The catcher in the gut: Tirzepatide, a dual incretin analog for the treatment of type 2 diabetes mellitus and obesity

Abstract

The ever-increasing burden of obesity, type 2 diabetes mellitus (T2DM) and related comorbidities is demanding a better pathophysiological understanding as well as new treatment options. Incretin based therapies are already available while the recent Food and Drug Administration (FDA) approval of the dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide appears to revolutionize the treatment of T2DM and obesity. GLP-1 and GIP exert pleiotropic physiological actions, including enhancement of insulin secretion, glycemic and appetite control, cardioprotection, and adipose tissue improved function among others. Evidence from recent clinical trials has shown that tirzepatide is at least or more effective compared to classic metabolic therapeutic agents, including insulin, when it comes to glycemic control in T2DM. Of importance, it also exerts remarkable weight-lowering actions, emerging as an alternative to bariatric surgery for obesity treatment. Overall, current data show that tirzepatide is a highly effective therapeutic option for T2DM. Numerous ongoing randomized controlled clinical trials are further examining its potential as a treatment for obesity.

Obesity has risen significantly in recent decades, becoming a major global public health concern that influences the likelihood and prognosis of a variety of diseases, including cardiovascular disease, metabolic syndrome, insulin resistance, Type 2 diabetes mellitus (T2DM), COVID-19, and cancer [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. Consequently, there is an urgent need for novel medications with weight-lowering and beneficial metabolic functions [16]. Obesity is a complicated and multifactorial chronic disease, defined by a body mass index (BMI) of 30 kg/m² or more, characterized by an excessive accumulation of white adipose tissue (AT) and AT dysfunction [17]. Abdominal or central obesity is more closely associated with metabolic dysfunction linked to cardiovascular disease and other comorbidities [12,[18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]].

Changes in lifestyle such as restricted caloric intake and enhanced physical activity are vital for reducing excess body weight; however, they are not always simple to implement or successful [16,29]. There are various available weight-lowering medications, including, orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide); however their use can be constrained due to side effects and limited effectiveness [16,30,31]. Bariatric surgery has a great and long-lasting weight-lowering potential, and reverses prediabetic state and T2DM in a considerable number of patients [16,32]. However, while bariatric surgery is an effective treatment for severe obesity and poorly controlled T2DM, it is often linked with serious side effects [32,33]. The recent approval of tirzepatide from the FDA and the positive opinion of the Committee for Medicinal Products for Human Use (CHMP) in the European Union which recommended the granting of a marketing authorization of tirzepatide for the treatment of T2DM is a hallmark for enriching the anti-obesity and anti-diabetes therapeutic armamentarium [34]. This commentary/mini-review aims to summarize the pleiotropic physiological actions of incretins, which through their receptors tirzepatide exerts its effects; to present evidence from recent clinical trials supporting tirzepatide as an anti-diabetic medication; and to explore its weight-lowering actions and potential for the management of obesity.

Tirzepatide is a single molecule combining dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors [[34], [35], [36]]. GLP-1, secreted by the enteroendocrine L-cells, and along with GIP, which is secreted by the enteroendocrine K-cells, are the major determinants of the incretin effect, i.e. enhancement of glucose-dependent insulin secretion from pancreatic beta cells following nutrient ingestion [[37], [38], [39], [40], [41]]. Both molecules exert pleiotropic physiological actions as presented in Fig. 1 [38,39,41]. Both GLP-1 and GIP present important insulin secreting actions and beneficial effects on beta cells proliferation and survival [42]. GLP-1 has satiety-promoting and anorexigenic properties, influencing food reward networks and the motivational drive for overeating. Its analogs are used for the management of obesity via mimicking these effects [43]. On top of those actions, delayed gastric emptying mediated through GLP-1 adds to the decreased eating [41,43]. GLP-1 appears to exert actions beyond the metabolic regulation as its receptors found in the cardiovascular system imply direct cardioprotective effects, apart from the indirect effects through weight loss and glycemic control [44]. GIP appears to add on the effects of GLP-1 on the pancreas increasing glucagon and somatostatin secretion, which is potentially beneficial against the hypoglycemic effects of insulin alone [41,42]. Of importance, GIP is linked to increased adipose tissue blood flow (ATBF) postprandially, which is usually blunted in individuals with obesity and/or T2DM, and potentially contributes to ectopic fat deposition linked to insulin resistance [12,21,41]. The increase in ATBF after a meal ingestion and the effects on adipocyte metabolism result in favor of accommodating lipid storage in AT [12,21]. Interestingly, GIP may improve bone turnover by reducing bone resorption, which can be of added value in older individuals [41]. Finally, the co-administration of GLP-1 and GIP may enhance the therapeutic efficacy of the former and reduce adverse effects like nausea and vomiting [45,46].

