Improvements in post‐challenge lipid response following tirzepatide treatment in patients with type 2 diabetes

Tirzepatide, a biological entity that acts as an agonist of both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM).1 Tirzepatide has shown to reduce glycated haemoglobin (HbA1c) by up to (28.2 mmol/mol) 2.6% and body weight by up to 13%,2, 3 by improving beta-cell function and insulin sensitivity, and reducing glucagon secretion.4 Patients with T2DM have increased concentrations of triglycerides (TGs) and small low-density lipoprotein (LDL) particles, decreased high-density lipoprotein (HDL) cholesterol, and increased atherosclerotic cardiovascular disease (ASCVD) risk.5 In a meta-analysis of randomized controlled trials, all three doses of tirzepatide (5, 10, and 15 mg) resulted in decreased TG (10%–19%) and LDL cholesterol concentrations (7%–9%), and increased HDL cholesterol concentrations (4%–7%).6 Impaired metabolism of postprandial TG-rich lipoproteins also contributes to increased ASCVD risk and is another feature of diabetic dyslipidaemia.7 Here, we report the effects of tirzepatide on circulating lipids and apolipoproteins during a standardized mixed-meal tolerance test (MMTT) and hyperglycaemic clamp, as compared with semaglutide or placebo. This multicentre, randomized, double-blind, parallel-arm, phase 1 study, conducted at two study centres in Germany, enrolled male and female participants aged 27 to 74 years with T2DM for at least 7 months, who were on stable doses of metformin and had baseline body mass index (BMI) between 25 and 45 kg/m2. The full study design, including key exclusion criteria, dose escalation, and study procedures, is published elsewhere.4 The current exploratory analyses focus on the effects of tirzepatide, semaglutide, or placebo on circulating lipids and apolipoproteins at after overnight fasting and during MMTT and hyperglycaemic clamp. The target glucose concentration for the hyperglycaemic clamp was 12 mmol/L (216 mg/dL). The hyperglycaemic clamp was performed to evaluate the effects of treatment on insulin secretion, an indicator of beta-cell function. The protocol was approved by local ethical review boards and was conducted in accordance with the Declaration of Helsinki guidelines on good clinical practice. Lipids and apolipoproteins, including free fatty acids (FFAs), TGs, total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB) and apolipoprotein C-III (apoC-III), were measured at baseline and after 28 weeks of treatment, in the fasting state and during the MMTT and hyperglycaemic clamp. Analyses were performed on the pharmacodynamic analysis set, which comprised all randomized patients who received at least one dose of the investigational product and had evaluable pharmacodynamic data. Baseline was defined as the last scheduled non-missing measurement collected during Visit 1 (screening) or Visit 2 (including lead-in) before first dose. All tests of treatment effects were conducted at a two-sided alpha level of 0.05, and the confidence interval (CI) was calculated at 95%, two-sided. Endpoints derived from the clamps and MMTT were assessed by analysis of covariance on log-transformed or original scale data, with study treatment as a fixed effect and baseline measurement as a covariate. Results on log-transformed data (i.e., the clamp outcomes) were converted back to the original scale for presentation. Among 117 patients, 45 received tirzepatide (15 mg)—62.06 mmol/mol, 44 received semaglutide (1 mg)—60.67 mmol/mol and 28 received placebo—62.85 mmol/mol. Baseline demographics and clinical characteristics were well balanced among the treatment groups, with mean baseline BMI values of 31.3, 30.8, and 32.2 kg/m2, respectively, and HbA1c concentrations of 7.8%, 7.7%, and 7.9%, respectively.4 At 28 weeks, tirzepatide reduced fasting TG (least squares mean [LSM] difference −0.74 mmol/L [95% CI −0.98, −0.49]; p < 0.0001), VLDL cholesterol (LSM difference −0.32 mmol/L [95% CI −0.43, −0.21]; p < 0.0001), apoC-III (LSM difference −0.03 g/L [95% CI −0.05, −0.02]; p < 0.0001) and