Who are the Best Candidate Patients with Diabetes for Tirzepatide?

Abstract

Background: Tirzepatide is a dual receptor agonist of the 2 incretin hormones: Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon- Like Peptide-1 (GLP-1) which is was recently approved for treatment of type 2 diabetes.

Objective: To define the most appropriate patients that may benefit from tirzepatide.

Methods: Pubmed search until August 10, 2022. Search terms were GLP- 1, GIP, tirzepatide, efficacy, safety, obesity. Clinical trials and pertinent animal studies and reviews were included.

Results: Tirzepatide was more effective in lowering hemoglobin A1c (HbA1c) levels and body weight than submaximal doses of semaglutide (1.0 mg once-weekly), dulaglutide (1.5 mg once-weekly), insulin degludec (mean daily dose 48.8 U) and insulin glargine (mean daily dose 43.5 U). In patients with type 2 diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD), tirzepatide significantly decreased Liver Fat Content (LVC). Safety profile of tirzepatide was generally similar to that of GLP-1 agonists, but frequency of Gastrointestinal (GI) adverse effects are slightly higher with tirzepatide. Incidence of severe hypoglycemia (blood glucose < 54 mg/dl) is also slightly higher with tirzepatide than semaglutide and dulaglutide, but much lower than insulin degludec and glargine. Drug discontinuation rates due to adverse effects were higher with tirzepatide compared with semaglutide, dulaglutide, and insulin.

Conclusions: Tirzepatide may be most appropriate for patients with type 2 diabetes who are obese, as alternative to GLP-1 agonists or basal insulin, and in patients with NAFLD.

Keywords: Tirzepatide; Semaglutide; Dulaglutide; GLP-1; GIP; Efficacy; Safety; Weight loss

Introduction

Tirzepatide (LY3298176) is a dual GIP/GLP-1 receptor agonist [1]. Its 39 amino acid sequence is mainly based on that of native GIP which consists of 42 amino acids [1]. Tirzepatide is attached to a 20-carbon fatty diacid moiety which binds to albumin. Albumin binding prolongs its half-life to approximately 5 days allowing once a week subcutaneous administration [2]. Tirzepatide has similar GIP receptor binding affinity to native GIP. Yet, it has 5 times lower affinity to GLP-1 receptor compared to native GLP-1 [2]. Tirzepatide is given in 3 weekly doses: 5,10,15 mg. To alleviate GI adverse effects, the drug is started with weekly dose of 2.5 mg that can be increased by 2.5 mg every 4 weeks until the desired dose is attained [3]. Tirzepatide (Mounjaro) was approved in May 2022 by the Federal Drug Administration (FDA) for treatment of type 2 diabetes [3]. The main purpose of this article is to define the most appropriate patients with type 2 diabetes for tirzepatide based on available data and drug profile.

The SURPASS Trials

Tirzepatide FDA approval was based on a series of phase 3 clinical trials (called SURPASS-1 through 5) [4-8]. Primary endpoint of SURPASS 1-5 trials was the change in HbA1c levels with tirzepatide compared to baseline versus comparator. SURPASS 1 and 5 studies were double-blind and placebo-controlled trials. The other 3 trials were open-label comparing tirzepatide with semaglutide (SURPASS-1), insulin degludec (SURPASS-3) and insulin glargine (SURPASS-3). Most patients in the SURPASS trials were obese with mean baseline HbA1c levels ranging from 7.9% to 8.5% [4-8]. Overview and main results of SURPASS trials are summarized in table 1 and discussed further below.

Mechanisms of Action of Tirzepatide

In SURPASS-1 trial, Rosenstock et al [4] have shown that tirzepatide decreased insulin resistance in comparison with placebo as assessed by the homeostatic model assessment. Using the gold standard method of evaluating insulin resistance, the glucose clamp disposition index, Heise et al [9] found that tirzepatide significantly increased both insulin secretion and sensitivity versus placebo and semaglutide 1 mg/week in patients with type 2 diabetes. In addition, tirzepatide decreased glucose excursions and inhibited plasma glucagon more than semaglutide during the mixed meal testing [9]. Greater weight loss with tirzepatide 15 mg (-11.2 kg) versus semaglutide 1 mg (-6.9 kg) may be a major factor behind these differences [9]. Meanwhile, experiments in mice have shown that tirzepatide improved insulin sensitivity in a weight-dependent and independent manners [10]. The mechanisms of weight-loss promoting action of tirzepatide are not fully understood. Animal studies suggest that GIP receptors in the hypothalamus mediate satiety [11]. Another factor that may contribute to weight loss induced by tirzepatide is the relatively common occurrence of nausea and vomiting associated with its use (see below). Comparison of the extent of weight loss between patients who reported nausea and vomiting with tirzepatide versus those who did not might clarify this issue. Unfortunately, investigators in the SURPASS-trials did not report such important information.

