Abstract
Context
Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control ...and weight loss (WL) compared with selective GLP-1RA dulaglutide.
Objective
Explore mechanisms of glucose control by tirzepatide.
Design
Post hoc analyses of fasting biomarkers and multiple linear regression analysis.
Setting
Forty-seven sites in 4 countries.
Patients or other Participants
Three hundred and sixteen subjects with type 2 diabetes.
Interventions
Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.
Main Outcome Measures
Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.
Results
Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.
Conclusions
Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists ...in type 2 diabetes mellitus (T2DM).
LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.
A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.
LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.
A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean LSM difference 95% CI: −49.12 mg/dL −78.14, −20.12 and −43.15 mg/dL −73.06, −13.21, respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference 95% CI: −1.75 kg −3.38, −0.12, −5.09 kg −6.72, −3.46 and −4.61 kg −6.21, −3.01, respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference 95% CI: −2.62 kg −3.79, −1.45 and −2.07 kg −3.25, −0.88, respectively.
The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.
Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.
•LY3298176 activates both GIP and GLP-1 receptor signaling in vitro.•LY3298176 lowers blood glucose in mice through actions on both incretin receptors.•LY3298176 reduced fasting glucose in humans with type 2 diabetes.•Weight loss was greater with LY3298176 than the selective GLP-1 receptor agonist, dulaglutide in healthy humans.•Tolerability of LY3298176 was comparable to GLP-1 receptor agonists.
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to ...fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943.
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•LY3437943 has triple agonist activity at the glucagon, GIP, and GLP-1 receptors•LY3437943 caused greater body weight loss in obese mice than tirzepatide•LY3437943 increased energy expenditure through glucagon receptor activation•Safety and tolerability of LY3437943 were similar to other incretin-based drugs
Coskun et al. demonstrate that LY3437943, a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes, can reduce body weight through increased energy expenditure and reduced calorie intake in obese mice. Its safety and tolerability in healthy participants were similar to other incretin-based therapies.
The effect of dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP‐1RAs ...in non‐clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet‐induced obese mice versus semaglutide or long‐acting GIP analogue alone. Participants with and without type 2 diabetes (T2DM) from a phase 1, 4‐week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP‐1's effect on GE. In participants with and without T2DM, once‐weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP‐1RAs.
Corannulene is a multifaceted polyaromatic compound. It has many interesting properties; for example, it has a bowl‐shaped molecular structure that, in addition, undergoes a dynamic inversion ...process. It has attracted much attention within the last decades. This is not only due to its structural properties but also its electronic properties and its various potential applications to materials chemistry. Here, synthetic approaches towards corannulene derivatives with electron‐withdrawing substituents are summarized. This includes both selective and unselective methods. Further, the electrochemical properties, that is, the reduction potentials, are analyzed and compared. As a main conclusion, one can state that the electron affinity depends roughly linearly on the number of substituents. Finally, the structural behavior of the substituted buckybowls in the solid state is highlighted. This also allows a general statement about the influence of the electronic and steric nature of substituents on the molecular structures and the solid‐state packing of the corannulene derivatives.
Bowled over: This review summarizes synthetic approaches towards corannulenes with electron‐withdrawing substituents. The article is focused on the introduction of perfluoroalkyl substituents. Recent advances on other functional groups are discussed in detail. The solid‐state structures and the electrochemical properties of the compounds are compared.
Background
Fatty acid uptake can be measured using PET and 14-(
R,S
)‐
18
Ffluoro‐6‐thia‐heptadecanoic acid (
18
FFTHA). However, the relatively rapid rate of
18
FFTHA metabolism significantly ...affects kinetic modeling of tissue uptake. Thus, there is a need for accurate chromatographic methods to analyze the unmetabolized
18
FFTHA (parent fraction). Here we present a new radiometabolite analysis (RMA) method, with comparison to a previous method for parent fraction analysis, and its use in a test-retest clinical study under fasting and postprandial conditions. We developed a new thin-layer chromatography (TLC) RMA method for analysis of
18
FFTHA parent fraction and its radiometabolites from plasma, by testing stationary phases and eluent combinations. Next, we analyzed
18
FFTHA, its radiometabolites, and plasma radioactivity from subjects participating in a clinical study. A total of 17 obese or overweight participants were dosed with
18
FFTHA twice under fasting, and twice under postprandial conditions and plasma samples were obtained between 14 min (mean of first sample) and 72 min (mean of last sample) post-injection. Aliquots of 70 plasma samples were analyzed using both methods, enabling head-to-head comparisons. We performed test-retest and group comparisons of the parent fraction and plasma radioactivity.