apoB (LSM difference −0.09 g/L [95% CI −0.16, −0.02]; p = 0.0102) concentrations, and increased HDL cholesterol concentrations (LSM difference 0.12 mmol/L [95% CI 0.06, 0.18]; p = 0.0002) versus placebo. Tirzepatide reduced fasting apoB (LSM difference −0.06 g/L [95% CI −0.12, 0.00]; p = 0.0489) and increased HDL cholesterol concentrations (LSM difference 0.06 mmol/L [95% CI 0.01, 0.11]; p = 0.0175) versus semaglutide. Semaglutide decreased fasting TG, VLDL cholesterol, and apoC-III concentrations, however, no statistically significant changes were observed for apoB or HDL cholesterol concentrations. No effects of either tirzepatide or semaglutide were seen in fasting FFA, total cholesterol or LDL cholesterol concentrations versus placebo (Table S1, Figure S1). The MMTT time courses and area under curve (AUC) percent changes from baseline at Week 28 are presented in Figure 1. Tirzepatide showed a significant reduction versus placebo in mean percent change from baseline for TG (LSM estimate difference −38.2 [95% CI −46.4, −28.8]; p < 0.0001), VLDL cholesterol (LSM estimate difference −37.8 [95% CI −46.3, −28.0]; p < 0.0001), apoC-III (LSM estimate difference −27.2 [95% CI −35.2, −18.3]; p < 0.0001) and apoB (LSM estimate difference −9.02 [95% CI −16.01, −1.44]; p = 0.0211) during the MMTT (Table 1). Similar reductions in lipid concentrations were seen with semaglutide, with no significant differences versus tirzepatide. FFA concentrations following the MMTT were not reduced in any treatment group at Week 28, with no treatment group differences when comparing Week 28 changes from baseline. 6.4% (6.5) 1.19 (0.08) | 1.11 (0.07) 2.0% (4.5) 1.00 (0.05) | 1.07 (0.05) −2.5% (4.4) 1.02 (0.05) | 1.02 (0.05) −4.4% (5.5) 11.17 (0.84) | 9.38 (0.54) −34.0% (2.8) 9.52 (0.53) | 6.48 (0.27) −40.9% (2.5) 9.41 (0.53) | 5.80 (0.25) −3.1% (5.8) 4.61 (0.33) | 4.08 (0.24) −32.6% (2.8) 4.20 (0.21) | 2.84 (0.12) −39.8% (2.6) 4.03 (0.21) | 2.53 (0.11) −1.6% (4.6) 0.48 (0.03) | 0.46 (0.02) −22.7% (2.7) 0.46 (0.02) | 0.36 (0.01) −28.4% (2.5) 0.46 (0.02) | 0.33 (0.01) −4.4% (3.1) 3.78 (0.22) | 3.52 (0.11) −6.7% (2.2) 3.56 (0.16) | 3.44 (0.08) −13.0% (2.1) 3.77 (0.17) | 3.21 (0.08) −8.2% (15.6) 0.84 (0.08) | 0.74 (0.13) −83.1% (2.2) 0.82 (0.06) | 0.14 (0.02) −89.3% (1.4) 0.78 (0.06) | 0.09 (0.01) −3.4% (6.5) 4.23 (0.32) | 3.68 (0.25) −40.8% (3.0) 3.72 (0.21) | 2.26 (0.11) −52.9% (2.4) 3.67 (0.21) | 1.79 (0.09) The hyperglycaemic clamp time courses and AUC percent changes from baseline at Week 28 for TG and FFA are presented in Figure 1. Tirzepatide showed a significant suppression versus placebo in mean percent changes from baseline for TG and FFA AUCs during the hyperglycaemic clamp (LSM estimate difference −51.2 [95% CI −58.8, −42.3]; p < 0.0001) and (LSM estimate difference −88.3 [95% CI −92.4, −82.2]; p < 0.0001) (Table 1). While these significant effects were similarly seen with semaglutide versus placebo, the mean percent reductions from baseline in both TG AUC and FFA AUC were larger for tirzepatide than for semaglutide (LSM estimate difference −20.5 [95% CI −31.0, −8.5], p = 0.0017 and −36.7 [95% CI −55.8, −9.1], p = 0.0137, respectively). The present study confirms that tirzepatide reduces the concentrations of fasting TG-rich lipoproteins and overall apoB-containing lipoproteins, as shown by reductions in TG, VLDL cholesterol, apoC-III and apoB concentrations, and increases in HDL cholesterol concentrations in patients with T2DM. Semaglutide did not show any effect on either fasting apoB or HDL cholesterol concentrations. In the SURPASS-2 study, tirzepatide 15 mg was superior to semaglutide 1 mg in reducing body weight, HbA1c, TG and VLDL cholesterol, and increasing HDL cholesterol concentrations.8 The present study further showed that tirzepatide treatment also improved postprandial lipaemia by reducing concentrations of TG, VLDL cholesterol, apoC-III and apoB following the MMTT, partly independent of fasting concentrations. Weight loss following reductions in appetite and food intake in response to treatment with tirzepatide or semaglutide