Tirzepatide outperforms insulin in controlling diabetes and promoting weight loss in clinical trials

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Sep 2 2024

Backed by a meta-analysis of over 4,300 patients, once-weekly tirzepatide slashes blood sugar, weight, and cardiovascular risks more effectively than daily insulin, offering a groundbreaking alternative for type 2 diabetes management.

Study: Tirzepatide outcompetes long-acting insulin in managing type 2 diabetes: a meta-analysis of three phase 3 randomized controlled trials. Image Credit: Dragana Gordic / Shutterstock

In a recent review and meta-analysis published in the International Journal of Obesity, researchers evaluated the safety and efficacy of once-weekly Tirzepatide, a revolutionary new anti-obesity and anti-diabetes drug, against conventional long- and ultra-long-acting insulin supplements in managing type 2 diabetes (T2D). Their comprehensive dataset was obtained from the SURPASS-3, SURPASS-4, and SURPASS-AP-Combo randomized clinical trials comprising 4,339 patients and ten biochemical tests.

Study findings revealed that Tirzepatide matched or outperformed conventional once-weekly insulin supplements in both safety and efficacy. This highlights that the novel drug could effectively replace non-surgical treatment options in managing T2D.

Background

Diabetes is a chronic medical condition characterized by abnormal blood glucose concentrations due to impaired insulin secretion or efficacy. Diabetes is one of the most common non-communicable diseases in the world, with the International Diabetes Federation (IDF) estimating that 10.5% of adults (ages 20–79) have diabetes. Type 2 diabetes (T2D) is the most common type of diabetes caused due to insulin resistance. It is associated with a number of potentially lethal comorbidities, including cardiovascular diseases (CVDs), some cancers, and obesity.

Alarmingly, the prevalence and mortality of T2D are rapidly rising, with estimates reporting increases of 27.4% and 47%, respectively, in just 30 years (1990-2019). This makes T2D a public health concern of extremely high importance, necessitating extensive research into therapeutic interventions against its risk factors. Studies have revealed that high body mass indices (BMIs) are the most significant contributors to T2D risk, with a predominant portion of research aimed at weight management as an indirect intervention against T2D.

Unfortunately, most non-surgical interventions against T2D have been revealed to offer only temporary (short-term) relief to patients. Furthermore, most pharmacological treatments have a high risk of adverse side effects, making discovering and validating novel high-efficacy, low-risk treatments imperative. Tirzepatide is one such next-generation drug promising potentially unprecedented efficacy and long-term weight loss. It is a dual agonist with characteristics of both glucagon-like peptides (GLP1s) and gastric inhibitory polypeptides (GIPs). Preliminary clinical trials have highlighted its improved and long-lasting efficacy compared to placebos and conventional GIP and GLP1 agonists.

Despite its potentially revolutionary benefits, the in vivo safety of Tirzepatide remains to be validated. Additionally, establishing the efficacy of the once-weekly drug against conventional once-weekly long- and ultra-long-lasting insulin supplements would allow for its increased global adoption, thereby overhauling the worldwide T2D treatment landscape.

About the study

The present review seeks to use a rigorous meta-analytic approach to investigate the safety and efficacy of Tirzepatide against conventional once-weekly insulin supplements in treating T2D. Data for the study was obtained from publications evaluating Tirzepatide’s safety or performance compared to insulin supplements across four online scientific repositories – PubMed, Scopus, Web of Science, and Google Scholar.  

Studies were included if they were clinical- or randomized controlled trials investigating the performance of Tirzepatide against insulin in any of the following outcomes – Body weight, fasting glucose, hemoglobin A1c (HbA1c), blood sugar (BS), blood pressure (BP; systolic or diastolic), triglyceride, and cholesterol (total, high- or low-density lipoprotein [HDL or LDL]). Data extraction included study characteristics, population metrics, interventions, and outcomes (safety or performance). All extracted data was converted into standardized units before meta-analysis.

To statistically evaluate insulin versus Tirzepatide performance, mean change, standard deviation (SD) change, odds ratios (ORs), and relative risks (RRs) were computed for all outcomes. Between-study heterogeneity was calculated using I² statistics, and the risk of bias was calculated using the Cochrane risk of bias tool.

Study findings

Of the 705 publications initially identified through title screening, abstract and full-text screening excluded 702, identifying only three studies (SURPASS-3, SURPASS-4, and SURPASS-AP-Combo randomized clinical trials) meeting all inclusion and exclusion criteria. These three studies included 4,339 patients (insulin cohort = 1,580; Tirzepatide cohort = 2,759).

“All included studies were multi-center, randomized, open-label, parallel-group phase 3 clinical trials conducted in several countries. Three doses of tirzepatide (5 mg, 10 mg, and 15 mg) were used in all studies. Patients with type 2 diabetes aged 18 years or older were included in all studies.”

The Cochrane risk of bias tool analysis revealed that while selection, reporting, and attrition bias were low between included studies, their detection and performance bias were high due to the SURPASS studies being open-label, non-blinded studies. Meta-analysis results revealed that Tirzepatide (all three doses – 5, 10, and 15 mg) significantly outperformed both long- and ultra-long-lasting insulin supplements, reducing weight in T2D patients by 10.61 kg, BP by 6.47 mmHg (systolic) and 2.3 mmHg (diastolic), and increasing pulse rate by 1.93 beats per minute (bpm).

Additionally, Tirzepatide was observed to significantly improve lipid profile metrics, such as reducing triglycerides (14.49%) and cholesterol (total—4.78%, LDL—5.98%, and very low-density lipoprotein [VLDL]—14.18%). The efficacy was dose-dependent, with higher doses (10 and 15 mg) showing greater improvements. Side effects of Tirzepatide were found to be generally equal to or lower than those of equivalent insulin doses.

“All in all, these findings suggest that, unlike long-acting insulin, tirzepatide maintains BS levels in a narrow and near-normal range and prevents fluctuations in BS levels. For example, analysis of data from the SURPASS-3 trial by Viljoen et al. revealed that the median time to first achieve the HbA1c of 7.0% was 8.1 weeks for each dose of tirzepatide compared with 12.1 weeks for insulin degludec, suggesting an accelerated treatment response to Tirzepatide.”

Conclusions

The present meta-analysis highlights the safety and performance benefits of Tirzepatide over conventional long- and ultra-long-lasting insulin supplements. Results reveal that Tirzepatide displays significantly shorter lag periods to achieve near-normal HbA1c readings compared to insulin supplements (8.1 versus 12.1 weeks). The novel drug outperformed conventional pharmacological interventions across all ten investigated metrics. Notably, while higher doses of Tirzapatide were associated with a slightly increased risk of hypoglycemia and nausea, these side effects were still equal to or lower than those observed from equivalent insulin dosages.

Together, these findings suggest that Tirzepatide can effectively replace insulin treatment as an improved clinical intervention for patients with T2D.