Results
The new TLC method separated seven
18
FFTHA radiometabolite peaks, while the previous method separated three. The new method revealed at least one radiometabolite that was not previously separable from
18
FFTHA. From the plasma samples, the mean parent fraction value was on average 7.2 percentage points lower with the new method, compared to the previous method. Repeated
18
FFTHA investigations on the same subject revealed reproducible plasma SUV and parent fractions, with different kinetics between the fasted and postprandial conditions.
Conclusions
The newly developed improved radio-TLC method for
18
FFTHA RMA enables accurate parent fraction correction, which is required to obtain quantitative data for modelling
18
FFTHA PET data. Our test-retest study of fasted and postprandial conditions showed robust reproducibility, and revealed clear differences in the
18
FFTHA metabolic rate under different study settings.
Trial registration
EudraCT No: 2020-005211-48, 04Feb2021; and Clinical Trials registry NCT05132335, 29Oct2021, URL:
https://classic.clinicaltrials.gov/ct2/show/NCT05132335
.
Polymorphisms in the fat mass‐ and obesity‐associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome‐wide association studies. We hypothesized that ...variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single‐nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two‐hundred and four subjects participated in a lifestyle intervention program and were examined after a follow‐up of 9 months. In the cross‐sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P < 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat (P ≤ 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P ≤ 0.1). However, the single‐nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P > 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.
In order to enhance efficiency of thermal energy supply in residential buildings, combined heat and power (short: CHP) systems are more and more replacing conventional heating systems. However, ...heat-controlled CHP systems either generate an excess of electrical energy, which is commonly fed into the power grid, or suffer from a lack of electrical energy, which has to be covered from the grid. In order to increase self-sufficiency and self-consumption, electrical energy storage should be integrated into a heat-controlled CHP system. Therefore, an electrical storage based on a Liquid Organic Hydrogen Carrier (LOHC) is investigated in this work. For this purpose a heat-controlled CHP system coupled with an LOHC system is modelled and simulated. The CHP system and the LOHC system were evaluated concerning key figures like self-sufficiency, self-consumption rate and primary energy demand. Moreover, a comparison between an LOHC system and a battery system was done. Both systems showed that with an additional electrical energy storage system the primary energy demand can be significantly decreased and the self-sufficiency and the self-consumption rate can be improved. Best results concerning electrical self-sufficiency could be achieved using a battery.
Both systems are able to reduce the primary energy equally, however with the LOHC technology slightly more primary energy can be saved.
•CHP system with a LOHC storage system as a novel electrical storage.•Dynamic simulation of the CHP system and its storage devices.•Comparison between a LOHC and a battery storage within a CHP system.•Comparison of different configurations of an LOHC system.
LY3298176 is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is being developed for the treatment of type 2 diabetes. We ...aimed to examine the efficacy and safety of co-stimulation of the GLP-1 and GIP receptors with LY3298176 compared with placebo or selective stimulation of GLP-1 receptors with dulaglutide in patients with poorly controlled type 2 diabetes.
In this double-blind, randomised, phase 2 study, patients with type 2 diabetes were randomly assigned (1:1:1:1:1:1) to receive either once-weekly subcutaneous LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1·5 mg), or placebo for 26 weeks. Assignment was stratified by baseline glycated haemoglobin A1c (HbA1c), metformin use, and body-mass index (BMI). Eligible participants (aged 18–75) had type 2 diabetes for at least 6 months (HbA1c 7·0–10·5%, inclusive), that was inadequately controlled with diet and exercise alone or with stable metformin therapy, and a BMI of 23–50 kg/m2. The primary efficacy outcome was change in HbA1c from baseline to 26 weeks in the modified intention-to-treat (mITT) population (all patients who received at least one dose of study drug and had at least one postbaseline measurement of any outcome). Secondary endpoints, measured in the mITT on treatment dataset, were change in HbA1c from baseline to 12 weeks; change in mean bodyweight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, and proportion of patients reaching the HbA1c target (≤6·5% and <7·0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% bodyweight loss from baseline to 26 weeks. This study is registered with ClinicalTrials.gov, number NCT03131687.
