Clinical Pearls: New Pharmacotherapy in the treatment of Type 2 diabetes - Tirzepatide

August 11, 2023
By Holly Wingate 
 
This article is part of a series appearing in Interactions, our biweekly newsletter, written and researched by CSHP's students. We've created this series as a valuable learning activity for pharmacy students undertaking rotations at CSHP. Crafting these pieces not only helps students gain in-depth knowledge of specific conditions, treatments, and resources, it also helps them hone their skills in research, critical appraisal, evaluation, synthesis, and writing – all of which will serve them well in clinical practice. The Professional Practice Team works with the students to select hot topics that are of interest and utility to both the students and to you, the reader. We hope you enjoy this piece by one of our future colleagues! Let us know what you think: If you would like to provide any comments or constructive feedback for our students, please email us at practice@cshp.ca.
 

Type 2 Diabetes Mellitus (T2DM) and Obesity: Background

Obesity and T2DM are both defined as chronic diseases by the American Medical Association (AMA), with obesity having been recognized officially in 2013.1 In Canada, the prevalence of obesity has been increased 3-fold since 1985, with an estimated 1.9 million (5%) Canadian adults living with severe obesity in 2016.2 In pediatrics, the prevalence of obesity has also been growing substantially, with ≤26% of 2-17 year olds being overweight and obese.3 Obesity, defined as a BMI >30kg/m2, is a complex condition with many factors interplaying including genetic, behavioral and environmental.2 Obesity poses significant health risks to an individual as excess body fat can alter glucose and metabolism, therefore leading to increased cardiometabolic and cancer risks, and reducing disease-free duration and life expectancy by 6-14 years.2 This adipose tissue can predispose individuals to many chronic diseases, such as T2DM, among other medical complications.2 On the other hand, T2DM is defined by a lack of insulin creation, insulin resistance, or a mix of both.4 In 2015, approximately 9.3% of Canadians had diabetes; this number is expected to rise to 12.1% by 2025, representing a 44% increase.4 If not treated properly, complications such as retinopathy, neuropathy, and nephropathy may occur, as well as increased risks for cardiovascular disease.4 If overweight, weight loss of approximately 5% of an individual's existing body weight may reduce the risk of progression from pre-diabetes to T2DM, thus demonstrating a correlation of T2DM with obesity.4 Treatments for each condition often overlap with the other, as this Clinical Pearl will demonstrate.

Tirzepatide Background

A new antihyperglycemic known as tirzepatide, was recently approved in November 2022 from Eli Lilly and Company, as the brand name MounjaroTM. It is indicated as a once-weekly subcutaneous injection as an adjunct to diet and exercise to improve glycemic control for the treatment of adult patients with T2DM. It can be used as monotherapy if metformin was intolerable/inappropriate, or in combination with metformin, a sulfonylurea, a sodium-glucose cotransport-2 inhibitor (SGLT2i), or basal insulin.5

Tirzepatide is a selective glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist (RA), where the GIP receptor activity is similar to endogenous GIP activity, and the GLP-1 receptor activity is lower compared to endogenous GLP-1.5 Prior to tirzepatide, it was thought that GIP had no benefits as a glucose-lowering therapeutic because of observations in T2DM patients.6 Recently, emerging evidence showed that co-administering GLP-1 and GIP RAs have a synergetic effect resulting in significantly increased insulin and glucagonostatic responses compared to separate administration of each hormone.6 As an incretin analogue, tirzepatide increases insulin secretion, insulin sensitivity, and reduces plasma glucagon levels, all in a dose dependent manner. As it also delays gastric emptying and increases satiety, it is associated with decreased food intake in patients and has shown to reduce fasting and post-prandial glucose levels.5

Place in Therapy for Type 2 Diabetes 

At the time of writing, Eli Lilly and Company is in the process of accumulating tirzepatide stock to supply Canada, therefore it is not currently included in the Canadian Diabetes Guidelines.7,4 However, the American Diabetes Association (ADA) mentions it as a highly effective glycemic-lowering and weight-lowering agent.8 ADA recommends guiding therapy by patient-centered treatment factors, including comorbidities and treatment goals. While tirzepatide treatment will help a patient achieve lower HbA1C and glycemic control goals due to the synergistic GLP-1 and GIP RA effect, other considerations such as weight management goals, if applicable for a patient, need to be assessed. Currently, the highest efficacy for weight loss is seen with tirzepatide and semaglutide.8 In general, tirzepatide is more efficacious than comparators in glycemic control, including HbA1C reductions, and in body weight reductions.9 While the benefits of tirzepatide are very appealing, cost effectiveness needs to be considered. Though the supply of MounjaroTM has not yet made it to Canada, the Alberta Blue Cross released estimated pricing, which it lists at $12,666 USD per year ($17,170 CAD).12 For reference, semaglutide (WejovyTM) is estimated at $4,726 CAD per year.12 At this time, metformin therapy is still considered first line before add on therapies such as tirzepatide.8 As trials have only been in patients who are overweight, as defined by a BMI >25kg/m2, tirzepatide is recommended if a patient is overweight and in need of HbA1C reductions, and who are in a financial position to be able to afford tirzepatide as there is no provincial, territorial, or NIHB coverage at the time of writing.11