partly contributed to the improvements in the fasting and postprandial lipid profile.9, 10 GLP-1 receptor agonism has previously been shown to decrease postprandial concentrations of TG, VLDL cholesterol, apoC-III, and apoB-48.11 The decrease in postprandial apoC-III concentrations with GLP-1 receptor agonists leads to enhanced lipoprotein lipase activity and liver uptake and clearance of postprandial lipoproteins and is believed to explain a large part of the changes in postprandial lipids.12, 13 Semaglutide similarly reduced postprandial concentrations of TG, VLDL cholesterol and apoC-III, although to a lesser extent than tirzepatide. The shorter duration (4 vs. 8 h) and the low fat content (40 vs. 60 g) of the MMTT may have limited the observation of differences between tirzepatide and semaglutide treatments, despite the greater weight loss and improvement in insulin sensitivity and glucose control with tirzepatide. The low insulin responses to the MMTT for both treatments were also not sufficiently different to produce postprandial TG differences between treatments. However, unlike tirzepatide, semaglutide did not reduce postprandial total apoB concentrations (we did not measure postprandial concentrations of apoB-48 in this study), and, therefore, postprandial atherogenic lipoprotein burden. The present study further indicates that agonism of GLP-1 and GIP receptors with tirzepatide is also effective in reducing FFA and TG concentrations during hyperglycaemic clamp in patients with T2DM. Tirzepatide and semaglutide both improved FFA and TG responses to hyperglycaemic clamp, with tirzepatide showing a greater effect than semaglutide. However, the differences between tirzepatide and semaglutide were no longer statistically significant after adjusting for weight change from baseline, thus suggesting that the greater decrease in body weight and HbA1c for tirzepatide (estimated treatment difference vs. semaglutide −4.3 kg [95% CI −6.8 to −1.9], p = 0.0005 and −4.4 mmol/mol [95% CI −6.8 to −2.0], p = 0.0004, respectively) could largely account for the greater reduction in FFA and TG concentrations during the hyperglycaemic clamp.4, 11 Both larger acute suppression of FFA release in the portal vein as a result of improved insulin sensitivity14 and GIP-induced increased stimulation of TG uptake by peripheral tissues15 could contribute to lesser hepatic TG production and increased TG clearance, respectively, and ultimately to the larger decrease in TG concentrations with tirzepatide in hyperglycaemic conditions. In conclusion, these data show that tirzepatide 15 mg improved postprandial lipid metabolism and resulted in greater TG and FFA suppression during the hyperglycaemic clamp versus semaglutide 1 mg. GIP receptor activation, together with greater improvement in insulin sensitivity, insulin secretion and glucose control, and reductions in body weight, could contribute to this difference. The reduction of fasting and postprandial TG concentrations could contribute to reductions in major adverse cardiovascular events. Tirzepatide is currently being investigated in the two ongoing cardiovascular outcomes studies in patients with obesity without diabetes (SURMOUNT-MMO, NCT05556512) and in those with T2DM (SURPASS-CVOT, NCT04255433). The funder of the study, Eli Lilly and Company, was involved in study design, data collection, data analysis, data interpretation, and writing of the report. The authors thank the participants, caregivers, and investigators. This study was funded by Eli Lilly and Company. Eric A. Rodriguez, PhD, from Eli Lilly and Company, provided writing and editorial assistance. All authors are employees and shareholders of Eli Lilly and Company. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15365. Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has received first regulatory authorization and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at http://www.vivli.org. TABLE S1. Fasting lipid profile. FIGURE S1. Changes from baseline in fasting lipids. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.