Between May 24, 2017, and March 28, 2018, 555 participants were assessed for eligibility, of whom 318 were randomly assigned to one of the six treatment groups. Because two participants did not receive treatment, the modified intention-to-treat and safety populations included 316 participants. 258 (81·7%) participants completed 26 weeks of treatment, and 283 (89·6%) completed the study. At baseline, mean age was 57 years (SD 9), BMI was 32·6 kg/m2 (5·9), duration from diagnosis of diabetes was 9 years (6), HbA1c was 8·1% (1·0), 53% of patients were men, and 47% were women. At 26 weeks, the effect of LY3298176 on change in HbA1c was dose-dependent and did not plateau. Mean changes from baseline in HbA1c with LY3298176 were −1·06% for 1 mg, −1·73% for 5 mg, −1·89% for 10 mg, and −1·94% for 15 mg, compared with −0·06% for placebo (posterior mean differences 80% credible set vs placebo: −1·00% –1·22 to −0·79 for 1 mg, −1·67% –1·88 to −1·46 for 5 mg, −1·83% –2·04 to −1·61 for 10 mg, and −1·89% –2·11 to −1·67 for 15 mg). Compared with dulaglutide (−1·21%) the posterior mean differences (80% credible set) for change in HbA1c from baseline to 26 weeks with the LY3298176 doses were 0·15% (−0·08 to 0·38) for 1 mg, −0·52% (−0·72 to −0·31) for 5 mg, −0·67% (−0·89 to −0·46) for 10 mg, and −0·73% (−0·95 to −0·52) for 15 mg. At 26 weeks, 33–90% of patients treated with LY3298176 achieved the HbA1c target of less than 7·0% (vs 52% with dulaglutide, 12% with placebo) and 15–82% achieved the HbA1c target of at least 6·5% (vs 39% with dulaglutide, 2% with placebo). Changes in fasting plasma glucose ranged from −0·4 mmol/L to −3·4 mmol/L for LY3298176 (vs 0·9 mmol/L for placebo, −1·2 mmol/L for dulaglutide). Changes in mean bodyweight ranged from −0·9 kg to −11·3 kg for LY3298176 (vs −0·4 kg for placebo, −2·7 kg for dulaglutide). At 26 weeks, 14–71% of those treated with LY3298176 achieved the weight loss target of at least 5% (vs 22% with dulaglutide, 0% with placebo) and 6–39% achieved the weight loss target of at least 10% (vs 9% with dulaglutide, 0% with placebo). Changes in waist circumference ranged from −2·1 cm to −10·2 cm for LY3298176 (vs −1·3 cm for placebo, −2·5 cm for dulaglutide). Changes in total cholesterol ranged from 0·2 mmol/L to −0·3 mmol/L for LY3298176 (vs 0·3 mmol/L for placebo, −0·2 mmol/L for dulaglutide). Changes in HDL or LDL cholesterol did not differ between the LY3298176 and placebo groups. Changes in triglyceride concentration ranged from 0 mmol/L to −0·8 mmol/L for LY3298176 (vs 0·3 mmol/L for placebo, −0·3 mmol/L for dulaglutide). The 12-week outcomes were similar to those at 26 weeks for all secondary outcomes. 13 (4%) of 316 participants across the six treatment groups had 23 serious adverse events in total. Gastrointestinal events (nausea, diarrhoea, and vomiting) were the most common treatment-emergent adverse events. The incidence of gastrointestinal events was dose-related (23·1% for 1 mg LY3298176, 32·7% for 5 mg LY3298176, 51·0% for 10 mg LY3298176, and 66·0% for 15 mg LY3298176, 42·6% for dulaglutide, 9·8% for placebo); most events were mild to moderate in intensity and transient. Decreased appetite was the second most common adverse event (3·8% for 1 mg LY3298176, 20·0% for 5 mg LY3298176, 25·5% for 10 mg LY3298176, 18·9% for 15 mg LY3298176, 5·6% for dulaglutide, 2·0% for placebo). There were no reports of severe hypoglycaemia. One patient in the placebo group died from lung adenocarcinoma stage IV, which was unrelated to study treatment.
The dual GIP and GLP-1 receptor agonist, LY3298176, showed significantly better efficacy with regard to glucose control and weight loss than did dulaglutide, with an acceptable safety and tolerability profile. Combined GIP and GLP-1 receptor stimulation might offer a new therapeutic option in the treatment of type 2 diabetes.
Eli Lilly and Company.
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