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Systematic Review and Meta-Analysis

Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis

Dutta, Deep,; Surana, Vineet1; Singla, Rajiv2; Aggarwal, Sameer3; Sharma, Meha4

Author Information
Indian Journal of Endocrinology and Metabolism: Nov–Dec 2021 - Volume 25 - Issue 6 - p 475-489
doi: 10.4103/ijem.ijem_423_21

Abstract

INTRODUCTION

Glucose-dependent insulinotropic peptide (GIP) is four amino acid incretin peptide, produced by K-cells of duodenum and proximal jejunum, released in response to oral carbohydrates and lipid load, having short half-life of 4–7 min and inactivated by dipeptidyl peptidase (DPP)-4 enzyme.[1] GIP receptors have been documented in heart, pancreas, gastric mucosa, adipose tissue, bone, adrenal cortex, and brain.[1] Unlike GLP-1, GIP has glucagonostatic in the hyperglycemic state, but glucagonotropic property during normoglycemic and hypoglycemic state.[1] Glucagon is known to prevent hypoglycemia. Hence, this glucagonotropic property in hypoglycemic states makes GIP-based therapy for type-2 diabetes (T2DM) really attractive due to the lower risk of hypoglycemia. T2DM is characterized by loss of insulinotropic property of GIP along with loss of glucagonostatic in the hyperglycemic state (GIP resistance).[2] Some studies have even documented glucagonotropic property of GIP during hyperglycemia, which is otherwise normally seen only during normoglycemia or hypoglycemia.[2] Hojberg et al.[3] demonstrated that supraphysiologic exogenous GIP administration in people with T2DM increased the insulin response (incretin effect), partly restoring insulinotropic properties. Physiologic studies have demonstrated that coinfusion of glucagon-like peptide (GLP)-1 and GIP has a synergetic effect resulting in significantly increased insulin response and glucagonostatic response resulting in a significant lowering of blood glucose, as compared to the separate administration of each of the hormone in T2DM.[4]

This lead to development of tirzepatide, a novel dual GIP/GLP-1 receptor agonist (twincretin), formulated as a synthetic peptide containing 39-amino acids, based on the native GIP.[5] Tirzepatide has a comparable GIP receptor binding affinity to native GIP and five times lower GLP-1 receptor affinity than that of native GLP-1.[5] The clinical efficacy, tolerability, and safety of tirzepatide have been reported in different randomized controlled trials (RCTs).[6] However, to date, there is no Cochrane meta-analysis available which has analyzed the clinical efficacy and safety of this novel twincretin in T2DM. Hence, the aim of this Cochrane meta-analysis was to evaluate the efficacy and safety of tirzepatide in the management of T2DM.

Since different doses of tirzepatide have been tried (5 mg weekly, 10 mg weekly, 12 mg weekly, and 15 mg weekly); in our meta-analysis, outcomes were assessed for patients receiving tirzepatide 10 mg/12 mg weekly compared to controls. This is based on available data which suggest maximal clinical benefits of tirzepatide with 10–15 mg weekly dose.

METHODS

Methodology

The recommendations of Cochrane Handbook for Systematic Reviews of Interventions were strictly followed which carrying out this meta-analysis.[7] The predefined protocol has been registered in PROSPERO having Registration number of CRD42021261242. All RCTs published till September 2021 were considered. This meta-analysis has been reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses, the filled checklist of which can be found at end of manuscript.[7] Since ethical approval already exists for individual studies, no separate approval was required for this meta-analysis. PICOS criteria were used to screen and select studies. The studies needed to have at least two treatment arms/groups, with one of the groups on tirzepatide and the other group receiving placebo or any other active comparator.

The primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in fasting plasma glucose (FPG), 2-h postprandial blood–glucose (PPBG), percentage of patients achieving HbA1c <6.5%, body weight, waist circumference, hypoglycemia, lipid parameters, adverse events, insulin resistance (IR) and glucagon. Analysis of primary and secondary outcomes were done based on control group received an active comparator – marked as active-control group (ACG) or placebo – marked as passive-control group (PCG).

