Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin.
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SUBMITTER: MacIsaac RJ
PROVIDER: S-EPMC10597955 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
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Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin.
MacIsaac Richard J RJ Deed Gary G D'Emden Michael M Ekinci Elif I EI Hocking Samantha S Sumithran Priya P Rasalam Roy R
Diabetes therapy : research, treatment and education of diabetes and related disorders 20231012 12
Tirzepatide is a first-in-class GIP/GLP-1 receptor agonist ('twincretin')-a single molecule that acts as an agonist at both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. In the SURPASS clinical trial program in type 2 diabetes mellitus (T2D), tirzepatide was associated with unprecedented reductions in HbA1c, clinically significant weight loss and other metabolic benefits, combined with low rates of hypoglycaemia across a wide range of patient c ...[more]
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Project description:Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) are already established in the treatment of type 2 diabetes (T2D). The development of novel dual- or triple-receptor agonists that bind to the receptors not only for GLP-1 but also to the receptors for glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon is intended to address different metabolic pathways for carbohydrate, lipid, and protein metabolism simultaneously. Dual- and triple-receptor agonists acting via different receptors and postreceptor pathways seem attractive in view of potentially additive or synergistic effects in the treatment of T2D and obesity. Recently, the first approval for a dual-receptor agonist marks an important step in this development. The GIP/GLP-1-receptor agonist tirzepatide was approved for the treatment of T2D by the Food and Drug Administration (FDA) in the USA for once-weekly subcutaneous injections in May 2022 and has just received a positive opinion from the European Medicines Agency (EMA). Tirzepatide dose-dependently leads to clinically significant reductions in glycemic parameters and body weight and has been shown to have stronger effects in reducing these parameters than standard antidiabetic therapy. This article summarizes the current clinical study program and the respective outcomes and highlights further potential indications for tirzepatide in the treatment of obesity and potentially other comorbidities of T2D.
| S-EPMC9606350 | biostudies-literature
Project description:PurposeTo better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes.MethodsWe compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions.ResultsThe number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of-mouth referral, and continuous patient-research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors.ConclusionsAdolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent "magic bullets," but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e.g., weight loss, body image, and stress management) combined with less tangible outcomes (e.g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities.
| S-EPMC4163943 | biostudies-literature
Project description:ImportanceDespite its demonstrated benefits in improving cardiovascular risk profiles, the association of tirzepatide with mortality and cardiovascular and kidney outcomes compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown.ObjectiveTo investigate the association of tirzepatide with mortality and adverse cardiovascular and kidney outcomes compared with GLP-1 RAs in patients with type 2 diabetes.Design, setting, and participantsThis retrospective cohort study used US Collaborative Network of TriNetX data collected on individuals with type 2 diabetes aged 18 years or older initiating tirzepatide or GLP-1 RA between June 1, 2022, and June 30, 2023; without stage 5 chronic kidney disease or kidney failure at baseline; and without myocardial infarction or ischemic or hemorrhagic stroke within 60 days of drug initiation.ExposuresTreatment with tirzepatide compared with GLP-1 RA.Main outcomes and measuresThe primary outcome was all-cause mortality, and secondary outcomes included major adverse cardiovascular events (MACEs), the composite of MACEs and all-cause mortality, kidney events, acute kidney injury, and major adverse kidney events. All outcomes were analyzed using Cox proportional hazards regression models.ResultsThere were 14 834 patients treated with tirzepatide (mean [SD] age, 55.4 [11.8] years; 8444 [56.9%] female) and 125 474 treated with GLP-1 RA (mean [SD] age, 58.1 [13.3] years; 67 474 [53.8%] female). After a median (IQR) follow-up of 10.5 (5.2-15.7) months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died. Tirzepatide treatment was associated with lower hazards of all-cause mortality (adjusted hazard ratio [AHR], 0.58; 95% CI, 0.45-0.75), MACEs (AHR, 0.80; 95% CI, 0.71-0.91), the composite of MACEs and all-cause mortality (AHR, 0.76; 95% CI, 0.68-0.84), kidney events (AHR, 0.52; 95% CI, 0.37-0.73), acute kidney injury (AHR, 0.78; 95% CI, 0.70-0.88), and major adverse kidney events (AHR, 0.54; 95% CI, 0.44-0.67). Treatment with tirzepatide was associated with greater decreases in glycated hemoglobin (treatment difference, -0.34 percentage points; 95% CI, -0.44 to -0.24 percentage points) and body weight (treatment difference, -2.9 kg, 95% CI, -4.8 to -1.1 kg) compared with GLP-1 RA. An interaction test for subgroup analysis revealed consistent results stratified by estimated glomerular filtration rate, glycated hemoglobin level, body mass index, comedications, and comorbidities.Conclusions and relevanceIn this study, treatment with tirzepatide was associated with lower hazards of all-cause mortality, adverse cardiovascular events, acute kidney injury, and adverse kidney events compared with GLP-1 RA in patients with type 2 diabetes. These findings support the integration of tirzepatide into therapeutic strategies for this population.