Evidence for Type 2 Diabetes

Five main SURPASS trials were used to obtain drug approval for tirzepatide and are summarized below (see Table 1).13 In the trials, tirzepatide showed more benefits for achieving glycemic control, including reductions in HbA1C and blood glucose control, with varying degrees of weight loss and without hypoglycemia; this was seen with monotherapy, in combination with metformin, an SGLT2i, or basal insulin, and when comparing placebo, semaglutide, and basal insulin.13 

Table 1: SUPRASS 1-5 Trials

To note, SURPASS-J-Mono compared tirzepatide to dulaglutide and showed very similar results to SURPASS-2, with Tirzepatide having more HbA1C and bodyweight reductions, and no significant hypoglycemia.5,23 SURPASS-J-Combo was a safety trial which monitored tirzepatide use in participants taking other anti-hyperglycemic medications to assess serious adverse events (SAE), defined as death, hospitalization, life-threatening experiences, persistent or significant disabilities, birth defects, or medical events that jeopardize the participant, at any point from baseline through to week 52.24 Only 2 SAE’s as defined above occurred; no participants experienced mortality.24


SURPASS-CVOT is comparing tirzepatide to dulaglutide on MACE in participants with T2DM and atherosclerotic cardiovascular disease for 54 months and will be completed in October 2024.25 The primary outcome is looking at time to first occurrence of death from cardiovascular causes, myocardial infarction or stroke.25 Finally, SURPASS-6 trial concluded in November of 2022, but has no results posted. SURPASS-6 aimed to compare safety and efficacy of tirzepatide to insulin lispro and insulin glargine, with primary outcome being the mean change in HbA1C from baseline to 52 weeks.26 

On the Horizon: Indication for Obesity (SURMOUNT)

SURMOUNT-1 was a placebo-controlled trial that looked at tirzepatides effect on body weight in people living with obesity without T2DM, as defined by a BMI≥30kg/m2, and those who are overweight, as defined by a BMI≥27 kg/m², with weight-related comorbidities.27  This study has two phases: the main phase, and an extension phase for participants with pre-diabetes.27 The main phase lasted 72 weeks, and the extension phase is continuing for 2 more years. The primary outcomes include percent change in body weight, and percent of participants achieving ≥5% body weight reduction.27 At the end of the main phase, tirzepatide at any dose had more percent changes in body weight compared to placebo, and more participants achieving ≥5% body weight reduction (5mg: 89.4%, 10mg: 96.1%, 15mg: 96.3% vs. Placebo 27.8%). When assessing ≥20% body weight reduction as a secondary outcome, the 10mg and 15mg tirzepatide groups had 55% and 62.8% of participants achieving this, respectively.27

There are many ongoing SURMOUNT trials. SURMOUNT-2 looks at tirzepatide in participants with T2DM who have obesity or are overweight (BMI≥30kg/m2 or BMI≥27kg/m2), with primary outcomes looking at the percent change in body weight, and number of participants with a ≥5% body weight reduction from baseline to 72 weeks.28 SURMOUNT-3 looks at how tirzepatide maintains body weight or adds to weight loss after an intensive lifestyle modification program with the same primary outcomes as SURMOUNT-2.29 SURMOUNT-4 looks at how tirzepatide maintains its body weight loss; the lead-in phase of this trial is when participants with obesity will take tirzepatide.30 Then, participants will be randomized at week 36 to either continue tirzepatide or switch to placebo for the rest of the trial. The primary outcome is the percent change in body weight from week 36-88.30Finally, SURMOUNT-J looks at how tirzepatide affects body weight with a low-calorie diet and physical activity in participants with obesity.31 The primary outcomes include percent change in body weight and participants achieving ≥5% body weight reduction from baseline to 72 weeks.31 

Looking further: Heart Failure with Preserved Ejection Fraction (HFpEF) (SUMMIT)

The SUMMIT trial began in April 2021, and will be completed in July 2024. This trial looks at tirzepatide in participants with HFpEF, as defined by ejection fraction ≥50% and a diagnosis of stable heart failure.32 This trial excludes patients with HbA1C >9.5%, among other criteria.32  There are two primary outcomes, including a composite outcome of all-cause mortality, heart failure events, 6-minute walk test distance (6MWD) and Kansas City cardiomyopathy questionnaire clinical summary score (KCCQ CSS)32. The second outcome is a change in exercise capacity as measured by 6MWD from baseline to week 52.32  