Fig. 1.

Major physiological roles of GLP-1 and GIP. Tirzepatide is acting as an agonist of GLP-1 and GIP receptors. Abbreviations: GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide. (All images are originated from the free medical site http://smart.servier.com/(accessed on November 28, 2022) by Servier licensed under a Creative Commons Attribution 3.0 Unported License).

The physiological roles of GLP-1 and GIP are mediated through tirzepatide resulting in effectiveness regarding both glycemic control and body weight reduction [[34], [35], [36],[47], [48], [49]]. The greater affinity of terzepatide to GIP receptors than to GLP-1 receptors in conjunction with distinct signaling properties at GLP-1 favor the increase in insulin secretion [50]. Interestingly, tirzepatide has been shown to elevate the levels of adiponectin, an insulin-sensitizing adipokine implicated in the regulation of both glucose and lipid metabolism [[51], [52], [53], [54], [55], [56], [57], [58], [59], [60]]. Tirzepatide improved glycemic control and body weight without increasing the risk of hypoglycemia, a safety profile comparable with GLP-1 receptor agonists [61]. Compared to the selective GLP-1 receptor agonist semaglutide in patients with T2DM (SURPASS-2 clinical trial), tirzepatide was superior in decreasing in a dose-dependent manner the mean glycated hemoglobin (HbA1c) levels (up to 2.3% reduction from baseline) [62]. Furthermore, compared to insulin degludec (SURPASS-3) and insulin glargine (SURPASS-4), once-weekly tirzepatide has shown greater reductions in HbA1c and body weight with lower adverse effects including hypoglycemia [63,64]. More recently, it was shown that in patients with poorly controlled T2DM, added tirzepatide to insulin glargine showed impressive benefits after titration of insulin dose (SURPASS-5) [65]. Overall, one-year of clinical use, tirzepatide was shown to be superior to dulaglutide, semaglutide, degludec, and insulin glargine regarding glycemic efficacy and excess weight reduction [36,66] Furthermore in SURMOUNT-1, a 72-week phase 3 double-blind, randomized, controlled trial, including participants with overweight or obesity, the anti-obesity effects of tirzepatide were directly explored [48]. The use of tirzepatide once weekly provided substantial and sustained reductions in body weight in a dose-dependent manner from −15% with 5 mg reaching up to −20.4% weight change with 15 mg dose versus −3.1% in the placebo group [48]. These observations, especially with the high dose regimen, are comparable to effects observed with bariatric/metabolic surgery [48]. The most frequently reported adverse events were gastrointestinal including nausea, diarrhea, and constipation, similar to those reported for selective GLP-1 receptor agonists [36,48]. Based on results on animals involving medullary thyroid carcinoma development, tirzepatide is contraindicated in patients with a family history of this cancer or MEN 2 (multiple endocrine neoplasia syndrome type-2) [67]. Currently fifteen randomized, double-blind, placebo-controlled trials examining the effects of tirzepatide in individuals with obesity or overweight and related comorbidities, including sleep apnea and heart failure are registered in ClinicalTrials. gov [68].

In conclusion, based on current literature, tirzepatide, a dual incretin analog mediating effects through the GLP-1 and GIP receptors, exerts remarkable beneficial actions in glycemic control and body weight reduction. The latter could be of great importance as an alternative to bariatric surgery for individuals with severe obesity. Its FDA approval as an anti-diabetic medication earlier this year indicates a landmark in the treatment of metabolic disorders. However, further research and real-world data are warranted to explore the long-term benefits, additional uses, and reveal potential side effects.

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Declaration of competing interest

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