Search method for identification of studies

A detailed electronic databases of Embase, Cochrane central register of controlled trials, medline, clinicaltrials.gov, ctri.nic.in, Google scholar, and global health were searched using a Boolean search strategy: (tirzepatide) AND (diabetes).

Data extraction and study selection

Data extraction was carried out independently by two authors using data extraction forms. Details have been elaborated elsewhere.[8] Patient characteristics of the included studies are elaborated in Supplementary Table 1.

T1
Table 1:
Summary of findings of the key outcomes of this meta-analysis

Assessment of risk of bias in included studies

Three authors independently assessed the risk of bias using the risk of bias assessment tool in Review Manager (Revman) Version 5.3 (The Cochrane Collaboration, Oxford, UK 2014) software. The details of the different biases looked into have already been elaborated elsewhere,[8] and for this meta-analysis, they have been elaborated in Figure 2a and 2b.

F1
Figure 1:
Flowchart elaborating on study retrieval and inclusion in the meta-analysis Reason-1: Four studies were found to be post-hoc analysis of RCTs[6 18 19 20] and hence have not been analyzed separately RCT: randomized controlled trial
F2
Figure 2:
(a) Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies and (b) risk of bias summary: review authors’ judgments about each risk of bias item for each included study

Measures of treatment effect

For continuous variables, outcomes were expressed as mean difference (MD). SI were used for analysis. Dichotomous outcomes results were expressed as risk ratio (RR) with 95% confidence interval (CI). Adverse events were presented as post treatment absolute risk differences (hazard ratios). RevMan 5.3 was used for comparing MD of outcomes.

Assessment of heterogeneity

Heterogeneity was initially assessed by studying the forest plot generated for outcomes. Subsequently heterogeneity was analyzed using a Chi-square test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test.[9] The details of interpretation of I2 values have already been elaborated elsewhere.[8]

Grading of the results

An overall grading of the evidence (certainty of the evidence) related to each of the outcomes of the meta-analysis was done using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.[10] The details of how GRADE was used to generate the summary of findings (SOF) table, and how grading of evidence was done as “high,” “moderate,” or “low,” have been elaborated elsewhere.[8] The SOF table has been presented as Table 1. Publication bias was assessed by plotting Funnel Plots.[10] The presence of one or more of the smaller studies outside inverted funnel plot signifies significant publication bias.[11] The detailed grading of results of the study has been elaborated in Table 1.

Data synthesis

Data were pooled as a random-effect model for the analysis of outcomes. Outcomes were expressed as 95% CI. Forrest plots were plotted with the left side of graph favoring tirzepatide and the right side favoring control. RevMan 5.3 software was used to plot Forrest plots.

RESULTS

The initial search revealed 34 articles [Figure 1]. Following screening of titles, abstracts, and full-texts, number of studies were narrowed to 23 studies which were evaluated in detail [Figure 1]. Data from six RCTs involving 3484 people with T2DM which fulfilled all criteria were analyzed.[121314151617] Pirro et al.[18] and Wilson et al.[6] published outcomes of tirzepatide on extended serum metabolic and lipid parameters. Hartman et al.[19] published outcomes of tirzepatide on fatty liver disease. Thomas et al.[20] published on impact of tirzepatide on beta-cell function and IR. Since papers by Pirro et al.,[18] Wilson et al.,[6] Hartman et al.,[19] and Thomas et al.[20] were post-hoc analysis of original RCT by Frias et al.[12](2018); in our analysis, the results from these four papers have been pooled with data from Frias et al. (2018) to avoid duplicity.

