Beyond glycemia: Comparing tirzepatide to GLP-1 analogues

Despite historical research stating GIP did not assist in lowering blood glucose even with supratherapeutic levels, the success of GLP-1 RAs has led to the approval of a novel GLP-1/GIP RA, tirzepatide [42]. The medication is a single molecule that targets both incretin receptors, GLP-1r and GIPr. When activated with GLP-1r, GIP seems to potentiate not only the weight loss mechanism of the incretin but also the glucose lowering effects [13]. GIP activation may additionally potentiate the insulin secretion effects of GLP-1 activation on the pancreas and the weight loss effects of GLP-1 activation on CNS [13]. GIP activation may also provide complimentary mechanisms by potentiating the expansion of white adipose tissue and lipid handling [13]. Finally, GIPr agonism may decrease the nauseating effects of GLP-1 agonism through area postrema inhibitory neurons potentially allowing for higher therapeutic doses of GLP-1 analogs with decreased adverse effects [13].

3.1

Tirzepatide effects: glucose lowering effects of tirzepatide

Tirzepatide, a once-weekly subcutaneous injection, was FDA approved in May 2022 as an adjunct treatment with diet and exercise to improve glycemic control in adults with Type 2 diabetes [43]. Its approval was preceded by the outcomes of five phase III trials, which are summarized in Tables 1 and 2, each of which compare tirzepatide at 5 mg, 10 mg, and 15 mg to other medications comparing similar clinical endpoints. These trials demonstrated its efficacy and safety in Type 2 diabetes with or without other anti-diabetic agents [42, 44,45,46,47]. Apart from characteristics noted in the study designs, baseline traits including age, race, and gender were similar among all of the SURPASS trials and did not impact outcomes [42, 44,45,46,47]. In depth inclusion and exclusion criteria are also included in Table 1. SURPASS-1 shows that tirzepatide alone, at all doses, was superior to placebo and revealed a dose-dependent reduction of HbA1c by up to 2.07% (p < 0.0001) from baseline to week 40 [47]. SURPASS-3, -4, and -5 are comparisons of HbA1c reduction between tirzepatide and other anti-diabetic agents [42, 44, 45]. When trialed in patients who were already taking either insulin degludec or glargine, tirzepatide achieved about double the percentage of A1C lowering effects (difference of up to 1.14%) [42, 45]. Tirzepatide is currently being studied in an ongoing trial as an alternative to prandial insulin in patients currently on a basal insulin to treat type 2 diabetes [48].

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Tirzepatide was also compared to GLP-1 RA’s. SURPASS-2 studied tirzepatide versus 1 mg semaglutide, a once-weekly injectable GLP-1 RA, in patients taking metformin monotherapy [46]. Over 40 weeks, the estimated difference between the 15 mg tirzepatide group and the semaglutide group was -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001). Tirzepatide showed further efficacy in A1c lowering when all doses outperformed placebo and higher doses (10 and 15 mg) outperformed dulaglutide 1.5 mg by 1.1%, another once-weekly GLP-1r injectable in a phase II randomized-controlled trial [50]. Since the trials, higher doses of dulaglutide (3 mg, 4.5 mg) and semaglutide (2 mg) have become available. Still, the ADA has included tirzepatide in its list of agents with “very high efficacy” along with semaglutide and high dose dulaglutide [38].

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3.2

Tirzepatide effects: weight loss effects of tirzepatide

Aside from assessing glucose-lowering effects in the SURPASS trials, tirzepatide was studied for weight loss and obesity in the SURMOUNT trials. SURMOUNT-1 assessed the efficacy and safety of tirzepatide compared to placebo in people with a BMI of 30 or more or a BMI of 27 with at-least one weight related complication, excluding diabetes. Tirzepatide was dosed at 5 mg, 10 mg, and 15 mg. The mean percentage of change in weight from baseline was 15.9%, 19.5%, and 20.9% (p < 0.001) respectively when compared with placebo. The trial showed that tirzepatide not only causes a dose-dependent lowering of blood glucose, but also a dose-dependent lowering of weight [48]. SURMOUNT-2 reached completion in April 2023 and aimed to assess the efficacy and safety in patients with both obesity and type 2 diabetes. This trial evaluated the use of 10 mg and 15 mg tirzepatide in 938 adult participants. Tirzepatide achieved up to 15.7% weight loss compared to placebo though the data evaluation of the trial is still in progress; the manufacturer will continue to evaluate the results and present them in the coming months. [51]. Tirzepatide’s approval for weight loss is anticipated though the results of SURMOUNT -3 and -4 trials are also being conducted.

