Skeletal Muscle Mass and Body Weight Fall Proportionally With Use of Dual Glucagon-Like Peptide 1/Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Tirzepatide: Case Report and Review of Literature

Abstract

Objective

Multiple studies have demonstrated that treatment with tirzepatide results in significant improvement in HgbA1c as well as meaningful weight loss. Although the loss of skeletal muscle mass has been well described with the use of glucagon-like peptide 1 receptor agonists, there is little information regarding the effect of dual glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide receptor agonist tirzepatide on skeletal muscle mass.

Methods

We performed serial body composition measurements in a 68-year-old male who presented with a body mass index of 31.2 kg/m2 and hemoglobin A1c of 5.9%. Treatment with tirzepatide resulted in a reduction of weight by 28.7 lbs, a decrease in body mass index to 26.8 kg/m2, and normalization of A1c (5.3%). The patient, however, also experienced a 9.9 lb loss of skeletal muscle mass, which was proportionate to a reduction in body weight - approximately 15% from the initial value for both. Muscle mass loss constituted 34% of the total body weight loss.

Results

To our knowledge this is the first report of multiple serial body composition measurements in a patient on treatment with tirzepatide. The time course and the magnitude of the loss of body weight, fat mass and skeletal muscle mass are detailed.

Conclusion

We propose that, in addition to weight measurements, serial body composition assessments should be obtained in patients on tirzepatide. If this is not available, our findings suggest that, at least in some cases, the percent of muscle mass lost is similar to the percent reduction of total body weight.

Highlights

• •When using dual-action incretin for weight loss, monitoring weight alone may not be adequate and both body fat and skeletal muscle mass should be assessed
• •Percent loss of body weight and skeletal muscle mass may be proportional with the use of dual-action incretin
• •Strength or resistance-based exercises may aid in preserving skeletal muscle mass when using dual-action incretin

Clinical Relevance

This research is clinically relevant because dual-action incretin is commonly used for diabetes management and weight management. While the significant benefits of this medication are well understood, it is important to study possible side effects and develop the ways to rectify them.

Introduction

Obesity is a complex chronic disease which can pose a significant impact on health and wellbeing. In the United States, 41.9% of adults are obese (defined as body mass index [BMI] > 30 kg/m2) and 9.2% are severely obese (defined as BMI > 40 kg/m2).¹ Obesity increases the risk of developing type 2 diabetes, cardiovascular disease, and certain cancers.² Obesity also has a significant impact on quality of life and on life expectancy.²

Lifestyle modifications, including diet, physical activity, and behavior change, are the foundation of treatment for obesity.³ For many patients, however, weight loss through lifestyle changes is not effective or does not provide the desired result. In contrast, pharmacological management of obesity can be very effective. The adjunctive use of antiobesity medications with lifestyle can result in significant weight loss and cardiometabolic improvement.³

Medical management may be considered for weight loss when lifestyle modifications are not sufficient. The Food and Drug Administration currently approves 6 antiobesity medications which are orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and tirzepatide.⁴ The latter 3 agents belong to the class of incretins used for both diabetes management and weight management. Glucagon-like peptide 1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists are components of tirzepatide, which is currently the only dual-action incretin receptor agonist available on the market. Tirzepatide provides significant weight loss, an average of 15% using 5 mg weekly, 19.5% using 10 mg weekly, and 20.9% using 15 mg weekly.⁵

It is important to remember, however, that weight lost through lifestyle modifications and the use of antiobesity medications may not be attributed entirely to fat loss. Weight loss caused by calorie restriction decreases skeletal muscle mass.^5,6 In order to maintain muscle mass during weight loss it is imperative to consume adequate protein and engage in strength-based exercise.⁷ There is limited information regarding muscle loss observed specifically with the use of tirzepatide.⁵

Case Report

A 68- year old male presented with a weight of 202.1 lbs and a BMI of 30.7 kg/m². On examination, fat distribution was primarily central. Patient had a history of prediabetes, with an A1c of 5.9% at presentation.

Patient was unable to lose weight despite multiple lifestyle interventions for obesity. He has had numerous consultations with registered dietitians over the past 5 years and had made dietary modifications. The patient maintains a consistent exercise routine as he walks briskly at least 5 miles on weekdays and 6 miles on weekends. In the past, he used dulaglutide and semaglutide but had to discontinue these medications because of gastrointestinal side effects such as nausea and abdominal cramping.

The patient has a past medical history of prediabetes, obesity, coronary artery disease, fatty liver disease, and hyperlipidemia. His medications include atorvastatin 10 mg daily and ezetimibe 10 mg daily. On initial evaluation in September 2020, body composition measurements (via seca medical body composition analyzer 514) demonstrated weight of 202.1 lbs, BMI of 30.7 kg/m², fat mass of 70.1 lbs (34.7%), fat-free mass of 131.9 lbs (65.3%), and skeletal muscle mass of 62.8 lbs (31.1%). In June 2022, body composition measurements were repeated and demonstrated total weight of 204.9 lbs, BMI of 31.3 kg/m², fat mass of 73.5 lbs (35.9%), fat-free mass of 131.4 lbs (64.1%), and skeletal muscle mass of 63.8 lbs (31.1%).

Laboratory values from June 2022 demonstrated plasma glucose of 121 mg/dL, HgbA1c of 5.9%, triglycerides of 145 mg/dL, total cholesterol of 163 mg/dL, high-density lipoproteins (HDLs) of 39 mg/dL, low-density lipoproteins of 95 mg/dL, non-HDLs of 124 mg/dL, aspartate aminotransferase of 33 U/L, and alanine transaminase of 50 U/L (Table).