In the study by Frias et al. (2018), patients were randomly assigned to receive tirzepatide 1 mg weekly, tirzepatide 5 mg weekly, tirzepatide 10 mg weekly, tirzepatide 15 mg weekly, dulaglutide 1.5 mg weekly, and placebo. In this meta-analysis, the outcomes of patients tirzepatide 10 mg weekly compared to those receiving dulaglutide 1.5 mg weekly have been analyzed under ACG as Frias 2018a. The outcomes of patients receiving tirzepatide 10 mg weekly compared to those receiving placebo have been analyzed under PCG as Frias 2018b. In the study by Frias et al. (2020),[13] the outcomes of patients gradually built up to tirzepatide 12 mg weekly and 15 mg weekly were compared to placebo. Since this study did not have tirzepatide 10 mg weekly arm, the outcomes of patients receiving tirzepatide 12 mg weekly were compared to those receiving placebo were analyzed under PCG. In the study by Frias et al. (2021),[14] patients were randomized to receive tirzepatide 5 mg weekly, 10 mg weekly, 15 mg weekly, or semaglutide 1 mg weekly.[14] The outcomes of patients tirzepatide 10 mg weekly compared to those receiving semaglutide 1 mg weekly have been analyzed under ACG. In the study by Rosenstock et al. (2021),[15] patients were randomized to receive tirzepatide 5 mg weekly, 10 mg weekly, 15 mg weekly, or placebo. The outcomes of patients receiving tirzepatide 10 mg weekly were compared to those receiving placebo were analyzed under PCG (Rosenstock et al. 2021). In the study by Ludvik et al. (2021),[16] patients were randomized to receive tirzepatide 5 mg weekly, 10 mg weekly, 15 mg weekly, or insulin degludec. The outcomes of patients receiving tirzepatide 10 mg weekly were compared to those receiving insulin degludec were analyzed under ACG (Ludvik et al. 2021). In the study by del Prato et al. (2021),[17] patients were randomized to receive tirzepatide 5 mg weekly, 10 mg weekly, 15 mg weekly, or insulin glargine. The outcomes of patients receiving tirzepatide 10 mg weekly were compared to those receiving insulin glargine were analyzed under ACG (del Prato et al. 2021). The durations of follow-up in the studies by Frias et al. (2018),[12] Frias et al. (2020),[13] Frias et al. (2021),[14] Rosenstock et al. (2021),[15] Ludvik et al. (2021),[16] and del Prato et al. (2021)[17] were 26, 12, 40, 40, 52, and 52 weeks respectively. Supplementary Table 1 elaborates the details of studies included. The details of four papers which have been post-hoc analysis of RCT by Frias et al. (2018) have been elaborated in Supplementary Table 2.

Risk of bias in the included studies

Summaries of risk of bias of the three studies included in the meta-analysis have been elaborated in Figure 2a, 2b, and Supplementary Table 3. Random sequence generation, allocation concealment bias, incomplete outcome data, and reporting bias were found to be at low risk in all six studies. Performance bias and detection bias were found to be low risk in three out of six studies (50%). Source of funding, especially funding from pharmaceutical organizations, and conflict of interests were looked into “other bias.” All six studies had high “other bias” risk [Figure 2a, 2b].

Effect of tirzepatide on primary outcomes

HbA1c

Data from four studies involving 3046 people were analyzed to find the impact of tirzepatide on HbA1c compared to ACG. Tirzepatide had significantly greater lowering HbA1c compared to dulaglutide/semaglutide/degludec/glargine [MD = -0.75% (95% CI: -1.05 to -0.45); P < 0.01; I2 = 100% (considerable heterogeneity); Figure 3a]. Data from three studies involving 371 people was analyzed to find the impact of tirzepatide on HbA1c compared to PCG. Tirzepatide had significantly greater lowering HbA1c compared to placebo [MD = -1.93% (95% CI: -1.95 to -1.90); P < 0.01; I2 = 0% (low heterogeneity); Figure 3b]

F3
Figure 3:
Forest plot highlighting the impact of tirzepatide on (a) HbA1c as compared to ACG; (b) HbA1c as compared to PCG; (c) fasting glucose as compared to ACG; (d) fasting glucose as compared to PCG; (e) postprandial group as compared to ACG; and (f) postprandial glucose as compared to PCG

Effect of tirzepatide on secondary outcomes

Fasting glucose

Data from four studies involving 3046 people were analyzed to find impact of tirzepatide on FPG compared to ACG. Tirzepatide had significantly greater lowering of FPG compared to dulaglutide/semaglutide/degludec/glargine [MD = -0.75 mmol/L (95%CI: -1.05 to -0.45); P < 0.01; I2 = 100%; Figure 3c]. Data from three studies involving 371 people was analyzed to find the impact of tirzepatide on FPG compared to PCG. Tirzepatide had significantly greater lowering of FPG compared to placebo [MD = -3.42 mmol/L (95% CI: -4.08 to -2.76); P < 0.01; I2 = 98%; Figure 3d].

