Two-Year Follow-up From the T1GER Study: Continued Off-Therapy Metabolic Improvements in Children and Young Adults With New-Onset T1D Treated With Golimumab and Characterization of Responders.

OBJECTIVE: The T1GER (A Study of SIMPONI to Arrest ß-Cell Loss in Type 1 Diabetes) study showed many metabolic benefits of the tumor necrosis factor-α blocker golimumab in children and young adults with type 1 diabetes (T1D). Off-therapy effects are reported. RESEARCH DESIGNS AND METHODS: T1GER was a phase 2, placebo-controlled, randomized trial in which golimumab or placebo was administered for 52 weeks to participants 6-21 years old diagnosed with T1D within 100 days of randomization. Assessments occurred during the 52-week on-therapy and 52-week off-therapy periods. RESULTS: After treatment was stopped, C-peptide area under the curve (AUC) remained greater in the treatment versus control group. At weeks 78 and 104, the golimumab group had lower reductions in the 4-h C-peptide AUC baseline than the placebo group, where specifically the golimumab group had reductions of 0.31 and 0.41 nmol/L, and the placebo group had reductions of 0.64 and 0.74 nmol/L. There were also trends in less insulin use, higher peak C-peptide levels and those in partial remission, and higher peak C-peptide levels in the golimumab group. Golimumab responders, defined as having an increase or minimal loss of C-peptide AUC and/or being in partial remission at week 52, showed even greater improvements in most metabolic parameters on and off therapy and had less hypoglycemia during the off-therapy period versus placebo. Adverse events, including infections, were similar between the groups during all time periods of the study. CONCLUSIONS: In children and young adults with new-onset T1D, golimumab preserved endogenous ß-cell function and resulted in other favorable metabolic parameters on and off therapy. A subpopulation had disease stabilization while on therapy, with improved metabolic parameters off therapy.

Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes.

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).

Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes.

OBJECTIVES: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754). BACKGROUND: Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain. METHODS: The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses. RESULTS: Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%). CONCLUSIONS: A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.

Coadministration of Canagliflozin and Phentermine for Weight Management in Overweight and Obese Individuals Without Diabetes: A Randomized Clinical Trial.

OBJECTIVE: To assess the efficacy and safety of coadministration of canagliflozin (CANA) and phentermine (PHEN) compared with placebo (PBO) and CANA or PHEN monotherapies in individuals who were overweight and obese without type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, phase 2a, randomized, double-blind, PBO-controlled, multicenter, parallel-group study enrolled individuals who were obese or overweight without type 2 diabetes (N = 335, aged 18-65 years, BMI ≥30 to <50 kg/m2 or BMI ≥27 to <50 kg/m2 with hypertension and/or dyslipidemia). Participants were randomized (1:1:1:1) to receive PBO, CANA 300 mg, PHEN 15 mg, or coadministration of CANA 300 mg and PHEN 15 mg (CANA/PHEN) orally once daily. The primary end point was percent change in body weight from baseline to week 26; key secondary end points were the proportion of participants achieving weight loss ≥5% and change from baseline in systolic blood pressure. RESULTS: CANA/PHEN provided statistically superior weight loss from baseline versus PBO at week 26 (least squares mean difference -6.9% [95% CI -8.6 to -5.2]; P < 0.001). CANA/PHEN also provided statistically superior achievement of weight loss ≥5% and reduction in systolic blood pressure compared with PBO. CANA/PHEN was generally well tolerated, with a safety and tolerability profile consistent with that of the individual components. CONCLUSIONS: CANA/PHEN produced meaningful reductions in body weight and was generally well tolerated in individuals who were overweight or obese without type 2 diabetes. Further studies are warranted to evaluate potential use of this combination for long-term weight management.

Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial.