Weight loss was also measured as a secondary endpoint in the SURPASS trials (also included in Table 2). In the trials versus insulin, the tirzepatide group achieved approximately 7-10 kg weight loss compared to approximately 2.3 kg weight gain in the insulin group (p < 0.0001) [44]. Though direct comparisons are lacking, tirzepatide seems to be more potent at lowering weight than any other weight loss medication available. In SURPASS-2, tirzepatide 15 mg resulted in a 11.2 kg reduction in body weight versus 5.7 kg with 1 mg semaglutide (p < 0.001) [46]. Similarly, the higher doses of tirzepatide resulted in greater weight loss than dulaglutide [50]. Again, new doses of semaglutide and dulaglutide have since been approved and direct comparisons of these higher doses to tirzepatide are lacking. Additionally, the comparative studies were done only in patients with diabetes limiting the generalizability of any conclusions made.

Table 3 lists FDA-approved weight loss medication regardless of diabetes status along with their average reductions of body weight. Prior to tirzepatide being on the market, semaglutide showed the largest amount of placebo-subtracted weight loss in comparison to other drugs. In addition to glucose lowering and weight loss, it is important to note that tirzepatide is a non-sympathomimetic drug, unlike some other FDA-approved weight loss drugs containing phentermine and bupropion. ADA 2023 emphasizes the importance of losing weight stating >10% weight loss can be disease modifying and may even lead to disease remission [38]. The SURPASS and SURMOUNT trials have led the ADA to consider tirzepatide, along with semaglutide, to be “very highly efficacious for weight loss” [38].

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3.3

Tirzepatide effects: cardiovascular, renal, hepatic, and other metabolic effects of tirzepatide

Due to concerns that type 2 diabetes medications increased cardiovascular risk, the FDA issued guidance for pharmaceutical companies to perform cardiovascular outcomes trials for new diabetes medications. As mentioned previously, liraglutide, dulaglutide, albiglutide, and semaglutide have been shown to reduce the risk of cardiovascular events in patients with diabetes and either established ASCVD or high-risk characteristics in randomized controlled trials [35, 36, 49]. Diabetes guidelines recommend these GLP-1 RA’s as pharmacologic agents in patients with ASCVD or with high-risk indicators for cardiovascular disease. These agents are integral in clinical practice to improve cardiovascular outcomes in patients with diabetes.

A meta-analysis of 42,920 participants from five randomized trials demonstrated that GLP-1 RA’s are associated with a significant reduction in the risk of the composite cardiovascular disease in patients with diabetes and established ASCVD [53]. While the impact of GLP-1 RA’s on cardiovascular outcomes has been shown to be directly correlated with the reduction in A1c, these agents exhibit pleiotropic effects [54]. These include reduction of systolic and diastolic blood pressure, body weight, vascular inflammation, and improvement of endothelial function [55,56,57,58]. Additionally, a phase 2 trial of patients with type 2 diabetes has shown tirzepatide improves cardiovascular biomarkers [59, 60].

The SURPASS-4 trial is the first randomized controlled trial assessing cardiovascular outcomes with Tirzepatide [45]. Tables 1 and 2 summarized the details of the study along with the glucose-lowering effects of tirzepatide as compared to insulin glargine. Additionally, the study looked at cardiovascular outcomes as a pre-specified secondary analysis which included a four-point composite endpoint of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina. Adjudicated MACE-4 events occurred in 109 participants and were not increased on tirzepatide compared with glargine (HR 0·74, 95% CI 0·51–1·08). These results suggest there is no excess cardiovascular risk with tirzepatide and are consistent with the improvements of numerous surrogate markers of cardiovascular health, including weight reduction, glycemic control with less hypoglycemia, blood pressure reduction, and improvements in the lipid profile. While SURPASS-4 was not powered to evaluate differences in MACE-4 incidence between tirzepatide treatment groups and glargine, it was designed to fulfill the MACE-4 non-inferiority analysis requested by regulatory authorities to evaluate the cardiovascular safety of new glucose lowering medications.

