Effective Date

Date of Origin 

01-01-2025            

10-01-2024

Saxenda®

(liraglutide)

Subcutaneous injection solution

Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in:

• Adults with an initial body mass index (BMI) of:
  • 30 kg/m^2 or greater (obese), or
  • 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
• Pediatric patients aged 12 years or older with:
  • Body weight above 60 kg, and
  • An initial BMI corresponding to greater than 30 kg/m^2 for adults (obese) by international cut-offs (Cole Criteria)

Limitations of Use:

• Contains liraglutide and should not be coadministered with other liraglutide-containing products or with any other GLP-1 receptor agonist
• The safety and effectiveness in pediatric patients with type 2 diabetes have not been established
• The safety and efficacy of Saxenda in combination with other products intended for weight loss have not been established

1

Wegovy®

(semaglutide)

Subcutaneous injection solution

In combination with a reduced calorie diet and increased physical activity:

• To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight
• To reduce excess body weight and maintain weight reduction long term in:
  • Adults and pediatric patients aged 12 years and older with obesity
  • Adults overweight in the presence of at least one weight-related comorbid condition

Limitations of Use: Coadministration with other semaglutide-containing products or with any other GLP-1 receptor agonist is not recommended

2

Zepbound®

(tirzepatide)

Subcutaneous injection solution

Vial

As an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

• 30 kg/m2 or greater (obesity) or
• 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

Limitations of Use:

• Coadministration with other tirzepatide-containing products or any GLP-1 receptor agonist is not recommended.
• The safety and efficacy of coadministration with other products for weight management have not been established.
• Zepbound has not been studied in patients with a history of pancreatitis.

3

Obesity

Obesity rates have increased sharply over the last 30 years, creating a global public health crisis. The National Health and Nutrition Examination Surveys show that nearly 2 of 3 US adults are overweight or obese, and 1 of 3 adults are obese. Adults with body mass index (BMI) 25-29.9 kg/m^2 are considered overweight; those with BMI greater than or equal to 30 kg/m^2 are considered obese.(5) Weight loss is difficult for most people and weight loss medications help reinforce behavioral strategies to lose weight. Medications for weight loss do not work on their own. Numerous guidelines recommend the addition of weight loss medications only in conjunction with lifestyle and behavioral modifications.(4,5,6,11)  

GLP-1 is an endogenous incretin hormone produced by L cells within the intestinal mucosa in response to the intake of nutrients. GLP-1 receptors are expressed in multiple organs, including pancreas, gastrointestinal (GI) tract, heart, brain, kidney, lung, and thyroid. This ubiquitous expression of GLP-1 receptors could be the reason for its pleiotropic benefits for T2DM, weight loss, and cardio protection. GLP-1 has numerous metabolic effects, including but not limited to, glucose-dependent stimulation of insulin secretion, delayed gastric emptying, inhibition of food intake, and modulation of β-cell proliferation. Semaglutide was approved for the management of obesity in 2021. Having a dose–response effect on weight loss, semaglutide was approved at doses higher than indicated for T2DM. GLP-1 RAs do not have the same neuropsychiatric adverse effects as other FDA-approved drugs on the market. Other benefits include inherent glucoregulatory properties and cardio protection in select populations.(11)

The American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity recommends the following:(5)

• The principal outcome and therapeutic target in the treatment of obesity should be to improve the health of the patient by preventing or treating weight related complications using weight loss, not the loss of body weight per se
• For overweight (BMI 25-29.9 kg/m^2) or obese (BMI greater than or equal to 30 kg/m^2) patients, evaluate for adiposity related complications (e.g., type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease, obstructive sleep apnea). 
• Pharmaceutical therapy should only be used as adjunct to lifestyle modifications and depends on the staging of obesity:
  • Overweight Stage 0 (BMI 25-29.9 kg/m^2 or 23-24.9 kg/m^2 in certain ethnicities* with no complications)
    • Lifestyle therapy – reduced-calorie healthy meal plan/physical activity/behavioral interventions
  • Obesity Stage 0 (BMI greater than or equal to 30 kg/m^2 or greater than or equal to 25 kg/m^2 in certain ethnicities* with no complications)
    • Lifestyle therapy – reduced-calorie healthy meal plan/physical activity/behavioral intervention
    • Weight loss medications – consider if lifestyle therapy fails to prevent progressive weight gain (BMI greater than or equal to 27 kg/m^2)
  • Obesity Stage 1 (BMI greater than or equal to 25 kg/m^2 or greater than or equal to 23 kg/m^2 in certain ethnicities* with greater than or equal to 1 mild/moderate complications)
    • Lifestyle therapy – reduced-calorie healthy meal plan/physical activity/behavioral interventions
    • Weight loss medications – consider if lifestyle therapy fails to achieve therapeutic target or initiate concurrently with lifestyle therapy (BMI greater than or equal to 27 kg/m^2)
  • Obesity Stage 2 (BMI greater than or equal to 25 kg/m^2 or greater than or equal to 23 kg/m^2 in certain ethnicities* with greater than or equal to 1 severe complications):
    • Lifestyle therapy – reduced-calorie healthy meal plan/physical activity/behavioral interventions
    • Weight loss medication – initiate concurrently with lifestyle therapy (BMI greater than or equal to 27 kg/m^2)
    • Consider bariatric surgery (BMI greater than or equal to 35 kg/m^2)