Ongoing Trials: Pediatric Populations

Eli Lilly and Company began a placebo-controlled trial of tirzepatide in pediatric patients 10-18 years old, for the treatment of T2DM inadequately controlled with metformin, basal insulin or both, as defined by an HbA1C of 6.5-11%, in April 2022.33 This trial is still ongoing; therefore, no results have been posted. The primary outcome is the change in HbA1C from baseline to week 30.33 There is also an active phase 1 trial that will be completed in July 2024, which is evaluating the pharmacokinetics, safety, and tolerability of tirzepatide in pediatric patients 6-11 years old with obesity, as defined by a BMI greater than the 95th percentile for a participants age and sex.34 The primary outcome is the number of participants with at least one treatment emergent or serious adverse event from baseline to week 13.34 

Drug specific Information

Tirzepatide has important drug specific characteristics that are summarized below (see Table 2). Refer to the MounjaroTM. Product Monograph for more detailed information, including patient monitoring. 

Table 2: Tirzepatide Information

Hospital Pharmacy Considerations

As research shows, the synergy of GLP-1 and GIP RA actions lead to significant benefits for HbA1C, fasting and postprandial glucose levels, insulin sensitivity and body weight reductions.36  We do not have guidelines indicating where tirzepatide use will land in respect to other anti-hyperglycemic medications for T2DM, however, we do know non-pharmacologic measures and metformin should be tried prior to tirzepatide, especially with its cost. It is difficult to articulate where to place tirzepatide in comparison with semaglutide or other GLP-1 RA’s, therefore at this time tirzepatide use remains patient specific. Based on trial data, tirzepatide is ideal for patients who are overweight with a BMI>25kg/m2 , in need of HbA1C reductions, and who are in a financial position to be able to afford tirzepatide, as there is no private or public coverage at the time of writing, and no way of predicting if such coverage will come.12   

At this time, it is unknown if tirzepatide will receive coverage on the hospital formulary, therefore if a patient who is taking once weekly tirzepatide injections is admitted to the hospital, and is to continue therapy, they will need to use their own supply. However, if a patient experiences severe nausea or diarrhea from treatment and is extremely ill, sick day management may include discontinuing tirzepatide to decrease the risk of acute kidney injury from dehydration.5  In the event a patient has missed their scheduled tirzepatide dose for less than four days, tirzepatide can be given as normal in hospital.5 If it has not been continued in hospital for a patient with diabetes, sliding scale insulin can be used in the interim, as would normally occur in hospital. Substituting a different GLP-1 RA in tirzepatide’s place, such as semaglutide, may make pharmacological sense, although there is no data describing titration in this instance, nor is there evidence for this substitution. This decision is entirely patient and situation specific.  

Predicting how tirzepatide will be used in T2DM in Canada is variable, especially as we await supply. The upcoming SURMOUNT and SUMMIT trial results may determine tirzepatide’s future in Canada.  

References

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  3. About Active Kids, Healthy Kids. Canadian Paediatric Society; 2022. Available from: https://cps.ca/en/active-actifs/about-active-kids-healthy-kids 
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  22. A Study of Tirzepatide (LY3298176) Versus Placebo in Participants with Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5). Eli Lilly and Company; 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT04039503  
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  25. A Study of Tirzepatide (LY3298176) Compared with Dulaglutide on Major Cardiovascular Events in Participants with Type 2 Diabetes (SURPASS-CVOT). Eli Lilly and Company; 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT04255433  
  26. A Study of Tirzepatide (LY3298176) Versus Insulin Lispro (U100) in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) With or Without Metformin (SURPASS-6). Eli Lilly and Company; 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT04537923  
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  31. A Study of Tirzepatide (LY3298176) in Participants with Obesity Disease (SURMOUNT-J). Eli Lilly and Company; 2023. Available from: https://clinicaltrials.gov/ct2/show/NCT04844918  
  32. A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction and Obesity (SUMMIT). Eli Lilly and Company; 2023. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04847557  
  33. A Study to Evaluate Tirzepatide (LY3298176) in Pediatric and Adolescent Participants With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin or Basal Insulin or Both (SURPASS-PEDS). Eli Lilly and Company; 2023. Available from: https://clinicaltrials.gov/ct2/show/study/NCT05260021 
  34. A Study of Tirzepatide (LY3298176) in Pediatric Participants With Obesity. Eli Lilly and Company; 2023. Available from: https://clinicaltrials.gov/ct2/show/study/NCT05696847 
  35. Frias JP, Nauck MA, Van J, Benson C, Bray R, Ciu X, et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab. 2020;22(6):938–946. doi:10.1111/dom.13979 
  36. Bastin M, Andreelli F. Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential. Diabetes, metabolic syndrome and obesity: targets and therapy. 2019;12:1973–1985. doi:10.2147/DMSO.S191438  

 

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