Postprandial glucose

Data from three studies involving 1,743 people were analyzed to find the impact of tirzepatide on PPBG compared to ACG. Tirzepatide had significantly greater lowering of PPBG as compared to active controls [MD = -0.87 mmol/L (95% CI: -1.12 to -0.61); P < 0.0; I2 = 99%; Figure 3e]. Data from one study involving 90 people were analyzed to find the impact of tirzepatide on PPG compared to PCG. Individuals receiving tirzepatide had significantly greater lowering of PPG as compared to placebo [MD-3.36 mmol/L (95% CI: -3.50 to -3.22); P < 0.01; Figure 3f].

Body weight

Data from four studies involving 3046 people were analyzed to find the impact of tirzepatide on body weight compared to ACG. Tirzepatide had significantly greater body weight lowering compared to dulaglutide/semaglutide/degludec/glargine [MD = -8.63 kg (95% CI: -12.89 to -4.36); P < 0.01; I2 = 100%; Figure 4a]. Data from three studies involving 375 people were analyzed to find the impact of tirzepatide on bodyvweight compared to PCG. Tirzepatide had a significantly greater body weight lowering compared to placebo [MD = -6.84 kg (95% CI: -8.02 to– -5.65); P < 0.01; I2 = 97% (considerable heterogeneity); Figure 4b].

F4
Figure 4:
Forest plot highlighting the impact of tirzepatide on (a) body weight as compared to ACG; (b) body weight as compared to PCG; (c) percentage of people HbA1c <7% as compared to ACG; (d) percentage of people HbA1c <7% as compared to PCG; (e) percent of people achieving HbA1c <6.5% as compared to ACG; and (f) percent of people achieving HbA1c <6.5% as compared to PCG

Body mass index (BMI)

Data from two studies (Frias 2018a and Frias 2021) involving 1028 people were analyzed to find the impact of tirzepatide on BMI compared to ACG. Tirzepatide had significantly greater BMI lowering compared to dulaglutide/semaglutide [MD = -1.80 kg/m2 (95% CI: -2.39 to -1.21); P < 0.01; I2 = 99% (considerable heterogeneity)]. Data from one study (Frias 2018b) involving 86 people were analyzed to find the impact of tirzepatide on BMI as compared to PCG. Tirzepatide had significantly greater BMI lowering compared to placebo [MD = -3.00 kg/m2 (95% CI: -3.12 to -2.88); P < 0.01].

Waist circumference

Data from two studies (Frias 2018a and Frias 2021) involving 1028 people were analyzed to find the impact of tirzepatide on waist circumference compared to ACG. Tirzepatide had significantly greater waist-circumference lowering compared to dulaglutide/semaglutide [MD = -4.43 cm (95% CI: -5.31 to -3.55); P < 0.01; I2 = 95% (considerable heterogeneity)]. Data from two studies (Frias 2018b and Frias 2020) involving 137 people were analyzed to find the impact of tirzepatide on waist circumference compared to PCG. Tirzepatide had greater waist circumference lowering compared to placebo [MD = -4.83 cm (95% CI: -9.73 to 0.07); P = 0.05; I2 = 99% (considerable heterogeneity)].

Percentage of people achieving HbA1c <7%, <6.5%, and <5.7%

Data from four studies involving 3046 patients were analyzed to evaluatethe impact of tirzepatide on attaining HbA1c <7% and <6.5% compared to ACG. Patients receiving tirzepatide had significantly higher odds of achieving HbA1c <7% [odds ratio (OR) = 4.28 (95% CI: 2.01–9.11); P < 0.01; I2 = 91% (considerable heterogeneity); Figure 4c] and <6.5% [OR = 4.39 (95% CI: 2.44–7.92); P < 0.01; I2 = 90% (considerable heterogeneity); Figure 4e] compared to active controls. Data from two study involving 320 patients were analyzed to evaluate the impact of tirzepatide on HbA1c <7% and <6.5% compared to PCG. Patients receiving tirzepatide had significantly higher odds of achieving HbA1c <7% [OR = 38.91 (95% CI: 20.41–74.20); P < 0.01; I2 = 0% (low heterogenity); Figure 4d] and <6.5% [OR = 55.42 (95% CI: 14.23– 206.54); P < 0.01; I2 = 43% (moderate heterogenity); Figure 4f] as compared to placebo.