*Certain ethnicities (A BMI cutoff point value of greater than or equal to 23 kg/m^2 should be used in the screening and confirmation of excess adiposity in South Asian, Southeast Asian, and East Asian adults)

The Endocrine Society clinical practice guidelines suggests medications approved for chronic weight management can be useful adjuncts to lifestyle change for patients who have been unsuccessful with diet and exercise alone. They recommend adherence to American Heart Association Guidelines (2013) [see below] which include advice for assessment and treatment with diet and exercise, as well as bariatric surgery for appropriate candidates.(4)

• Diet, exercise, and behavioral modification should be included in all overweight and obesity management approaches for BMI greater than or equal to 25 kg/m^2 and other tools [e.g., pharmacotherapy (if BMI greater than or equal to 27 kg/m^2 with comorbidity or BMI greater than 30 kg/m^2) and bariatric surgery (BMI greater than or equal to 35 kg/m^2 with comorbidity or BMI greater than 40 kg/m^2)] should be used as adjuncts to behavioral modification to reduce food intake and increase physical activity when possible. Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications.
• Assessment of efficacy and safety of prescribed weight loss medications should be performed at least monthly for the first 3 months, then at least every 3 months thereafter.
• Clinicians are recommended to perform annual and symptom-based screening for major obesity related chronic conditions in all adult patients with a BMI greater than or equal to 30 kg/m^2, including diabetes, cardiovascular disease, hypertension, hyperlipidemia, obstructive sleep apnea, non-alcoholic fatty liver disease, osteoarthritis, and major depression.
• Prescribers should identify chronic medications, for concomitant medical conditions, that contribute to weight gain, and prescribe drugs that are weight neutral or that will promote weight loss when possible.
• If a patient's response to a weight loss medication is deemed effective (weight loss greater than or equal to 5% of body weight at 3 months) and safe, it is recommended that the medication be continued. If deemed ineffective (weight loss less than 5% at 3 months) or if there are safety or tolerability issues at any time, the medication should be discontinued and alternative medications or referral for alternative treatment approaches instead considered.

The American Heart Association/American College of Cardiology/Obesity Society Guideline (2013) suggests if weight and lifestyle history indicates the patient has never participated in a comprehensive lifestyle intervention program as defined in the guidelines (i.e., trained interventionist or nutritional professional supervision of diet, exercise, and behavior therapy), it is recommended that the patient undertake such a program before addition of adjunctive therapies (e.g., pharmacotherapy), since a substantial proportion of patients will lose sufficient weight to improve health with comprehensive lifestyle management alone. If a patient has been unable to lose weight or sustain weight loss with comprehensive lifestyle intervention and has BMI greater than or equal to 30 kg/m^2 or greater than or equal to 27 kg/m^2 with greater than or equal to 1 obesity-associated comorbid condition(s), adjunctive therapy may be considered. The expert panel did not review comprehensive evidence on pharmacotherapy for weight loss. Medications should be FDA approved and clinicians should be knowledgeable about the product label. The provider should weigh potential risks of the medication vs. potential benefits of successful weight loss for the individual patient. If the patient is currently taking an obesity medication but has not lost at least 5% of initial body weight after 12 weeks on a maximal dose of the medication, the provider should reassess the risk-to-benefit ratio of that medication for the patient and consider discontinuation of that drug.(6)

The American Gastroenterological Association (AGA) clinical practice guidelines (2022) strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index 30 kg/m^2 or greater, or 27 kg/m^2 or greater with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap.(11) 

Pediatric Obesity

Pediatric obesity has become an epidemic and international problem. In the United States, the prevalence of obesity in children has risen from 5% in 1970 to 17% in 2004. Genetics and environment are the underlying causes of the increase in pediatric obesity. Obese children and adolescents are at risk of developing the same comorbid conditions as obese and overweight adults. Obesity and overweight in children are defined on percentages specific for age and gender defined BMI values. The American Academy of Pediatrics (AAP) define obesity as a BMI greater than or equal to 95th percentile or a BMI greater than or equal to 30 kg/m^2, whichever is lower, and overweight as a BMI within 85th to 94th percentile for children and adolescents 2 years of age and older.(9,10)