| S-EPMC11320168 | biostudies-literature
Project description:Tirzepatide is a promising drug with dual-acting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor activation that has revolutionized the treatment of type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise. In phase 3 clinical trials (SURPASS 1-5), the dose-dependent efficacy and safety of tirzepatide were assessed by once-weekly subcutaneous injection (5 mg, 10 mg, and 15 mg), as monotherapy or combination therapy, in individuals with T2DM. Tirzepatide has been shown to achieve better glycemic control in terms of glycosylated hemoglobin reduction and improved fasting and postprandial glucose levels as compared to other diabetic medications. Moreover, the studies demonstrate a reduction in body weight (-6.2 to -12.9 kg), and other cardiovascular benefits by altering the lipid profile, reducing blood pressure, and visceral adiposity. Tirzepatide has acceptable side effects and is well tolerated, with a low risk of hypoglycemia. The SURPASS 4 clinical trial has shown positive cardiovascular outcomes in people with T2DM and elevated cardiovascular risk. Additionally, encouraging results from SURMOUNT trials and ongoing SURPASS-CVOT studies will shed more light on cardiovascular safety in the future. In this review, we have summarized the clinical trials and their respective outcomes and highlighted the potential future indications for tirzepatide in the management of obesity, heart failure, and nonalcoholic steatohepatitis.
| S-EPMC10231274 | biostudies-literature
Project description:IntroductionTirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, is approved for glycaemic control for people with type 2 diabetes (T2D). The SURPASS-1 to -5 clinical trials assessed the efficacy of once weekly tirzepatide (5, 10 and 15 mg) versus placebo or active comparators (semaglutide 1 mg, insulin degludec and insulin glargine) in T2D. We evaluated patient-reported outcomes (PROs) that measured overall quality of life (QoL), treatment satisfaction and weight-related attributes across the five SURPASS studies.MethodsPRO instruments utilised at baseline and primary timepoint (40 weeks for SURPASS-1, -2 and -5; 52 weeks for SURPASS-3 and -4) or early termination visit were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only).ResultsAcross all five studies at week 40/52, tirzepatide improved patients' QoL measured by general health and weight-related PROs over the comparator. Generally, higher doses of tirzepatide resulted in greater increases in PRO scores.ConclusionOverall, tirzepatide produced significant health and weight-related QoL improvements versus comparators in the five SURPASS studies.Clinical trial registrationSURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.
| S-EPMC10570242 | biostudies-literature
Project description:BackgroundTirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (- 1.9 to - 2.6%), body weight (- 6.6 to - 13.9%) and systolic blood pressure (SBP) (- 2.8 to - 12.6 mmHg) at the end of study treatment.MethodsPost-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials.ResultsThe difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was - 1.3 to - 5.1 mmHg (tirzepatide 5 mg), - 1.7 to - 6.5 mmHg (tirzepatide 10 mg) and - 3.1 to - 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP.ConclusionsTirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.
