Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.

BACKGROUND: According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses. METHODS: In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA1c) of 7·0-10·5% (53·0-91·3 mmol/mol), and BMI of 25-50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785. FINDINGS: Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were -0·43% (SE 0·20; -4·68 mmol/mol [2·15]) for the 0·5 mg group, -1·39% (0·14; -15·24 mmol/mol [1·56]) for the 4 mg escalation group, -1·30% (0·22; -14·20 mmol/mol [2·44]) for the 4 mg group, -1·99% (0·15; -21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, -1·88% (0·21; -20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and -2·02% (0·11; -22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus -0·01% (0·21; -0·12 mmol/mol [2·27]) for the placebo group and -1·41% (0·12; -15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study. INTERPRETATION: In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme. FUNDING: Eli Lilly and Company.

Associations of plasma sphingolipids with measures of insulin sensitivity, ß-cell function, and incident diabetes in Japanese Americans.

BACKGROUND AND AIMS: To prospectively investigate associations of plasma sphingolipids with insulin sensitivity, ß-cell function, and incident diabetes in the Japanese American Community Diabetes Study. METHODS AND RESULTS: Baseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species. Adjusted regression models examined cross-sectional and longitudinal associations with insulin sensitivity (HOMA2-%S), ß-cell function (oral disposition index: DIo) and with incident diabetes over 5 years follow-up. Concentrations of four species (Ceramide C16:0, C18:0, C20:0, and C22:0) were inversely associated with HOMA2-%S at baseline (all P values < 0.05, Q values < 0.05) and change in HOMA2-%S over 5 years (all P values < 0.05, Q values < 0.05). No sphingolipids were associated with baseline or change in DIo. Of the four species associated with HOMA2-%S, only Ceramide C18:0 was significantly and positively associated with incident diabetes (RR/1SD 1.44, 95 % CI 1.10-1.80, P = 0.006, Q = 0.024). The association of plasma Ceramide C18:0 with the risk of diabetes was partially mediated by change in HOMA2-%S between baseline and 5 years (mediation proportion: 61.5 %, 95 % CI 21.1%-212.5 %). CONCLUSION: Plasma Ceramide C18:0 was associated with higher risk of incident diabetes which was partially mediated through a decrease in insulin sensitivity between baseline and five years. Circulating Ceramide C18:0 could be a potential biomarker for identifying those at risk of developing diabetes.

Breast Cancer Knowledge Among Amish and Mennonite Women.

Breast cancer is the most common cancer diagnosis for women in the USA and ranks second in cancer-related deaths. Disproportionately higher breast cancer rates can be found in rural and Appalachian regions due to several social drivers of health, including poverty, access to healthcare, and lack of culturally sensitive health education. Amish and Mennonite communities, religious groups with distinct cultural practices and beliefs, experience lower mammography screening and higher breast cancer mortality rates (among Amish women). This study focuses on knowledge about breast cancer and causes of cancer among Amish and Mennonite women. A total of 473 women participated in the study at 26 separate women's health clinics throughout Ohio, consisting of 348 Amish and 121 Mennonite women, the largest study conducted on breast cancer knowledge spanning dozens of communities. Statistically significant differences were found in total knowledge scores between Amish and Mennonite women (rpb = .178, n = 466, p = .007), with Amish women having lower scores and stronger beliefs in myths associated with breast cancer cause and symptoms (χ(1) = 7.558, p = .006). Both groups often provided scientifically accurate descriptions of cancer etiology. The majority of participants underestimated breast cancer risk, highlighting the need for culturally appropriate health education programs that consider numeracy and health literacy. By implementing targeted interventions and fostering partnerships with community stakeholders using a multifaceted approach that incorporates cultural sensitivity, community engagement, and collaboration, significant progress can be made towards reducing breast cancer disparities and improving health outcomes.

LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.

BACKGROUND: Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study. METHODS: In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20-70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7·0-10·5%, body-mass index of 23-50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802. FINDINGS: Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference -2·8 mmol/L [90% CI -4·63 to -0·94] for 3 mg; -3·1 mmol/L [-4·91 to -1·22] for 3/6 mg; and -2·9 mmol/L [-4·70 to -1·01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (-1·4% [90% CI -2·17 to -0·56] for 3 mg; -1·6% [-2·37 to -0·75] for 3/6 mg; and -1·2% [-2·05 to -0·45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to -8·96 kg [90% CI -11·16 to -6·75] in the 3/6/9/12 mg group). INTERPRETATION: In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development. FUNDING: Eli Lilly and Company.

Medical Mistrust Among Food Insecure Individuals in Appalachia.

This study focused on the relationship between food insecurity and medical mistrust within Appalachia. Food insecurity has negative consequences on health, while medical mistrust can lead to a decrease in health care use, creating additive consequences to already vulnerable populations. Medical mistrust has been defined in various ways, with measures addressing health care organizations and individual health care providers. To determine whether food insecurity has an additive impact on medical mistrust, a cross-sectional survey was completed by 248 residents in Appalachia Ohio while attending community or mobile clinics, food banks, or the county health department. More than one-quarter of the respondents had high levels of mistrust toward health care organizations. Those with high food insecurity levels were more likely to have higher levels of medical mistrust than those with lower levels of food insecurity. Individuals with higher self-identified health issues and older participants had higher medical mistrust scores. Screening for food insecurity in primary care can reduce the impact of mistrust on patient adherence and health care access by increasing patient-centered communication. These findings present a unique perspective on how to identify and mitigate medical mistrust within Appalachia and call attention to the need for further research on the root causes among food insecure residents.

Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human.

The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.

Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans.

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the "athlete's paradox." We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.

Circulating FGF21 proteolytic processing mediated by fibroblast activation protein.

Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications.

Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans.

AIMS/HYPOTHESES: Ceramides and other sphingolipids comprise a family of lipid molecules that accumulate in skeletal muscle and promote insulin resistance. Chronic endurance exercise training decreases muscle ceramides and other sphingolipids, but less is known about the effects of a single bout of exercise. METHODS: We measured basal relationships and the effect of acute exercise (1.5 h at 50% [Formula: see text]) and recovery on muscle sphingolipid content in obese volunteers, endurance trained athletes and individuals with type 2 diabetes. RESULTS: Muscle C18:0 ceramide (p = 0.029), dihydroceramide (p = 0.06) and glucosylceramide (p = 0.03) species were inversely related to insulin sensitivity without differences in total ceramide, dihydroceramide, and glucosylceramide concentration. Muscle C18:0 dihydroceramide correlated with markers of muscle inflammation (p = 0.04). Transcription of genes encoding sphingolipid synthesis enzymes was higher in athletes, suggesting an increased capacity for sphingolipid synthesis. The total concentration of muscle ceramides and sphingolipids increased during exercise and then decreased after recovery, during which time ceramide levels reduced to significantly below basal levels. CONCLUSIONS/INTERPRETATION: These data suggest ceramide and other sphingolipids containing stearate (18:0) are uniquely related to insulin resistance in skeletal muscle. Recovery from an exercise bout decreased muscle ceramide concentration; this may represent a mechanism promoting the insulin-sensitising effects of acute exercise.

Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2).

CONTEXT: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and ß-cell function to a greater extent than comparators. OBJECTIVE: Explore changes in biomarkers of ß-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. DESIGN: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). SETTING: Post hoc analysis of 128 sites in 8 countries. PARTICIPANTS: A total of 1879 participants with type 2 diabetes. INTERVENTIONS: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. MAIN OUTCOMES MEASURES: Change in homeostatic model assessment indices for pancreatic ß-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin. RESULTS: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. CONCLUSION: In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline ß-cell function and insulin resistance, compared with semaglutide.

Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .

Effects of Tirzepatide vs Semaglutide on ß-cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.

CONTEXT: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE: To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. DESIGN: A 28-week double-blind, randomized, placebo-controlled trial. SETTING: Two clinical research centers in Germany. PATIENTS: Patients with type 2 diabetes treated with metformin. INTERVENTIONS: Tirzepatide 15 mg, semaglutide 1 mg, placebo. MAIN OUTCOME MEASURES: Glycemic control, model-derived ß-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), ß-cell glucose (ß-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved ß-CG responsiveness. MMTT-derived ß-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSIONS: These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.

Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

Tirzepatide as Monotherapy Improved Markers of Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes (SURPASS-1).

Context: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes (T2D). SURPASS-1, a phase 3 trial of tirzepatide monotherapy in people with early T2D, enables evaluating effects of tirzepatide on pancreatic beta-cell function and insulin sensitivity (IS) without other background antihyperglycemic medications. Objective: Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy. Design: Post hoc analyses of fasting biomarkers with analysis of variance and mixed model repeated measures. Setting: Forty-seven sites in 4 countries. Patients: Four hundred seventy-eight T2D participants. Intervention: Tirzepatide (5, 10, 15 mg), placebo. Main Outcome Measures: Analyze biomarkers of beta-cell function and IS at 40 weeks. Results: At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs -0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs -0.1%) (P < .001, all doses vs placebo). Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs -1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo). IS improved as indicated by reductions from baseline in homeostatic model assessment for insulin resistance (9-23% vs +14.7%) and fasting insulin levels (2-12% vs +15%), and increases in total adiponectin (16-23% vs -0.2%) and insulin-like growth factor binding protein 2 (38-70% vs +4.1%) with tirzepatide vs placebo at 40 weeks (P ≤ .031, all doses vs placebo, except for fasting insulin levels with tirzepatide 10 mg). Conclusions: As monotherapy for early T2D, tirzepatide achieved significant improvements in biomarkers of both pancreatic beta-cell function and IS.

Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes.

OBJECTIVE: To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS: In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS: Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS: Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.

Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease.

Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aims to determine if patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial.

BACKGROUND: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes. METHODS: This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete. FINDINGS: Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m-2 L min-2 kg-1 (SE 0·03) at baseline by 1·9 pmol m-2 L min-2 kg-1 (0·16) to total 2·3 pmol m-2 L min-2 kg-1 (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m-2 L min-2 kg-1 [SE 0·04]; change from baseline 0·0 pmol m-2 L min-2 kg-1 [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59-2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m-2 L min-2 kg-1 [95% CI 0·46-1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min-1 m-2 [51·84-152·33]) and insulin sensitivity (ETD 1·52 mg min-1 kg-1 [0·53-2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths. INTERPRETATION: The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely ß-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies. FUNDING: Eli Lilly.