<p dir="ltr"><b>OBJECTIVE</b></p><p dir="ltr">To assess the impact of concomitant metformin use on gastrointestinal adverse events during the initiation and titration of GLP-1RA.</p><p dir="ltr"><b>RESEARCH DESIGN AND METHODS</b></p><p dir="ltr">Using data from four clinical trials of liraglutide and semaglutide (LEADER, STEP-2, SUSTAIN-6, and PIONEER-6), we compared the incidence of gastrointestinal adverse events during GLP-1RA initiation and titration in participants with and without concomitant metformin use.</p><p dir="ltr"><b>RESULTS</b></p><p dir="ltr">Of 16,996 participants, 12,928 (76%) were treated with metformin. Concomitant metformin use did not increase the percentage of participants who developed gastrointestinal adverse events or their severity during the observation window. Among participants experiencing gastrointestinal adverse events, metformin use did not increase study product discontinuation. Within treatment arms (GLP-1RA and placebo), a numerically higher percentage of metformin non-users experienced GI adverse events and discontinued study product compared to metformin users.</p><p dir="ltr"><b>CONCLUSIONS</b></p><p dir="ltr">Concomitant metformin use does not increase occurrence of gastrointestinal symptoms during GLP-1RA initiation or impact GLP-1RA discontinuation.</p>
Receptor activity modifying proteins (RAMPs) associate with G-protein-coupled receptors (GPCRs) at the plasma membrane and together bind a variety of peptide ligands, serving as a communication interface between the extracellular and intracellular environments. The collection of RAMP-interacting GPCRs continues to expand and now consists of GPCRs from families A, B and C, suggesting that RAMP activity is extremely prevalent. RAMP association with GPCRs can regulate GPCR function by altering ligand binding, receptor trafficking and desensitization, and downstream signaling pathways. Here, we elaborate on these RAMP-dependent mechanisms of GPCR regulation, which provide opportunities for pharmacological intervention.
The cyclin-dependent kinase 6 (CDK6) regulates the transition through the G1-phase of the cell cycle, but also acts as a transcriptional regulator. As such CDK6 regulates cell survival or cytokine secretion together with STATs, AP-1 or NF-κB. In the hematopoietic system, CDK6 regulates T cell development and promotes leukemia and lymphoma. CDK4/6 kinase inhibitors are FDA approved for treatment of breast cancer patients and have been reported to enhance T cell-mediated anti-tumor immunity. The involvement of CDK6 in T cell functions remains enigmatic. We here investigated the role of CDK6 in CD8+ T cells, using previously generated CDK6 knockout (
GI symptoms are common side effects reported with both GLP-1RA and metformin use, yet these agents are often prescribed in combination. GLP-1RA are initiated at low dose and escalated to minimize the occurrence of GI side effects. Still, most treatment related GI adverse events occur during the dose titration period. We evaluated whether concomitant metformin use increases the rate of GI adverse events during the GLP-1RA titration period. Using data from 4 clinical trials, LEADER (1.8 mg liraglutide), STEP-2 (1/2.4 mg semaglutide), SUSTAIN-6 (0.5/1 mg semaglutide), and PIONEER-6 (14 mg oral semaglutide), we compared the incidence of GI adverse events during the titration period defined as the expected time to steady state of the respective drug (3 weeks-5 months, see table) in participants with and without concomitant metformin use. Of the 16,996 participants in these trials, 12,928 (76%) were treated with metformin. The percent of participants who developed new or serious GI adverse events during the titration period was similar across those with or without concomitant metformin use in each group (GLP-1RA or placebo) in all trials (Table). The occurrence of individual GI event (nausea, vomiting, diarrhea, and constipation) was also similar (data not shown). In summary, concomitant metformin use does not increase the occurrence of GI symptoms during early GLP-1RA treatment. Disclosure K.R.Klein: None. K.K.B.Clemmensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. E.Fong: Employee; Novo Nordisk A/S. S.Olsen: None. T.J.Abrahamsen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S, Genmab A/S. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim.
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.