Diabetes reversal has often been defined as achieving normoglycemia (HbA1c <5.7%). Data from two studies (Del Prato 2021 and Ludvick 2021) involving 2018 patients were analyzed to evaluate the impact of tirzepatide on attaining HbA1c <5.7% compared to ACG. Patients receiving tirzepatide had significantly higher odds of achieving HbA1c <5.7% [OR = 12.54 (95% CI: 9.08–17.32); P < 0.01; I2 = 0% (low heterogeneity)], compared to active controls. Data from one study (Rosenstock 2021) involving 234 patients were analyzed to evaluate the impact of tirzepatide on attaining HbA1c <5.7% compared to PCG. Patients receiving tirzepatide had significantly higher odds of achieving HbA1c <5.7% [OR = 47.44 (95% CI: 6.38–352.93); P < 0.01], compared to placebo.

People achieving weight loss of >5, 10, and 15%

Data from three studies involving 2956 patients were analyzed to evaluate the impact of tirzepatide on attaining more than 5, 10, and 15% weight loss as compared to active controls. Patients receiving tirzepatide had significantly higher odds of achieving weight loss more than 5% [OR = 19.18 (95% CI: 2.34–157.17); P < 0.01; I2 = 99% (considerable heterogeneity); Supplementary Figure 1a], 10% [OR = 21.40 (95% CI: 2.36–193.94); P < 0.01; I2 = 98% (considerable heterogeneity); Supplementary Figure 1b] and 15% [OR = 32.84 (95% CI: 2.27–474.33); P = 0.01; I2 = 96% (considerable heterogeneity); Supplementary Figure 1c] as compared to ACG. Data from one study (Rosenstock 2021) involving 234 patients were analyzed to evaluate the impact of tirzepatide on attaining more than 5, 10, and 15% weight loss as compared to those receiving placebo. Patients receiving tirzepatide had significantly higher odds of achieving weight loss more than 5% [OR = 19.23 (95% CI: 9.80–37.73); P < 0.01], 10% [OR = 71.14 (95% CI: 9.60–526.86); P < 0.01], and 15% [OR = 45.85 (95% CI: 2.74–767.76); P < 0.01] as compared to PCG.

Lipid parameters

Data from two studies involving 1026 were analyzed to evaluate the impact of tirzepatide on triglycerides and LDL-C compared to ACG. Patients receiving tirzepatide did not have significantly different triglycerides [MD-0.60 mmol/L (95% CI: -1.34 to 0.13); P = 0.11; I2 = 100%; Supplementary Figure 2a] and LDL-C [MD = 0.10 mmol/L (95% CI: -0.08 to 0.28); P = 0.27; I2 = 98%; Supplementary Figure 2b] as compared to dulaglutide/semaglutide. Data from one study involving 84 patients were analyzed to evaluate the impact of tirzepatide on triglycerides and LDL-C compared to PCG. Patients receiving tirzepatide had significantly lower triglycerides [MD = -1.83 mmol/L (95% CI: -1.93 to -1.73); P < 0.01; Supplementary Figure 2c] and LDL-C [MD = -0.19 mmol/L (95% CI: -0.24 to -0.14); P < 0.01; Supplementary Figure 2d] compared to placebo.

Data from two studies involving 1026 patients were analyzed to evaluate the impact of tirzepatide on HDL-C compared to ACG. Patients receiving tirzepatide had significantly higher HDL-C compared to dulaglutide/semaglutide [MD0.04 mmol/L (95% CI: 0.04–0.04); P < 0.01; I2 = 0%; Supplementary Figure 2e]. Data from one study involving 84 patients were analyzed to evaluate the impact of tirzepatide on HDL-C compared to PCG. Patients receiving tirzepatide had significantly higher HDL-C as compared to placebo [MD0.03 mmol/L (95% CI: 0.02–0.04); P < 0.01; Supplementary Figure 2f].