Table.

Anthropometric and Laboratory Values^a

	Jun-22	Aug-23
Anthropometric measures
Weight (lbs)	205	176
BMI (kg/m2)	31	27
Body fat (lbs)	74	55
Body fat (%)	36	31
Skeletal muscle mass (lbs)	64	54
Skeletal muscle mass (%)	31	31
Lab values
Plasma glucose (mg/dL)	121	95
HgbA1c (%)	5.9	5.3
Lipid panel
Triglycerides (mg/dL)	145	60
Total cholesterol (mg/dL)	163	105
HDL (mg/dL)	39	37
LDL (mg/dL)	95	57
Non-HDL (mg/dL)	124	69
AST (SGOT) (U/L)	33	30
ALT (SGPT) (U/L)	50	35

Abbreviations: ALD = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase.

^aAll changes are from baseline to wk 61.

On evaluation in June 2022, the patient initiated a treatment of tirzepatide at a dose of 2.5 mg weekly. He reported decreased hunger, slight tolerable gastrointestinal discomfort, decreased cravings, and early satiety. Within the first weeks of tirzepatide treatment, weight and BMI gradually decreased. Patient attempted to titrate up the dose of tirzepatide to 5 mg weekly multiple times, but each time discontinued the higher dose because of gastrointestinal side effects.

Over 61 weeks, total body weight decreased by 28.7 lbs or 13.9% (see Fig. 1). BMI decreased to 26.6 kg/m² (at this point indicative of overweight status rather than obese). HgbA1c decreased to 5.3% (at this point no longer in the prediabetes range). Fat mass decreased by 18.9 lbs or 25.8% (see Fig. 2). Skeletal muscle mass decreased by 9.9 lbs or 15.5% (see Fig. 2). A total of 34% of lost weight was muscle mass.

Fig. 1.

Change in total body weight (lb) and the percent of weight lost from baseline to week 61.

Fig. 2.

A. Change in total weight, fat mass, and skeletal muscle mass in pounds. B. Change in fat mass, skeletal muscle mass, and total weight as percentage of initial value.

During subsequent follow up in July 2023, serum glucose was 95 mg/dL, HgbA1c was 5.3%, triglyceride level was 60 mg/dL, total cholesterol was 105 mg/dL, high-density lipoprotein was 37 mg/dL, low-density lipoprotein was 57 mg/dL, non-HDL was 69 mg/dL, aspartate aminotransferase was 30 U/L, and alanine transaminase was 35 U/L (see Table).

Discussion

As illustrated by this case, the use of tirzepatide may substantially benefit patients who have prediabetes and patients who are also obese. GLP-1 agonists have been used for diabetes and weight management, but the use of GIP receptor agonist in conjunction with GLP-1 receptor agonist is still relatively new. Like GLP-1, GIP is one of the predominant hormones necessary for insulin secretion postprandially.⁸ GLP-1 improves insulin secretion and reduces appetite and food intake.⁸ In animal models, GIP produced improvements in glycemia and prevented obesity.⁸ Use of GIP resulted in prevention of diet-related obesity and a significant improvement in postprandial insulin secretion in people with type 2 diabetes with mild hyperglycemia.⁸ Dual GLP-1/GIP receptor agonist activates multiple pathways that lead to weight reduction, including delayed gastric emptying which results in decreased hunger, increased insulin sensitivity, and increased levels of adiponectin.⁹ The dual-action mechanism of tirzepatide leads to a more significant decrease in appetite and reduction in hyperglycemia than GLP-1 receptor agonists alone.⁹

Weight loss observed with tirzepatide, however, may not be entirely due to the loss of fat. Weight loss of any kind, whether or not antiobesity medications are utilized, elicits skeletal muscle mass loss in addition to fat loss.⁶ Jastreboff et al found that with use of tirzepatide 15 mg weekly, for every 3 lbs of fat lost, 1 lb of skeletal muscle mass loss was observed.⁵ Heise et al found that with use of tirzepatide 15 mg weekly, 86% of weight loss was attributed to fat loss.¹⁰ In our case, for every 1.9 lbs of fat lost, 1 lb of skeletal muscle mass was lost. We found that total body weight and skeletal muscle mass fell proportionally to the level of approximately 85% of their initial value, while body fat decreased more significantly to the level of 75% of the initial value. This resulted in body fat percentage decreasing significantly, while the skeletal muscle mass percentage remained stable (see Table).

We conclude that, at least in some cases of patients treated with tirzepatide, up to one third of lost body weight may be due to the loss of skeletal muscle mass and that body weight and skeletal muscle mass may fall proportionally while the loss of fat mass is more significant. Body composition in our case was measured via seca medical body composition analyzer 514. This is a stand-on multifrequency analyzer which uses 8 electrodes and measures impedance at frequencies ranging from 1 kHz to 1 MHz.¹¹ We propose that, in addition to weight measurements, serial body composition assessments should be obtained in patients on tirzepatide. If this is not available, our findings suggest that, at least in some cases, the percent of muscle mass lost is similar to the percent reduction in total body weight. It remains to be determined if adequate protein consumption and strength-based exercise would ameliorate skeletal muscle mass loss observed with tirzepatide treatment.

Patient Consent

Patient consent was obtained.

Disclosure

The authors have no conflicts of interest to disclose.