Sattar et al. conducted a pre-specified cardiovascular meta-analysis that included all seven randomized controlled trials with a duration of at least 26 weeks from the SURPASS trials [61]. The primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events including cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina between tirzepatide groups and control groups. 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed and 142 participants had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (0.57–1.11) for MACE-4; 0.90 (0.50–1.61) for cardiovascular death; and 0.80 (0.51–1.25) for all-cause death. The cardiovascular safety demonstrated by tirzepatide in this analysis and SURPASS-4 paved the way for a large-scale cardiovascular outcomes trial.

SURPASS-CVOT is a phase 3 study enrolled approximately 13,000 patients at least 40 years of age and have a diagnosis of type 2 diabetes, confirmed atherosclerotic cardiovascular disease, HbA1c ≥7.0% to ≤10.5% and a body mass index (BMI) ≥25 kilograms per meter squared (kg/m2). Patients were excluded if they had a major cardiovascular event within the last 60 days, type 1 diabetes mellitus, history of pancreatitis, or a history of severe hypoglycemia. The primary endpoint is a three-point major adverse cardiovascular event endpoint that includes death from cardiovascular causes, non-fatal myocardial infarction (MI), or nonfatal stroke over a study period of 54 months. The study compares tirzepatide with the long-acting GLP-1 RA, dulaglutide for non-inferiority and superiority, and is currently in progress [61]. SURPASS-CVOT will not compare tirzepatide to placebo as commonly done. SURPASS-CVOT is unique, in that it compares the dual incretin agonist with a GLP-1 RA that has been shown to have cardiovascular benefit in people with type 2 diabetes and high risk ASCVD. The results of the SURPASS-CVOT will define the impact of tirzepatide on cardiovascular disease. Currently, the ADA does not include tirzepatide as part of their agents with cardiorenal benefit [38].

In addition to cardiovascular and renal effects, tirzepatide has shown promising hepatic effects. In a 26-week study, tirzepatide was studied to determine its effect on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with T2DM. When compared to dulaglutide and placebo, tirzepatide statistically significantly displayed improvement in ALT and AST from baseline. Other NASH-related biomarkers were decreased, and adiponectin was increased in patients with T2DM [62].

SURPASS-3 MRI, a sub-study of the phase-3 SURPASS-3 trial assessed tirzepatide administered once per week versus insulin degludec on liver fat content (LFC). A total of 296 participants without a history of significant alcohol consumption were randomly assigned to active treatment. The study looked at the change from baseline in LFC as assessed by MRI-proton density fat fraction (MRI-PDFF) at week 52. The absolute reduction in LFC at week 52 was significantly greater for the tirzepatide 10 mg and 15 mg group versus the insulin degludec group. The reduction in LFC was significantly correlated (p≤0.0006) with baseline LFC (ρ=-0.71), reductions in visceral adipose tissue, and abdominal subcutaneous adipose tissue in the tirzepatide groups [63].

Although these findings explore surrogate endpoints for liver disease, the results offer a promising future for tirzepatide in NASH and NAFLD populations. A randomized, double-blind, placebo-controlled phase 2 study comparing the efficacy and safety of tirzepatide versus placebo in 196 patients with nonalcoholic steatohepatitis (SYNERGY-NASH) with or without diabetes is currently underway and is estimated to complete in 2024. The primary outcome is the percentage of participants with absence of NASH with no worsening of fibrosis on liver histology [64].

With improved weight loss and the additional pleiotropic benefits of GIP, other metabolic risk factors are improved with tirzepatide. In a post-hoc analysis of the published SURPASS trials, the change in systolic blood pressure was greater for tirzepatide versus the comparators of the trials (tirzepatide 5 mg: -5.1 to -1.3 mmHg, tirzepatide 10 mg: -6.5 to -1.7 mmHg, tirzepatide 15 mg: -11.5 to -3.1 mmHg) [65]. The authors stated changes in SBP were primarily, but not solely, mediated by weight loss showing a weak (r = 0.18 – 0.22), but significant (p< 0.001), correlation between changes in body weight and SBP [65]. Additionally, a difference was seen between some doses of tirzepatide and semaglutide 1 mg when SURPASS-2 was reviewed. The 10 mg dose of tirzepatide showed greater weight reduction versus semaglutide 1 mg by -1.8 mmHg (-3.4 to -0.1) while the 15 mg dose of tirzepatide reduced an additional -3 mmHg (-4.6 to -1.3) compared to semaglutide [65].