AIMS: The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes. MATERIALS AND METHODS: CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events. Patients were randomly assigned to once-daily placebo or canagliflozin 100 mg (with optional uptitration to 300 mg) for a planned average of 2.5 years of follow-up. The primary outcome is kidney disease progression, defined by class change in albuminuria. The two secondary outcomes are the composite of hospitalized heart failure or cardiovascular death, and cardiovascular death alone. Effects on end-stage renal disease and a range of other outcomes will also be explored. RESULTS: A total of 5812 participants were recruited at 422 sites in 24 countries between January 2014 and May 2015. The mean baseline age was 64 years, mean duration of diabetes was 14 years, mean glycated haemoglobin level was 8.3% and mean body mass index was 32 kg/m2 . Of these participants, 37% were women, 71% had a history of cardiovascular disease, 22.3% had microalbuminuria and 8.7% had macroalbuminuria. The mean baseline estimated glomerular filtration rate was 76 mL/min/1.73 m2 . The study will have at least 90% power ( P = .05) to detect a 22% or greater reduction in the risk of progression of albuminuria. CONCLUSIONS: The trial should define the potential renoprotective effect of canagliflozin and will provide additional important new data about its effects on vascular outcomes, death and kidney failure.

Canagliflozin: a sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus.

The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin is a novel treatment option for adults with type 2 diabetes mellitus (T2DM). In patients with hyperglycemia, SGLT2 inhibition lowers plasma glucose levels by reducing the renal threshold for glucose (RTG ) and increasing urinary glucose excretion (UGE). Increased UGE is also associated with a mild osmotic diuresis and net caloric loss, which can lead to reductions in body weight and blood pressure (BP). After promising results from preclinical and phase I/II studies, the efficacy and safety of canagliflozin was evaluated in a comprehensive phase III development program in over 10,000 patients with T2DM on various background therapies. Canagliflozin improved glycemic control and provided reductions in body weight and BP versus placebo and active comparators in studies of up to 2 years' duration. Canagliflozin was generally well tolerated, with higher incidences of adverse events (AEs) related to the mechanism of action, including genital mycotic infections and AEs related to osmotic diuresis. Results from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT2 inhibitor approved in the United States, and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with T2DM.

Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial.

INTRODUCTION: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy. METHODS: The CANagliflozin cardioVascular Assessment Study (CANVAS) is a double-blind, placebo-controlled cardiovascular outcomes study that randomized participants to placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. Participants in the CANVAS trial are men and women aged ≥30 years with T2DM and a history or high risk of cardiovascular disease, and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥7.0% and ≤10.5%) on current antihyperglycemic therapies. The primary objective of this prespecified substudy was to assess change from baseline to 18 weeks in HbA1c among patients on sulfonylurea monotherapy. RESULTS: Of the 4330 patients enrolled in CANVAS, 127 met the entry criteria for the sulfonylurea monotherapy substudy (placebo, n = 45; canagliflozin 100 mg, n = 42; canagliflozin 300 mg, n = 40). At 18 weeks, placebo-subtracted changes (95% confidence interval) in HbA1c were -0.74% (-1.15, -0.33; P < 0.001) and -0.83% (-1.24, -0.42; P < 0.001) with canagliflozin 100 and 300 mg, respectively. Relative to placebo, canagliflozin 100 and 300 mg also decreased fasting plasma glucose (FPG; -2.1 mmol/L [-3.0, -1.2] and -2.7 mmol/L [-3.6, -1.7], respectively). Body weight was lower with canagliflozin 300 mg (-1.8% [-3.2, -0.4]; P = 0.014) but unchanged with canagliflozin 100 mg (-0.4% [-1.8, 1.0]; P = 0.557). Canagliflozin 300 mg increased hypoglycemia episodes compared to canagliflozin 100 mg and placebo (15%, 0%, and 4.4%, respectively). Adverse events (AEs) of male and female genital mycotic infections, pollakiuria, and thirst were more common with canagliflozin. CONCLUSIONS: Canagliflozin added to ongoing sulfonylurea monotherapy produced improvements in HbA1c, FPG, and body weight, with an increased incidence of AEs consistent with the mechanism of action of SGLT2 inhibition. FUNDING: Janssen Research & Development, LLC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629.

Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study.

OBJECTIVE: To assess the efficacy/safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS: In this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTS: At week 104, reductions from baseline in A1C were -0.65%, -0.74%, and -0.55% (-7.1, -8.1, and -6.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (-4.1%, -4.2%, and 0.9%, respectively) and systolic blood pressure (-2.0, -3.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONS: Canagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.

Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.

OBJECTIVE: There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS: The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTS: Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m(2), estimated glomerular filtration rate of 75 mL/min/1.73 m(2), fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; -6.8 mmol/mol [95% CI -7.5, -5.9]; P < 0.001) and -0.73% (95% CI -0.81, -0.65; -8.0 mmol/mol [95% CI -8.9, -7.1]; P < 0.001) at 18 weeks and -0.58% (95% CI -0.68, -0.48; -6.3 mmol/mol [95% CI -7.4, -5.2]) and -0.73% (95% CI -0.83, -0.63; -8.0 mmol/mol [95% CI -9.1, -6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONS: Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.

Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type 2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor canagliflozin lowered blood glucose, blood pressure, and body weight, with increased risk of urogenital infections in Phase 2 studies. Effects on macrovascular complications of diabetes remain to be determined. CANVAS is a double-blind, placebo-controlled trial designed to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about 2 years to substantiate potential cardiovascular protection by assessing key biomarkers and to achieve initial safety objectives. By the end of mid-September 2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are female and 57% had a history of atherosclerotic vascular disease. Participants will be followed up to achieve primary safety and tolerability objectives and to investigate secondary outcomes. The planned second phase will not be undertaken. CANVAS will define the effects of canagliflozin on biomarkers and provide data on cardiovascular safety against established regulatory parameters.

Center-size as a predictor of weight-loss outcome in multicenter trials including a low-calorie diet.

It has not been studied yet whether factors such as the number of subjects recruited by specialized centers for multicenter trials may influence weight loss during a low-calorie diet (LCD). This study aimed at determining whether the number of recruited subjects per center might predict relative weight loss. This is a post hoc analysis of an existing database: 701 obese subjects (77% women, 23% men, mean BMI: 38.9 kg/m(2)) were enrolled at 22 sites (4-85 subjects/site) in five countries to follow a LCD providing 800-1,000 kcal/day during 8 weeks. The main outcome measure was the percentage weight loss after the 8-week LCD. Mean weight loss differed significantly between participating centers (5.8-11.8% of the initial weight; P < 0.001). There was a significant positive correlation between relative weight loss and the number of recruited subjects per center (r = 0.38; P < 0.001). In a multiple stepwise regression analysis, the number of recruited subjects per center appeared to be the main predictive factor of weight loss (R(2) = 0.07; P < 0.001). As the number of participants within each center is clustered, we applied a hierarchical model to model the average weight loss vs. the number of participants included at each center. This model allows to predict that for 10 extra patients in a center, the average weight loss would increase by 0.5%. This is the first study suggesting that the number of recruited subjects per center may impact weight loss, and could therefore be considered as a new predictor for weight loss that is independent from the individual.

Effect of a dietary-induced weight loss on liver enzymes in obese subjects.

BACKGROUND: Weight loss was shown to be associated with improvements in liver enzymes and improvements of nonalcoholic fatty liver disease. However, some evidence also shows that liver enzymes may transiently increase immediately after a dietary-induced weight loss. OBJECTIVE: The aim was to assess the outcome of liver enzymes after a low-calorie diet (LCD) as well as during a follow-up period and to identify predictors for potential changes in these liver enzymes. DESIGN: In this post hoc analysis of an existing database, liver enzymes were assessed before and immediately after a highly standardized soy-based meal replacement LCD providing 800 kcal/d, as well as 32 and 60 wk after the end of the LCD. RESULTS: Data emanating from 147 obese subjects (104 women and 43 men) without known hepatic disease were included in this study. The LCD led to a median weight loss of 12.1 kg (range: 7.7-27.6 kg). In men, a significant decrease in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was observed immediately after the LCD, whereas, in women, these enzymes increased significantly, although mildly; however, this increase was transient. Sex was the only identifiable predictor of these changes in liver enzymes. CONCLUSIONS: This study showed that mild, transient increases in ALT and AST values can be observed immediately after an LCD in women, but not in men. These changes are probably of multifactorial origin and may be considered as benign as long as they remain transient.