OBJECTIVE Despite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulin-induced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis. RESEARCH DESIGN AND METHODS SimpliciT1 was a phase 1b/2 adaptive study. Phase 2 activities were conducted in two parts. Part 1 randomly assigned 20 participants using continuous glucose monitors and continuous subcutaneous insulin infusion (CSII). Part 2 randomly assigned 85 participants receiving multiple daily injections of insulin or CSII. In both parts 1 and 2, participants were randomly assigned to 800 mg TTP399 or matched placebo (fully blinded) and treated for 12 weeks. The primary end point was change in HbA1c from baseline to week 12. RESULTS The difference in change in HbA1c from baseline to week 12 between TTP399 and placebo was −0.7% (95% CI −1.3, −0.07) in part 1 and −0.21% (95% CI −0.39, −0.04) in part 2. Despite a greater decrease in HbA1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in part 2. In both parts 1 and 2, plasma β-hydroxybutyrate and urinary ketones were lower during treatment with TTP399 than placebo. CONCLUSIONS TTP399 lowers HbA1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.
Internalizing disorders are common in lesbian, gay, bisexual, transgender, queer, questioning, and otherwise non-heterosexual or non-cisgender (LGBTQ+) people. Few studies have evaluated the efficacy of cognitive behavior therapy (CBT), a well-established treatment for internalizing disorders, in LGBTQ+ people. The current study quantitatively synthesized outcomes from existing trials of CBT for internalizing disorders in LGBTQ+ people. Seven databases were searched, identifying 14 relevant studies with a total of 414 participants. A medium within-group effect size was found for depressive symptoms from pre-treatment to post-treatment (k = 14; g = 0.60; 95% CI: 0.44–0.76; I2 = 71.59) and pre-treatment to 2–6-month follow-up (k = 7; g = 0.63; 95% CI: 0.40–0.86; I2 = 71.59). For anxiety and related disorder symptoms, a medium within-group effect size was found from both pre-treatment to post-treatment (k = 10; g = 0.73; 95% CI: 0.47–0.99; I2 = 71.59) and to 3–9-month follow-up (k = 5; g = 0.70; 95% CI: 0.54–0.87; I2 = 36.04). Exploratory analyses indicated small between-group effects at post-treatment between intervention and control groups. Effect sizes were comparable to those in the general population, indicating preliminary support for treating internalizing disorders in LGBTQ+ people with CBT.
Free and conjugated ether-soluble phenols in blood of uremic patients have been determined by a specific and reliable method. Free phenol and cresol are not elevated in the great majority of these patients. Reasons are given for discounting the role of elevated conjugated phenols and free phenolic acids in the pathogenesis of the anemia of chronic renal disease.
TTP273, an oral, non-peptide GLP-1R agonist showed significant placebo-subtracted reductions in A1c of 0.9 and 0.7% when dosed at 150mg QPM or BID, respectively, in LOGRA, a 12-week, phase 2, double-blind, placebo-controlled randomized study [Diabetes 2017 Jun; 66 (S 1) A326]. In addition, less nausea was observed in the active groups than in the placebo group and the only incidence of vomiting occurred in the placebo group. A post hoc analysis of patients from the LOGRA study with Stage 2 hypertension that completed 12 weeks of dosing revealed a subgroup with a nominally statistically significant reduction in systolic blood pressure (SBP). Entry criteria allowed patients on standard of care treatment for hypertension, but excluded patients with persistent, uncontrolled hypertension at screening (SBP ≥ 160mmHg and/or diastolic blood pressure (DBP) ≥ 90mmHg). Approximately 25% of the patients that completed the study were considered to have Stage 2 hypertension at baseline (defined by SBP ≥ 140mmHg or DBP ≥90mmHg) and around 75% of those patients received 1 or more concomitant medications to treat hypertension. Among treatment groups, characteristics were relatively well balanced with an approximately equal number of patients enrolled per treatment group with similar baseline values for SBP/DBP and pulse rate among treatment groups (mean baseline values of 147/85 mmHg and 73 bpm). The post hoc analysis demonstrated a mean decrease from baseline in SBP of 17 in the 150mg QPM arm (n=9) (p < 0.05 vs. placebo), 12 in the 150mg BID TTP273 arm (n=10) and of 6 mmHg in the placebo arm (n=8), respectively. No significant changes in DBP or pulse rate were observed with either active group compared to placebo. Results from this post hoc analysis suggest that TTP273 could provide an additional benefit of reducing SBP, in line with other GLP-1R agonists. Unlike other GLP-1R agonists, these effects occurred without the side effects of nausea and vomiting. Disclosure C. Valcarce: Employee; Self; vTv Therapeutics. I. Dunn: None. J.L.R. Freeman: Employee; Self; vTv Therapeutics. Stock/Shareholder; Spouse/Partner; vTv Therapeutics.