Candidate Patients for Tirzepatide

As Alternative to GLP-1 Agonists

Tirzepatide versus semaglutide: Current data suggest that the GLP-1 receptor agonist semaglutide is the most effective GLP-1 agonist both in terms of anti-hyperglycemic and weight loss effects [12-14]. Meanwhile, emerging evidence suggests that tirzepatide may be more effective than semaglutide. In SURPASS-2 trial, patients with type 2 diabetes on metformin were randomized to receive once weekly tirzepatide 5 mg, 10 mg, 15 mg or semaglutide 1 mg once weekly [5]. At 40 weeks, mean HbA1c reductions from baseline with tirzepatide 5 mg, 10 mg, and 15 mg were -2.01, -2.24 and -2.30%, respectively, as compared with -1.86% with semaglutide [6]. Moreover, reductions in weight were greater with tirzepatide than with semaglutide (see below). Therefore, results of SURPASS-2 trial suggest that tirzepatide may be a viable alternative to semaglutide in patients requiring additional reductions in HbA1c and weight. However, tirzepatide was less tolerated than semaglutide. Thus, withdrawal due to adverse effects were 6-8.5% and 4.1% in the tirzepatide and semaglutide groups, respectively [5]. In addition, tirzepatide was not compared with the maximal effective dose of semaglutide 2.4 mg/week. An indirect comparison by Vadher et al [15] showed that HbA1c and weight reductions were significantly greater with tirzepatide 10 and 15 mg/week versus semaglutide dose of 2.0 mg/week. Clearly, direct head to head trials are needed to confirm the superiority of tirzepatide over semaglutide 2.4 mg/week.

Tirzepatide versus dulaglutide: Similar results as above were reported when tirzepatide was compared with dulaglutide. In a phase 2 trial of 26-week duration (n=316), tirzepatide in weekly doses of 10 mg and 15 mg (but not 5 mg) was more effective than dulaglutide 1.5 mg once weekly with differences in HbA1c values of 0.67% and 0.73% in favor of semaglutide 10 mg and 15 mg, respectively [16]. Weight loss was also greater with tirzepatide 15 mg (11.3 kg) versus dulaglutide (2.7 kg). Meanwhile, the highest dose of tirzepatide 15 mg/week was less tolerated than dulaglutide, with discontinuation rates as result of adverse effects being 24.5% and 11.1%, respectively [16]. In addition, the highest effective dose of dulaglutide 4.5 mg once weekly was not evaluated in this study [17].

Patients with Overweight or Obesity

Tirzepatide exerts a potent dose-related effect on weight loss that was more pronounced compared with that caused by semaglutide 1 mg. The differences being -1.9 kg, -3.6 kg, -5.5 kg with the 5, 10, and 15 mg tirzepatide doses, respectively [5]. Contrary to their effects on HbA1c levels that plateaued after 24 weeks, weight reduction associated with tirzepatide and semaglutide use continued until the end of intervention at 40 weeks [5]. In fact, due to its high efficacy in promoting weight loss, tirzepatide was recently evaluated as anti-obesity agent in subjects without diabetes in the SURMOUNT trial [18]. The latter was a large (n=2,539), double-blind, placebocontrolled, randomized multi-center trial including. At baseline, the mean body weight was 104.8 kg and mean body mass index (BMI) was 38.0 kg/m² [18]. At week 72, the placebo-adjusted mean percentage change in weight was -11.9% (95% CI -13.4 to -10.4), -16.4% (95% CI, -17.9 to -14.8), and -17.8% (95% CI, -19.3 to -16.3) for the 5 mg-dose, 10mg-dose and 15 mg-dose, respectively (P<0.001 vs placebo) [18].

