Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Treated With Metformin and Sulfonylurea

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Aim: As a pre-specified sub-study of the Phase 3 VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled with metformin and sulfonylurea (SU). Methods: Patients with T2DM, established ASCVD, and HbA1c 7.0–10.5% on stable metformin (≥1500 mg/day) and SU doses as defined per protocol were randomized to once-daily ERTU (5 mg or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ERTU on HbA1c compared with placebo and to evaluate safety and tolerability during 18-week follow-up. Key secondary endpoints included proportion of patients achieving HbA1c <7%, fasting plasma glucose (FPG), body weight, and systolic blood pressure. Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. Results: Of the 8246 patients enrolled in the VERTIS CV trial, 330 patients were eligible for this sub-study (ERTU 5 mg, n=100; ERTU 15 mg, n=113; placebo, n=117). Patients had a mean (SD) age of 63.2 (8.4) years, T2DM duration 11.4 (7.4) years, estimated glomerular filtration rate 83.5 (17.8) mL/min/1.73 m2, and HbA1c 8.3% (1.0) (67.4 [10.6] mmol/mol). At Week 18, ERTU 5 mg and 15 mg were each associated with a significantly greater least squares mean (95% CI) HbA1c reduction from baseline versus placebo; the placebo-adjusted differences for ERTU 5 mg and 15 mg were –0.7% (–0.9, –0.4) and –0.8% (–1.0, –0.5), respectively (P<0.001). A higher proportion of patients in each ERTU group achieved HbA1c <7% relative to placebo (P<0.001). ERTU significantly reduced FPG and body weight (P<0.001, for each dose versus placebo), but not systolic blood pressure. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ERTU 5 mg, 15 mg, and placebo groups, respectively. Genital mycotic infections were experienced by significantly higher proportions of male patients who received ERTU 5 mg and 15 mg (4.2% and 4.8%, respectively) versus placebo (0.0%; P≤0.05) and by a numerically, but not significantly, higher proportion of female patients who received ERTU 15 mg (10.3%) compared with placebo (3.8%) (P=0.36). The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusion: Among patients with T2DM and ASCVD, ERTU (5 mg and 15 mg) added to metformin and SU for 18 weeks improved glycemic control (HbA1c and FPG) and reduced body weight, and was generally well tolerated with a safety profile consistent with the SGLT2 inhibitor class

Melanocortin receptors in GtoPdb v.2023.1

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test. setmelanotide was approved by the US FDA for weight management in patients with POMC, PCSK1 or LEPR defiency, bremelanotide was approved by the US FDA for generalized hypoactive sexual desire disorder in premenopausal women, and NDP-MSH (afamelanotide) was approved by the EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development

Melanocortin receptors in GtoPdb v.2021.3

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development

Melanocortin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [36]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development

Molecular Cloning and Structural Analysis of Canine Gastric H+, K+-ATPase

Gastric hydrogen-potassium ATPase (H+, K+-ATPase) is a heterodimeric protein which participates in the formation of hydrochloric acid. We cloned canine H+, K+-ATPase [alpha] and [beta] subunit cDNAs from canine gastric cDNA libraries and the [alpha] subunit gene from a canine genomic library. The [alpha] subunit gene is 13 kb in length and contains 21 introns ranging from 77 to 1,076 bp. Its 5'-flanking region contains putative regulatory motifs for transcription that are similar to those found in H+, K+-ATPase genes from other species. The open reading frames of [alpha] and [beta] subunit cDNAs are 3,500 and 870 bp in length and encode proteins of 1,034 and 290 amino acids, respectively. They are 80 - 90% homologous to corresponding cDNAs previously identified in porcine and rodent gastric tissues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30452/1/0000076.pd

Mapping of the Gene Encoding the Melanocortin-1 ([alpha]-Melanocyte Stimulating Hormone) Receptor (MC1R) to Human Chromosome 16q24.3 by Fluorescence in Situ Hybridization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31833/1/0000780.pd

Inhibition of Adipogenesis by Ghrelin

Ghrelin, a novel gastric hormone, regulates food intake and energy metabolism via central mechanisms. The peripheral effect of ghrelin on adiposity is poorly understood. We established a stable 3T3-L1 cell line expressing ghrelin to study the direct effect of ghrelin on adipogenesis. Cells overexpressing ghrelin demonstrate significantly attenuated differentiation of preadipocytes into adipocytes. Expression of peroxisome proliferator-activator receptor-γ is significantly inhibited as demonstrated by decrease of peroxisome proliferator-activator receptor-γ mRNA and protein. Both ghrelin overexpression and exogenous ghrelin stimulate cell proliferation. Phosphorylation of mitogen-activated protein kinase is increased after treatment of cells with ghrelin. Ghrelin binding activity is demonstrated in both native and ghrelin-overexpressing 3T3-L1 cells by radiolabeled ghrelin, although reverse transcription-polymerase chain reaction with the primer sequence of the previously identified ghrelin receptor subtypes detected no signal. Our results demonstrate that ghrelin inhibits adipogenesis by stimulation of cell proliferation via the mediation of a ghrelin receptor, likely a novel unidentified subtype