Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective.

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non-cirrhotic non-alcoholic steatohepatitis. The Phase 3 SURPASS 1-5 clinical trial programme was designed to assess efficacy and safety of once-weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (-1.87 to -2.59%, -20 to -28 mmol/mol) and body weight (-6.2 to -12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS-2, these reductions were greater than with the GLP-1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP-1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.

Control of P2X3 channel function by metabotropic P2Y2 utp receptors in primary sensory neurons.

Purinergic signaling contributes significantly to pain mechanisms, and the nociceptor-specific P2X3 ATP receptor channel is considered a target in pain therapeutics. Recent findings suggesting the coexpression of metabotropic P2Y receptors with P2X3 implies that ATP release triggers the activation of both ionotropic and metabotropic purinoceptors, with strong potential for functional interaction. Modulation of native P2X3 function by P2Y receptor activation was investigated in rat dorsal root ganglia (DRG) neurons using whole cell patch-clamp recordings. Application of the selective P2Y receptor agonist UTP decreased peak amplitudes of α,ß-meATP-evoked homomeric P2X3-mediated currents, but had no effect on heteromeric P2X2/3-mediated currents. Treatment with phospholipase C inhibitor U73122 significantly reversed P2X3 current inhibition induced by UTP-sensitive P2Y receptor activation. We previously reported the modulation of P2X receptors by phospholipids in DRG neurons and injection of exogenous phosphatidylinositol-4,5-bisphosphate (PIP(2)) fully reverses UTP-mediated regulation of P2X3 channel activity. Pharmacological as well as functional screening of P2Y receptor subtypes indicates the predominant involvement of P2Y2 receptor in P2X3 inhibition, and immunolocalization confirms a significant cellular coexpression of P2X3 and P2Y2 in rat DRG neurons. In summary, the function of P2X3 ATP receptor can be inhibited by P2Y2-mediated depletion of PIP(2). We propose that expression of P2Y2 purinoceptor in nociceptive sensory neurons provides an homeostatic mechanism to prevent excessive ATP signaling through P2X3 receptor channels.

Neurotrophic factor changes in the rat thick skin following chronic constriction injury of the sciatic nerve.

BACKGROUND: Cutaneous peripheral neuropathies have been associated with changes of the sensory fiber innervation in the dermis and epidermis. These changes are mediated in part by the increase in local expression of trophic factors. Increase in target tissue nerve growth factor has been implicated in the promotion of peptidergic afferent and sympathetic efferent sprouting following nerve injury. The primary source of nerve growth factor is cells found in the target tissue, namely the skin. Recent evidence regarding the release and extracellular maturation of nerve growth factor indicate that it is produced in its precursor form and matured in the extracellular space. It is our hypothesis that the precursor form of nerve growth factor should be detectable in those cell types producing it. To date, limitations in available immunohistochemical tools have restricted efforts in obtaining an accurate distribution of nerve growth factor in the skin of naïve animals and those with neuropathic pain lesions. It is the objective of this study to delineate the distribution of the precursor form of nerve growth factor to those cell types expressing it, as well as to describe its distribution with respect to those nerve fibers responsive to it. RESULTS: We observed a decrease in peptidergic fiber innervation at 1 week after the application of a chronic constriction injury (CCI) to the sciatic nerve, followed by a recovery, correlating with TrkA protein levels. ProNGF expression in CCI animals was significantly higher than in sham-operated controls from 1-4 weeks post-CCI. ProNGF immunoreactivity was increased in mast cells at 1 week post-CCI and, at later time points, in keratinocytes. P75 expression within the dermis and epidermis was significantly higher in CCI-operated animals than in controls and these changes were localized to neuronal and non-neuronal cell populations using specific markers for each. CONCLUSIONS: We describe proNGF expression by non-neuronal cells over time after nerve injury as well as the association of NGF-responsive fibers to proNGF-expressing target tissues. ProNGF expression increases following nerve injury in those cell types previously suggested to express it.

Association of Dulaglutide Initiation Timing With Treatment Patterns and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus in the United States.