Cardiovascular events

Data from one study (del Prato 2021) were analyzed to evaluate the impact of tirzepatide on MACE-4 (transient ischemic attacks, coronary revascularizations, hospitalizations for heart failure, and mortality) and hospitalization for heart failure as compared to active controls. 4-MACE events [RR = 0.83 (95% CI: 0.48–1.44); P = 0.50] and hospitalization for heart failure [RR = 0.51 (95% CI: 0.06–4.22); P = 0.53] were not significantly different in patients receiving tirzepatide as compared to glargine.

Safety

Data from four studies involving 3091 patients were analyzed to evaluate the impact of tirzepatide on treatment emergent adverse event (TAEs) and severe adverse events (SAEs) compared to ACG. The occurrence of TAEs [RR = 1.43 (95% CI: 1.14–1.80); P < 0.01; I2 = 40% (moderate heterogeneity); Figure 5a;] but not SAEs [RR1.00 (95%CI: 0.64–1.57); P = 1.00; I2 = 49%(moderate heterogeneity); Figure 5b] was significantly higher in people receiving tirzepatide as compared to active controls.

F5
Figure 5:
Forest plot highlighting the side-effect profile of the use of tirzepatide (a) total adverse events (TAEs) as compared to ACG; (b) severe adverse events (SAEs) as compared to ACG; (c) TAEs as compared to PCG; (d) SAEs as compared to PCG; (e) hypoglycemia as compared to ACG; and (f) hypoglycemia as compared to PCG

Data from three studies involving 393 patients were analyzed to evaluate impact of tirzepatide on TAEs and SAEs compared to PCG. Occurrence of TAEs [RR = 2.28 (95% CI: 0.86–6.08); P = 0.10; I2 = 75% (moderate heterogeneity); Figure 5c] and SAEs [RR = 1.34 (95% CI: 0.36–4.91); P = 0.66; I2 = 0% (low heterogeneity); Figure 5d] was not significantly different in people on tirzepatide compared to placebo.

Data from four studies involving 3091 patients were analyzed to evaluate the occurrence of hypoglycemia due to tirzepatide compared to ACG. Tirzepatide was associated with significantly lower occurrence of hypoglycemia [RR = 0.32 (95% CI: 0.17–0.60); P < 0.01; I2 = 78% (moderate heterogeneity); Figure 5e] as compared to those receiving dulaglutide/semaglutide/degludec/glargine (ACG). Data from three studies involving 393 patients were analyzed to evaluate the occurrence of hypoglycemia in patients receiving tirzepatide compared to PCG. Tirzepatide was associated with increased hypoglycemia [RR = 4.22 (95% CI: 1.26–14.15); P = 0.02; I2 = 0% (low heterogeneity); Figure 5f] as compared to placebo.

Most common adverse events noted across RCTs were gastrointestinal namely nausea, vomiting, diarrhea and gastro intestinal discomfort. Data from four studies involving 3091 patients were analyzed to evaluate occurrence of nausea, vomiting, and diarrhea in patients receiving tirzepatide compared to ACG. Patients receiving tirzepatide had similar occurrence of nausea [RR = 2.86 (95% CI: 0.56–14.52); P = 0.21; I2 = 97% (considerable heterogeneity); Supplementary Figure 3a], vomiting [RR = 2.63 (95% CI: 0.62–11.16); P = 0.19; I2 = 93% (considerable heterogeneity); Supplementary Figure 3b], and diarrhea [RR = 2.52 (95% CI: 0.92–6.92); P = 0.07; I2 = 93; Supplementary Figure 3c] as compared to active controls. Data from three studies involving 594 patients were analyzed to evaluate occurrence of nausea, vomiting and diarrhea in patients receiving tirzepatide compared to PCG. Patients receiving tirzepatide had significantly higher nausea [RR = 3.02 (95% CI: 1.51–6.05); P < 0.01; I2 = 0% (low heterogeneity); Supplementary Figure 3d], vomiting [RR = 3.63 (95% CI: 1.13–11.67); P = 0.03; I2 = 0% (low heterogeneity); Supplementary Figure 3e], and diarrhea [RR = 3.17 (95% CI: 1.64–6.15); P < 0.01; I2 = 31%; Supplementary Figure 3f] as compared to placebo.

