Tirzepatide in Type 2 Diabetes Mellitus: Comparison
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Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, currently under trial to assess glycemic efficacy and safety in people with type 2 diabetes.

  • LY3298176
  • tirzepatide
  • diabetes
  • glucose

1. Introduction

Diabetes mellitus affects over 463 million people globally as of 2019, with this number projected to grow to 700 million by 2045 [1]. The well-recognized microvascular and macrovascular damages associated with type 2 diabetes mellitus (T2DM) make it among the leading causes of serious complications, including blindness, kidney failure, and cardiovascular complications, and associated mortality [2,3][2][3]. Optimal management of T2DM is required to effectively prevent the occurrence of diabetes-related complications or delay the deterioration of these complications if they are already present [4]. A range of drug classes with different modes of action have been in use for the management of diabetes and/or its major clinical sequelae.
While the various classes of T2DM medications have their own benefits, ideal treatments would be those that are effective in reducing blood glucose levels, are associated with less risk of hypoglycemia and weight gain, and have added benefits for cardiovascular or renal outcomes [5]. Some of the newly emerging treatments used for T2DM, such as glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium-glucose cotransporter-2 inhibitors, have, for example, showed promising outcomes in recent years in terms of providing additional cardiorenal benefits in addition to controlling diabetes [6].
GLP-1 agonists, which include short-acting or long-acting agents, have been associated with improved glycemic control and cardiovascular outcomes, as well as body weight reduction in people with T2DM [7]. The other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), despite its similarity with GLP-1 and its receptors, is devoid of effects like the inhibition of appetite and food intake, which is seen with the use of GLP-1 [8]. Therefore, combining the GLP-1 agonists with other agents that act on glucose-dependent insulinotropic polypeptide (GIP) receptors has been hypothesized to produce a more effective control of glycemia along with a significant weight reduction effect [9]. Tirzepatide is a novel antidiabetic treatment recently developed and has demonstrated favorable body weight, cardiovascular, and renal-related outcomes [10]. It acts as an agonist of both GLP-1 and GIP receptors, rendering it with an additive effect of producing a more pronounced insulin response than can be achieved through individual hormone administration [5,11,12][5][11][12].
Early evidence revealed that tirzepatide is associated with a significantly positive outcome in controlling both blood glucose and body weight [8]. In light of additional emerging evidence based on phase II and III clinical trials investigating the effect of tirzepatide on glycemic and other added benefits, there is a need for more comprehensive data to consolidate the evidence and guide future research and potential clinical use.

2. Tirzepatide in Type 2 Diabetes Mellitus

T2DM is a chronic disease characterized by hyperglycemia and progressive dysregulation of the insulin-glucose feedback mechanism, and glucose-lowering is a mainstay of treatment [21][13]. Novel glucose-lowering drugs such as selective GLP-1 receptor agonists, especially once-weekly dulaglutide and semaglutide, showed a substantial improvement in glucose control and promoted weight loss [22][14]. Despite these advances in therapy for the management of hyperglycemia, many people with T2DM did not achieve optimal glycemic control. Notably, the co-administration of the GLP-1 receptor agonist and GIP in mice with T2DM and obesity showed a greater improvement in glycemic and body weight than with selective GLP-1 receptor agonists [23][15]. This rationale paved the way to target both incretin hormones and the development of a dual GLP-1/GIP receptor agonist, referred to as a “twincretin” for the treatment of T2DM [9]. Tirzepatide is a novel therapeutic agent administered once a week as a dual GLP-1/GIP receptor, formulated as a 39-amino acid synthetic peptide, based on the native GIP sequence [9]. In individual RCTs, tirzepatide alone or added to metformin was shown to improve glycemic control with weight loss compared with a placebo or selective GLP-1 receptor agonists (dulaglutide or semaglutide) [17,18,19,20][16][17][18][19].

Compared to the placebo or the selective GLP-1 receptor agonists, tirzepatide improved glycemic control (−2.0 to −1.8% in HbA1c and −62.0 to −47.3 mg/dL in FSG) and reduced body weight (−9.6 to −7.2 kg). All three tirzepatide doses showed significant HbA1c reductions, and the robust glycemic effect was consistently maintained from week 12 to week 40. Available evidence from the published RCTs also suggested a greater decrease in HbA1c, FSG, and body weight [19,20,21,22][18][19][13][14]. Given the limited data available for postprandial self-monitored blood glucose profile, however, the effect of tirzepatide on the achievement of the guidelines’ recommended HbA1c targets and weight loss of 5% or greater should be further investigated. Overall, the highest dose of tirzepatide had superior effects on HbA1c reduction, and the change in the HbA1c presumably occurred as early as 12 weeks, with no differences noted at week 26 or 40. The most recent phase 3 trial (SURPASS-1) has indeed demonstrated a similar reduction in HbA1c, FSG, and body weight in patients with T2DM treated with tirzepatide (5, 10, and 15 mg) as monotherapy [17][16]. Ongoing RCTs [24,25,26,27,28,29][20][21][22][23][24][25] will confirm whether similar benefits could be expected in an overweight or obese population with (SURMOUNT-2) [29][25] or without T2DM (SURMOUNT-3, SURMOUNT-4) [25,26][21][22] and in patients with T2DM inadequately controlled on insulin glargine with/without metformin (SURPASS-6) [27][23]. Moreover, a recently completed phase 1 trial on tirzepatide (NCT03951753) may provide further evidence on the relationship between HbA1c and body weight reduction in patients with T2DM [28][24].

Along with changes in HbA1c, some marginal differences with tirzepatide doses on FSG and body weight. The highest dose of tirzepatide (15 mg) reduced FSG to a greater extent than other doses (5 mg and 10 mg). Conversely, tirzepatide 10 mg and 15 mg did not differ in the extent of body weight reduction.

As for safety, tirzepatide therapy did not lead to a higher incidence of all AEs than the placebo or selective GLP-1 receptor agonists, and individual studies indicated that most AEs were mild or moderate in severity [17,18,19,20][16][17][18][19]. The most prevalent AEs were gastrointestinal (44%), including nausea and diarrhea, and similar AEs observed in current GLP-1 analogs [30][26]. Moreover, a limited proportion of participants experienced hypoglycemia (3%) and AEs leading to the discontinuation of tirzepatide (7%), most of which are dose-dependent incidences. Ongoing RCTs [5,6,7,9][5][6][7][9] will confirm whether tirzepatide exhibits long-term safety, and SURPASS-CVOT (NCT04255433) [31][27] will provide more data on the cardiovascular safety of tirzepatide compared with dulaglutide.

Tirzepatide, a novel incretin-based therapy for T2DM, showed robust HbA1c (−1.94%), FSG (−54.7 mg/dl), and body weight (−8.5 kg) reductions, without an increased risk of hypoglycemia. At the highest dose (15 mg), tirzepatide reduced: HbA1c (−2.1%), FSG (−61.1 mg/dl), and body weight (−8.6 kg). The study also found that tirzepatide had an acceptable safety profile similar to the GLP-1 receptor agonists for the treatment of T2DM. Further research is needed to determine the long-term safety and efficacy of tirzepatide in achieving guideline-recommended cardiometabolic targets.

References

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