PURPOSE: To describe clinical characteristics and treatment outcomes for early or late initiation of dulaglutide therapy in patients with type 2 diabetes. METHODS: This retrospective, claims-based analysis evaluated adults with type 2 diabetes, ≥1 claim for dulaglutide 0.75 mg or 1.5 mg once-weekly injection (between November 2014 and August 2019), and no prior use of glucagon-like peptide 1 receptor agonists or insulin. Cohorts were defined based on the number of oral antidiabetic drug (OAD) classes used within the 24-month baseline period before dulaglutide therapy initiation: 1 OAD, 2 OADs, or ≥3 OADs. The number of OAD classes used before dulaglutide therapy initiation served as a proxy for timing of initiation, with a higher number of OAD classes indicating a longer duration of T2D. Baseline demographic and clinical characteristics were compared across each cohort. Six-month follow-up outcomes, including change in glycosylated hemoglobin (HbA1c) and treatment patterns, were descriptively assessed within each cohort. FINDINGS: The study population consisted of 18,121 patients across the 1 OAD (n = 4822), 2 OADs (n = 6293), and ≥3 OADs (n = 7006) cohorts. Mean age at baseline was 54.7 years. Males were more prevalent in the ≥3 OADs cohort. Most patients (67%-70%) initiated treatment with dulaglutide 0.75 mg. Dose escalation to 1.5 mg was uncommon (15%-20%) but trended higher in the ≥3 OAD cohort. Adherence to dulaglutide at 6-month follow-up (61%-67%) increased with higher baseline OAD use. The HbA1c assessment (n = 3178) included 761 patients in the 1 OAD cohort, 1088 patients in the 2 OADs cohort, and 1329 patients in the ≥3 OADs cohort. Baseline mean [SD] HbA1c level increased with number of OAD classes (1 OAD: 8.18% [1.80]; 2 OADs: 8.56% [1.66]; and ≥3 OADs: 8.73% [1.51]). Patients in the early dulaglutide therapy initiator group experienced larger reductions in HbA1c levels (1 OAD: -1.39%; 95% CI, -1.50 to -1.27; 2 OADs: -1.30%; 95% CI, -1.39 to -1.20; and ≥3 OADs: -1.01%; 95% CI, -1.09 to -0.93) versus the patients in the delayed initiator group. Patients in the early dulaglutide therapy initiator group also achieved HbA1c <7% at 6-month follow-up more frequently than those in the later initiator group (1 OAD: 68%; 2 OADs: 51%; and ≥3 OADs: 33%). IMPLICATIONS: Cohorts of dulaglutide therapy initiators, defined by prior OAD use as a proxy of timing of initiation, differed in their baseline characteristics and short-term follow-up outcomes. Earlier dulaglutide therapy initiation was associated with lower mean HbA1c levels and increased probability of achievement of HbA1c <7% during the 6-month follow-up period.

Gastrointestinal Tolerability of Once-Weekly Dulaglutide 3.0 mg and 4.5 mg: A Post Hoc Analysis of the Incidence and Prevalence of Nausea, Vomiting, and Diarrhea in AWARD-11.

BACKGROUND: Gastrointestinal (GI) events are the most frequent treatment-emergent adverse events (TEAEs) reported for glucagon-like peptide-1 receptor agonist therapies. This post hoc analysis of the AWARD-11 phase 3 trial assessed the GI tolerability of dulaglutide at once-weekly doses of 1.5, 3.0, and 4.5 mg. METHODS: The AWARD-11 trial randomized patients to once-weekly dulaglutide 1.5 mg (n = 612), 3.0 mg (n = 616), or 4.5 mg (n = 614) for 52 weeks. Patients started on dulaglutide 0.75 mg for 4 weeks before escalating stepwise every 4 weeks until the final randomized dose was reached. This study analyzes the onsets, incidences, prevalences, and severities of nausea, vomiting, and diarrhea events reported through 52 weeks. RESULTS: The highest incidences of nausea (≤ 8%), vomiting (≤ 2%), and diarrhea (≤ 4%) were primarily observed soon after the initiation of dulaglutide treatment at 0.75 mg. Incidence then declined throughout the remainder of the study, even with dose escalation to 1.5, 3.0, and 4.5 mg. Most of these GI TEAEs were mild to moderate in severity, with severe nausea, vomiting, or diarrhea events occurring in ≤ 0.6% of patients. Treatment discontinuation due to nausea was low across treatment groups (≤ 1.5%). CONCLUSIONS: The tolerability profiles of dulaglutide 3.0 mg and 4.5 mg were consistent with that of the 1.5-mg dose. Patients experiencing GI events were most likely to do so within 2 weeks of treatment initiation, and few patients experienced a new GI event after escalating to the 3.0-mg or 4.5-mg dose. Severe events were infrequent, and when they did occur, no relationship with dose at time of event was observed. Supplementary file1 (MP4 33880 kb).

Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) prescribed for the treatment of type 2 diabetes (T2D). The most frequently reported side effects of GLP-1 RAs are nausea, vomiting, or diarrhea. This analysis of a 52-week study in adult patients with T2D details the tolerability of dulaglutide injected once weekly at a dose of 1.5 mg, 3 mg, or 4.5 mg, as assessed by looking at the nausea, vomiting, and diarrhea events reported during the study. All patients started dulaglutide at 0.75 mg before escalating to 1.5 mg after 4 weeks. Depending on the group they were randomly assigned to, the patients then either remained on the 1.5-mg dose, escalated to 3 mg after another 4 weeks and remained on this dose, or escalated further to 4.5 mg after another 4 weeks. The minority of patients who experienced nausea, vomiting, or diarrhea events (less than 16% of patients in each case) generally did so at the beginning of treatment, when all groups were taking the same dose (0.75 mg). Episodes of nausea, vomiting, or diarrhea then became less frequent, even as patients escalated to each of the higher doses. Most of these events were mild to moderate in severity, and most did not cause patients to stop taking the treatment. In general, this analysis shows that, for the minority of patients who experienced nausea, vomiting, or diarrhea, these events were most likely to happen shortly after starting treatment and lessened over time, even as patients escalated to higher dulaglutide doses.

Delayed reinnervation by nonpeptidergic nociceptive afferents of the glabrous skin of the rat hindpaw in a neuropathic pain model.

Painful peripheral neuropathies have been associated with a reorganization of skin innervation. However, the detailed changes in skin innervation by the different afferent fiber types following a neuropathic nerve injury have never been characterized in an animal model of neuropathic pain. Our objective was to thoroughly characterize such changes in the thick skin of the foot in a well-established rat model of neuropathic pain, namely, the chronic constriction injury (CCI) of the sciatic nerve. We used the immunofluorescence detection of calcitonin gene-related peptide (CGRP), purinergic receptor P2X3, and NF200 as markers of peptidergic nociceptive fibers, nonpeptidergic nociceptive C fibers, and myelinated afferents, respectively. We observed that CCI-operated animals developed significant mechanical allodynia and hyperalgesia as well as thermal hyperalgesia. At 3 days following nerve injury, all CCI-operated animals had a significant decrease in the density of fibers immunoreactive (IR) for CGRP, P2X3, and NF200 within the upper dermis. A recovery of CGRP-IR fibers occurred within 4 weeks of nerve injury and sprouting above control levels was observed at 16 weeks. However, the myelinated (NF200-IR) fibers never recovered to control levels within a period of 16 weeks following nerve injury. Interestingly, the P2X3-IR fibers took considerably more time to recover than the CGRP-IR fibers following the initial loss. A loss in P2X3-IR fibers persisted to 16 weeks and recovered to levels above that of control at 1.5 years following nerve injury. Further studies are required to clarify the relevance of these innervation changes for neuropathic pain generation and maintenance.

Distribution of P2X(3)-immunoreactive fibers in hairy and glabrous skin of the rat.

The skin is innervated by two populations of unmyelinated sensory fibers, the peptidergic and nonpeptidergic, which transmit nociceptive information to the central nervous system. The peptidergic population expresses neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) and has both cutaneous and visceral targets. The nonpeptidergic population expresses the purinergic receptor P2X(3), binds the isolectin B4 (IB4), and innervates mainly the epidermis. To date, the peptidergic nociceptor population in cutaneous tissue of the rat has been well characterized, whereas the nonpeptidergic innervation pattern has lacked an adequate description. To this aim, we used light microscopic immunocytochemistry to investigate the pattern of P2X(3)-immunoreactive (-IR) fiber innervation of both hairy and glabrous skin from male Sprague-Dawley rats. Our results show extensive P2X(3)-IR fibers throughout the upper and lower dermis. Thick bundles of P2X(3)-IR fibers were found to run in parallel with the dermal-epidermal junction and projected multiple thin collateral axons that penetrated the epidermal layer, creating a dense network of innervation throughout the entire epidermis. The distribution of P2X(3)-IR fibers in the epidermis was far more extensive than the distribution of CGRP-IR fibers. P2X(3)-IR fibers also innervate hair follicles but were rarely found in close proximity to glands and blood vessels. The present results suggest a primary role for P2X(3)-IR fibers in the detection of noxious stimuli in cutaneous tissue and provide an anatomical basis for future studies examining a possible functionally distinct role of nonpeptidergic nociceptors in the transmission of nociceptive signals.