatment of patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01798264. © 2013 Elsevier HS Journals, Inc. Source

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