| S-EPMC10039543 | biostudies-literature
Project description:IntroductionQualitative exit interviews can supplement clinical trial results by providing a rich and detailed picture of the patient's experience, while highlighting the treatment benefits that are meaningful to patients. Exit interviews can be particularly useful for providing insight into newer medications when less is known about the patient's subjective experience of treatment. Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist for type 2 diabetes mellitus. The purpose of this study was to conduct exit interviews with patients following participation in two trials to better understand the impact of tirzepatide from the patients' point of view.MethodsTelephone interviews were conducted with patients with type 2 diabetes treated with tirzepatide soon after completing one of two trials (SURPASS-2, SURPASS-3). Interviews, conducted according to a semi-structured interview guide, were recorded, transcribed, and analyzed following a content analysis approach using ATLAS.ti.ResultsA total of 28 patients (64% female; mean age 57.6 years) completed interviews. All participants (100%) reported at least one treatment benefit. Patients provided descriptions of treatment benefits, including improved glycemic control (reported by 96% of the sample), weight loss (93%), decreased appetite (79%), and increased energy (79%), as indicated by qualitative coding. All participants said these treatment-related changes mattered to them. Patients described improvements in quality of life and daily activities associated with these treatment benefits. Despite adverse events reported by some patients (most commonly nausea, reported by 13 patients), all 28 said they would recommend tirzepatide to others, and 27 said they would be willing to continue treatment. Examples of representative quotations are presented for descriptions of treatment benefits, quality-of-life impact, and adverse events.DiscussionThe current results indicate that treatment benefits observed in clinical trials of tirzepatide are important to patients. As demonstrated in quotations from patients, the most enthusiastic descriptions of treatment outcomes focused on the weight loss associated with tirzepatide. The study also highlights the usefulness of exit interviews, which can supplement quantitative trial data by showing how these benefits have a meaningful impact on patients' quality of life.
| S-EPMC9095514 | biostudies-literature
Project description:ImportanceTirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described.ObjectiveTo assess the efficacy and safety of tirzepatide vs insulin lispro as an adjunctive therapy to insulin glargine.Design, setting, and participantsThis open-label, phase 3b clinical trial was conducted at 135 sites in 15 countries (participants enrolled from October 19, 2020, to November 1, 2022) in 1428 adults with type 2 diabetes taking basal insulin.InterventionsParticipants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).Main outcomes and measuresOutcomes included noninferiority of tirzepatide (pooled cohort) vs insulin lispro, both in addition to insulin glargine, in HbA1c change from baseline at week 52 (noninferiority margin, 0.3%). Key secondary end points included change in body weight and percentage of participants achieving hemoglobin A1c (HbA1c) target of less than 7.0%.ResultsAmong 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was -2.1% vs -1.1% with insulin lispro, resulting in mean HbA1c levels of 6.7% vs 7.7% (estimated treatment difference, -0.98% [95% CI, -1.17% to -0.79%]; P < .001); results met noninferiority criteria and statistical superiority was achieved. Estimated mean change from baseline in body weight was -9.0 kg with tirzepatide and 3.2 kg with insulin lispro (estimated treatment difference, -12.2 kg [95% CI, -13.4 to -10.9]). The percentage of participants reaching HbA1c less than 7.0% was 68% (483 of 716) with tirzepatide and 36% (256 of 708) with insulin lispro (odds ratio, 4.2 [95% CI, 3.2-5.5]). The most common adverse events with tirzepatide were mild to moderate gastrointestinal symptoms (nausea: 14%-26%; diarrhea: 11%-15%; vomiting: 5%-13%). Hypoglycemia event rates (blood glucose level <54 mg/dL or severe hypoglycemia) were 0.4 events per patient-year with tirzepatide (pooled) and 4.4 events per patient-year with insulin lispro.Conclusions and relevanceIn people with inadequately controlled type 2 diabetes treated with basal insulin, weekly tirzepatide compared with prandial insulin as an additional treatment with insulin glargine demonstrated reductions in HbA1c and body weight with less hypoglycemia.Trial registrationClinicalTrials.gov Identifier: NCT04537923.
| S-EPMC10548360 | biostudies-literature
Project description:The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.
| S-EPMC10088547 | biostudies-literature
Project description: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.
| S-EPMC10087310 | biostudies-literature