Data from two studies (Frias 2018a and Frias 2021) involving 1043 were analyzed to evaluate the impact of tirzepatide on liver enzyme ALT compared to ACG. Patients receiving tirzepatide had lower ALT as compared to dulaglutide/semaglutide [MD = -4.34 U/L (95% CI: -9.14 to 0.46); P = 0.08; I2 = 99%], which approached statistical significance. Data from one study (Frias 2018b) involving 102 patients were analyzed to evaluate the impact of tirzepatide on ALT compared to PCG. Patients receiving tirzepatide had significantly lower ALT compared to placebo [MD = -4.80U/L (95% CI: -5.52 to -4.08); P < 0.01].

Insulin resistance and glucagon

Data from two studies (Frias 2018a and Frias 2021) involving 1028 patients were analyzed to evaluate the impact on IR as estimated using homeostatic model of insulin resistance (HOMA-IR) compared to ACG. Patients receiving tirzepatide had significantly lower IR compared to dulaglutide/semaglutide [MD-0.44 (95% CI: -0.75 to -0.14); P < 0.01; I2 = 99%]. Data from one study (Frias 2018b) involving 86 patients were analyzed to evaluate the impact of treatment on HOMA-IR compared to PCG. Patients receiving tirzepatide had significantly lower IR compared to placebo [MD = -0.70 (95%CI: -0.78 to -0.62); P < 0.01].

Data from two studies (Frias 2018a and Frias 2021) involving 1028 patients were analyzed to evaluate the impact on fasting glucagon compared to ACG. Patients receiving tirzepatide had lower glucagon when compared to dulaglutide/semaglutide [MD = -3.37 pmol/L (95% CI: -6.99 to 0.25); P = 0.07; I2 = 95%], which approached statistical significance. Data from one study (Frias 2018b) involving 86 patients were analyzed to evaluate the impact of treatment on glucagon as compared to PCG. Patients receiving tirzepatide had significantly lower glucagon when compared to placebo [MD = -3.20 (95%CI: -3.60 to -2.80); P < 0.01].

The funnel plot evaluating the presence of publication bias has been elaborated in Supplementary Figure 4.

DISCUSSION

This is the first Cochrane meta-analysis to analyze and highlight the glycemic efficacy, weight loss properties, impact of different parameters of metabolic syndrome, tolerability, and side effect, and profile of tirzepatide in T2DM. Our meta-analysis follows a recently published meta-analysis involving smaller numbers of patients with fewer RCTs (2783 patients; four RCTs) published Bhagavathula et al.[21] Bhagavathula et al. did a pooled analysis of data of patients receiving tirzepatide 5, 10, and 15 mg/day and documented greater lowering of HbA1c (-1.94%, 95% CI: -2.02 to -1.87), fasting glucose (-54.72 mg/dL, 95% CI: -62.05 to -47.39), and weight (-8.47%, 95% CI: -9.66 to -7.27).[21] We instead focused on the detailed analysis of patients receiving 10 mg of tirzepatide per day as that was observed to be the most acceptable dose across trials.

Tirzepatide at 10 mg/12 mg per week was found to be superior to dulaglutide, semaglutide, degludec, and glargine insulin with regards to glycemic efficacy (HbA1c, FPG, PPG reduction, and percentage of patients achieving HbA1c <7, <6.5, and <5.7%) as well as reduction in obesity (body weight, BMI, waist circumference reduction, percentage of people achieving >5, 10%, and 15% weight loss). These results suggest that tirzepatide may be the most potent agent developed till date to tackle diabesity. Tirzepatide is an imbalanced dual agonist in favor of GIPR over GLP-1R activity. It shows equal affinity for the GIPR compared with native GIP but binds the GLP-1R with approximately 5-fold weaker affinity than native GLP-1.[2] This imbalanced activity of this novel multiincretin may explain the unprecedented impact on glycemic control, weight loss, and other pleotropic benefits of tirzepatide. Tirzepatide has the same potency and affinity as endogenous GIP but is comparatively weaker at the GLP-1R. The strong GIPR-induced glucose lowering shown in different mechanistic studies of GLP1R-null mice, along with the synergistic GLP-1R agonism, explains the excellent glycemic benefits with tirzepatide[5] Tirzepatide contains a C20 unsaturated di-acid acyl chain contributes to albumin binding and the overall properties of the molecule, enhancing its half-life enabling once-weekly dosing.[22]