Patients who are Reluctant to Take Insulin

Many patients with type 2 diabetes refuse to take insulin because of fear of frequent injections, weight gain and/or hypoglycemia. There is good evidence that tirzepatide is superior to titrated once daily basal insulin in terms of glycemic control and weight reduction. In SURPASS-3, from a mean baseline HbA1c of 8.17%, the reductions in HbA1c levels at week 52 were 1.93%, 2.20%, and 2.37% in the tirzepatide 5, 10, 15 mg groups, respectively, compared with a decrease of 1.34% in the insulin degludec group (mean daily dose at week 52 was 48.8 U) [6]. The estimated treatment difference between tirzepatide and degludec ranged from 0.59 to 1.04% [6]. In a substudy of 243 patients enrolled in SURPASS-3 trial, Battelino et al [19] compared diurnal glucose profile of tirzepatide 10 mg and 15 mg pooled groups with insulin degludec by continuous glucose monitoring. After 52 weeks, tirzepatide-treated patients had 25% (95% CI, 16-33) greater proportion of time spent in target range (71-140 mg/dl) than degludec-treated patients [19]. Moreover, the use of tirzepatide (10-15 mg) was associated with significant decrease in within-day glucose variability of -8.2%. Conversely, insulin degludec was associated with an increase in variability of 4.8% [19]. With respect to weight changes, form a baseline weight of 94.3 kg, all tirzepatide doses decreased weight by 7.5 to 12.9 kg, whereas degludec was associated with mean weight increase of 2.3 kg [6]. Similar findings were reported in SURPASS-4 trial comparing tirzepatide with insulin glargine (mean daily dose 43.5 U) [7]. Thus, after 52 weeks, HbA1c levels were 0.80%-1.14% and weight was 9-13.5 kg lower in the 3 tirzepatide groups versus glargine group [7]. A third advantage of using tirzepatide in place of insulin is the lower risk of hypoglycemia (see “Hypoglycemia” below). Yet, despite these advantages, discontinuation rates due to adverse effects were much higher with tirzepatide 7-11% versus either degludec (1%) or glargine (5%) (Table 1) [6,7].

  


    
Trial name, patient number (n), percentage of    females (F), mean age, mean *BMI, and      duration

    
Comparator

    
Change in mean HbA1c

    
Change in mean weight (kg)

    
Proportions of patients who discontinued drug due    to adverse effects

  

  


    
SURPASS-1, n=478, 48% F, 54 years, 31.9 kg/m2,    40 weeks [4]

    
Placebo (P)

    
-1.87% to -2.07% with tirzepatide (T) and + 0.04%    with P

    
-7.0 to -9.5 with T vs P - 0.7

    
3 to 7% with T vs 3% with P

  

  


    
SURPASS-2, n=1,879, 53% F, 56 years, 34.2 kg/m2,    40 weeks [5]

    
Semaglutide (S) 1 mg/week

    
-2.01% to -2.30% with T vs -1.86% with S    (p<0.001 vs S)

    
-7.6 to -11.2 with T vs -5.7 with S  (p<0.001 vs S).

    
6 to 8.5% with T vs 4.1% with S

  

  


    
SURPASS-3, n=1,437, 56% F, 57 years, 33.5 kg/m2,    52 weeks [6]

    
Once daily titrated insulin degludec. Mean (SD)    dose at 52 weeks 48.8 (30.4) U/d

    
-1.93% to -2.37% with T vs degludec -1.34%    (p<0.001)

    
-7.5 to -12.9 with T vs degludec +2.3    (p<0.0001)

    
7 to 11% with T vs degludec 1%

  

  


    
SURPASS-4, n=1,995, 38% F, 63 years, 32.6 kg/m2,    52 weeks [7]

    
Once daily titrated insulin glargine. Mean (SD)    dose at 52 weeks 43.5 (24.9) U/d

    
-2.43% to -2.58% with T vs -1.44% with glargine    (P<0.0001 for T 10-15 mg vs glargine)

    
-9.0 to -13.5 with T vs glargine (P<0.0001). Weight    changes compared to baseline were not reported.

    
9 to 11% with T vs glargine 5%

  

  


    
SURPASS-5, n=475, 44% F, 60 years, 33.4 kg/m2,    40 weeks [8]

    
Placebo (P). All patients were on insulin    glargine

    
-2.11% to -2.40% with T vs -0.86% with P    (p<0.001 vs P)

    
-5.4 to -8.8 with T vs +1.6    with P (p<0.001)

    
6.0 to 10.8% with T vs 2.5% with P

  

  


    
*BMI: Body    Mass Index 

  

Table 1: Main results of the SURPASS trials of tirzepatide 5, 10, 15 mg once weekly.