Tirzepatide also showed improvements in lipids and cardiovascular risk factors compared to dulaglutide 1.5 mg and placebo. In a double-blind, placebo-controlled, phase 2b trial, patients with diabetes were administered all doses of tirzepatide, dulaglutide, or placebo. Blood samples of these patients were collected at baseline, week 4, week 12, and week 26. At week 26, LDL-C was reduced by 19.0% (-36.0% to -1.9%, p=.029) in the tirzepatide 15 mg group compared to placebo while it was reduced by 17.8% (-33.7% to -2.0%, p= 0.028) in the dulaglutide 1.5 mg group compared to placebo though differences between the 2 medications were not seen [60]. Triglycerides were significantly reduced at all doses of tirzepatide compared to placebo. Additionally, along with lowering triglycerides against placebo, tirzepatide 10 mg (-23.6%, CI: -34.3% to -10.5%, p<.001) and 15 mg (-27.9%, CI: -38.9% to -15.0%, p<.001) reduced triglycerides compared to dulaglutide 1.5 mg [60]. HDL-C did not change between tirzepatide and either placebo or dulaglutide [60]. Tirzepatide 10 and 15 mg also decreased large triglyceride-rich lipoprotein particles, small low-density lipoprotein particles, and lipoprotein insulin resistance score [60]. Finally, the study found that the largest predictor of triglyceride lowering in the tirzepatide groups was change in apoC-III levels and not body weight [60].

Lastly, a post-hoc analysis of the aforementioned 26-week trial analyzed biomarkers to assessed insulin sensitivity and beta-cell function. Homeostatic model assessment (HOMA) 2-B provides a validated tool to assess beta-cell function. The study showed significant decreases in HOMA2-B scores, proinsulin/insulin ratios, and proinsulin/C-peptide ratios in both tirzepatide (all doses) and dulaglutide compared to placebo [66]. Additionally, tirzepatide 10 mg decreased HOMA2-IR, a tool that measures insulin resistance, compared to both placebo and dulaglutide [66]. Multiple linear regression analysis showed that weight loss significantly (p<.028) explained only 13% of HOMA2-IR improvement for tirzepatide 10 mg and only 21% of improvement for tirzepatide 15 mg [66].

3.4

Tirzepatide effects: adverse effects of tirzepatide

Gastrointestinal adverse effects of tirzepatide are similar to GLP-1 RAs, which include nausea and vomiting likely caused by the appetite-suppressing mechanism of incretins [47]. Other common adverse effects include diarrhea, constipation, dyspepsia, abdominal pain, and decreased appetite [47]. 6.6% of patients discontinue tirzepatide due to adverse effects during its phase 3 trial [47]. It is important to note that as with GLP-1 RAs, adverse effects of tirzepatide are dose-dependent. Hypoglycemia is a potential adverse effect though this is rare given the glucose-dependent mechanism and is usually seen in patients taking insulin or insulin secretagogues [47]. Other rare adverse effects include pancreatitis and cholelithiasis; the medication should be used with caution in patients with a history of either of these conditions [45]. Adverse effects are similar in patients using the medication for diabetes to those using the medication for weight loss [67]. Finally, similar to GLP-1 RAs, the medication should not be used in patients with a history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [31, 43].

3.5

Cost-comparison of tirzepatide

Although very effective, GLP-1 RA’s are among the highest cost class of medications for the treatment of diabetes. Tirzepatide has a slightly higher cost than GLP-1 RAs for diabetes. Although cost to patient will differ based on insurance, Table 4 shows the average wholesale price (AWP) of tirzepatide compared to other diabetes drug classes. One example from each of the common diabetes classes is listen in Table 4 since other medications in the same class typically have similar costs. Despite likely being a similar tier as GLP-1 RAs and SGLT2is for many patient insurances, this elevated AWP is important to note for patients with co-insurances, deductibles, the Medicare coverage gap, patients without insurance, and for the total cost of healthcare.

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Table 5 also shows the cost of tirzepatide compared to other weight loss medications. It is important to recall that tirzepatide for weight loss is not yet approved and this table assumes that the cost of tirzepatide for weight loss will be the same as the cost for diabetes though this may not be as in the case of semaglutide. It is also important to note that combination weight loss products are brand name but are sometimes split into their generics by practitioners, an off-label method of getting similar doses and weight loss at a lower cost.

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