Our meta-analysis showed that the impact on lipid parameter by tirzepatide is largely similar to that seen with dulaglutide and semaglutide, except of a significantly greater improvement in serum HDL-C levels with tirzepatide. A greater reduction in IR and glucagon levels were noted with tirzepatide as compared to dulaglutide and semaglutide. These may also contribute to the better glycemic and metabolic outcomes with tirzepatide when compared to the GLP1R analogues.

Patients receiving tirzepatide have increased occurrence of treatment emergent side effects both compared to active controls and placebo controls. The occurrences of SAEs were not different with tirzepatide as compared to active or placebo controls. Gastrointestinal side effects were predominant type of side effects noted with tirzepatide, which is similar to GLP-1R analogues. It has been suggested in some studies that the significantly lower GLP-1R affinity of tirzepatide as compared to the GLP-1R analogues dulaglutide or semaglutide may explain marginally lower gastrointestinal side effects with this molecule. The reported antiemetic effect of GIP agonism may also contribute to the better gastrointestinal tolerability of tirzepatide.[21] How much of this translates into clinical evidence remains to be documented. The impressive impact on glycemia, weight loss, with lower risk of hypoglycemia from this meta-analysis suggests that tirzepatide will soon be approved for clinical use across the globe. Tirzepatide is a welcome armamentarium in the war against diabesity and should help in diabetes reversal in the real-world scenario. The side-effect profile especially gastrointestinal tolerance and monthly cost of therapy would have an important impact on the acceptability of this molecule in clinical practice, especially in the developing world. It must be realized that most of the evidence generated in this meta-analysis is of moderate to poor grade, due to significant associated data heterogeneity and publication bias. Hence, the need for better higher quality data on the use of tirzepatide in diabesity remains.

To conclude, it may be said that though this meta-analysis provides us with exciting data on impressive glycemic efficacy and weight loss properties of tirzepatide over 1-year clinical use. Need for more long-term efficacy and safety data of higher grade remains with regard to use of tirzepatide in diabesity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplementary Figure 1

Percentage of people having weight loss (a) >5% as compared to ACG; (b) >10% as compared to ACG; (c) >15% as compared to ACG

Supplementary Figure 2

Forest plot highlighting the impact of tirzepatide on (a) triglycerides as compared to ACG; (b) LDL-C as compared to ACG; (c) triglycerides as compared to PCG; (d) LDL-C as compared to PCG; (e) HDL-C compared to ACG; and (f): HDL-C as compared to PCG

Supplementary Figure 3

Forest plot highlighting the gastrointestinal side-effect profile of the use of tirzepatide (a): nausea as compared to ACG; (b) vomiting as compared to ACG; (c) diarrhea as compared to ACG; (d) nausea as compared to PCG; (e) vomiting as compared to PCG; and (f): diarrhea as compared to PCG

Supplementary Figure 4

Evaluating the presence of publication bias for (a) HbA1c ACG; (b) fasting glucose ACG; (c) weight loss >5% ACG; (d) weight loss >10% ACG; (e): treatment emergent adverse events ACG; (f) hypoglycemia ACG; and (g) HbA1c <6.5% ACG

Supplementary Table 1

Characteristics of patients in the six different randomized controlled trials evaluated in this meta-analysis on use of tirzepatide in type-2 diabetes

Supplementary Table 2

Study details of the three post-hoc analysis data of the study done by Frias et al. (2018) evaluated in this meta-analysis

Supplementary Table 3

Risk of bias assessment table

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Keywords:

Meta-analysis; safety; tirzepatide; twincretin; type-2 diabetes

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