<b>Objective</b> <p>Despite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulin-induced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis. </p> <p><b>Research design and methods</b></p> <p>SimpliciT1 was a Phase 1b/2 adaptive study. Phase 2 activities were conducted in 2 parts. Part 1 randomized 20 participants using continuous glucose monitors (CGM) and continuous subcutaneous insulin infusion (CSII). Part 2 randomized 85 participants on multiple daily injections of insulin or CSII. In both Part 1 and 2, participants were randomized to TTP399 800 mg or matched placebo (fully blinded) and treated for 12-weeks. The primary endpoint was the change in HbA1c from baseline to week 12.</p> <p><b>Results</b></p> <p>The difference in the change in HbA1c from baseline to week 12 between TTP399 and placebo was -0.7% (95% CI -1.3, -0.07) in Part 1 and -0.21 (95% CI -0.39, -0.04) in Part 2. Despite a greater decrease in HbA1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in Part 2. In both Part 1 and Part 2, plasma beta-hydroxybutrate and urinary ketones were lower during treatment with TTP399 than placebo. </p> <p><b>Conclusions</b></p> <p>TTP399 lowers HbA1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.</p>
Abstract Background Azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was evaluated in an 18‐month Phase 3 study as a treatment for patients with mild Alzheimer’s disease (AD) (the STEADFAST Study). Post‐hoc analyses in a T2D subgroup (HbA1c ≥ 6.5%) found that azeliragon‐treated patients exhibited less cognitive decline (ADAS‐cog11), less whole brain atrophy, less hippocampal atrophy, less ventricular enlargement, and reduced plasma inflammatory cytokine concentrations compared to patients treated with placebo. The current retrospective exploratory analysis was performed to evaluate ADAS‐cog and CDR symptom domains and individual test items to ascertain which were sensitive to treatment effects. Method STEADFAST was a randomized, double‐blind, placebo‐controlled trial in 875 patients with probable mild AD (MMSE 21‐26, CDR global 0.5‐1) receiving stable acetylcholinesterase inhibitors and/or memantine, evaluating the efficacy and safety of 18 months of treatment with azeliragon 5 mg/day relative to placebo. STEADFAST included two separate studies (A‐Study completed as planned, B‐Study prematurely terminated following negative results from the A‐Study) under a single protocol. Patients in the A‐Study with T2D (HbA1c ≥ 6.5%) were analyzed with mean changes from baseline calculated for ADAS‐cog11 and CDR individual item and symptom domain scores. Standard effects sizes were determined using Cohen d. Treatment differences in Month 18 change from baseline were evaluated using both t‐test (presented herein) and Wilcoxon test. Result Forty‐seven patients (26 azeliragon, 21 placebo of whom 19 and 17 had Month 18 data) were analyzed. ADAS‐cog Language and Praxis domains were nominally significantly different favoring azeliragon (p=0.01 and p=0.049, respectively) with Cohen d values of 0.86 and 0.66. A trend for less decline in the Memory domain (p=0.07, effect size 0.62) was noted. No significant differences were noted on CDR cognitive or functional domains. Nominal significant differences favoring azeliragon were noted for ADAS‐cog comprehension (p=0.005, effect size 0.99), ideational praxis (p=0.012, effect size 0.84) and spoken language (p=0.067, effect size 0.62) items and the CDR Memory item (p=0.032, effect size 0.73). Conclusion Results suggest that azeliragon may have benefits over placebo with less decline in memory, language, and praxis over 18 months in patients with mild AD and T2D.
Abstract Aims To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D). Materials and methods Twenty‐three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n = 12) or placebo (n = 11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10 hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta‐hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater. Results During the 7‐ to 10‐day treatment period, mean fasting plasma glucose was significantly reduced ( −27.6 vs. −4.4 mg/dL [−1.5 vs. −0.2 mmol/L]; P = 0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399‐treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399‐treated participants. As a result of higher bicarbonate values, none of the TTP399‐treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo‐treated participants. Conclusions When used as an adjunctive therapy to insulin, TTP399 improves glycaemia without increasing hypoglycaemia in individuals with T1D. During acute insulin withdrawal, TTP399 did not increase BHB concentrations and decreased the incidence of DKA.