The AAP recommends that clinicians should assess medical and behavioral risks in any child with a BMI above the 85th percentile before initiating any intervention.(9,10) The Endocrine Society Pediatric Obesity Treatment Guidelines also recommend that clinicians should evaluate for potential comorbidities in children and adolescents with a BMI greater than or equal to 85th percentile.(8)

The 2023 AAP guidelines recommend the use of weight loss agents in conjunction with lifestyle and behavioral changes. Pediatricians and other primary healthcare providers should treat children and adolescents for overweight with comorbidities (BMI greater than or equal to 85th percentile; comorbidities such as dyslipidemia, prediabetes, Type 2 diabetes, fatty liver disease, hypertension) and obesity (BMI greater than or equal to 95th percentile).(10)

The 2017 Endocrine Society guidelines only recommend the use of FDA approved pharmacotherapy in pediatric patients as adjunctive therapy to lifestyle modifications of the highest intensity available and only by clinicians that are experienced in the use of anti-obesity agents.(8)

• Suggest pharmacotherapy in children or adolescents with obesity (greater than or equal to 95^th percentile for age and gender) only after a formal program of intense lifestyle modifications has failed to limit weight gain or to ameliorate comorbidities.
• Recommend against using obesity agents in children and adolescents less than 16 years of age who are overweight, but not obese, except in the context of clinical trials.
• Anti-obesity agents should be discontinued, and patients reevaluated if the patient does not have a greater than 4% BMI reduction after 12 weeks at the medication’s full dosage.
• Discourages prescribing weight loss medications off-label to pediatric patients less than 16 years of age.

Cardiovascular

Wegovy (semaglutide) was studied to determine its effect relative to placebo on major adverse cardiovascular events (MACE) when added to current standard of care, which included management of cardiovascular risk factors and individualized healthy lifestyle counseling (including diet and physical activity), in patients who are overweight or with obesity, and without diabetes. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Inclusion requirements of the trial included:(12)

• Patients who have established cardiovascular disease (CVD) as determined by having at least one of the following:
  • Prior myocardial infarction
  • Prior stroke (ischemic or hemorrhagic stroke)
  • Symptomatic peripheral arterial disease (intermittent claudication with ankle-brachial index <0.85 (at rest), peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease)
• Patients with a BMI greater than or equal to 27 kg/m^2
• Patients 45 years of age or over

Guidelines recommend that patients work towards a goal of tobacco cessation and avoiding tobacco exposure, managing hypertension to goal, and managing lipid levels to goal as risk reduction measures for CVD secondary prevention.(13,14,15)

Metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolic dysfunction-associated steatohepatitis (MASH)

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. SLD occurs when your body begins storing fat in your liver. While some fat in your liver is normal, when more than 5 to 10% of the liver's weight is fat, it is classified as steatosis. MASLD and ALD (alcohol intake >50 g/day for females and >60 g/day for males) comprise the most common causes of SLD. A new category, requiring further characterization, termed MetALD, describes those with MASLD who consume greater amounts of alcohol (20-50 g/day for females and 30-60 g/day for males, respectively), but do not meet the criteria for ALD. The history of alcohol consumption is an important factor as the current drinking pattern may not necessarily reflect previous drinking behavior. Importantly, despite sharing the same prevalence of cardiometabolic risk factors, MetALD is associated with a higher risk of all-cause mortality, underpinning MetALD as a distinct subclass of SLD with poorer prognosis. Therefore, diagnostic and treatment recommendations provided for MASLD cannot be extended to the MetALD population.(19,22,27,28)

The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). With MASH, fat buildup progresses to inflammation, then tissue damage and scarring (fibrosis). Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of the liver caused by excess fat cell deposits in it (steatotic liver disease). MASH is characterized by histological features of hepatocellular ballooning and lobular inflammation. Chronic inflammation causes progressive liver damage. MASL refers to the presence of MASLD in the absence of steatohepatitis.(19,27,28)

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease, and its prevalence will likely continue to rise. Often, MASLD has no symptoms. When symptoms do occur, they may include fatigue, weakness, weight loss, loss of appetite, nausea, abdominal pain, spider-like blood vessels, yellowing of the skin and eyes (jaundice), itching, fluid buildup and swelling of the legs (edema) and abdomen (ascites), and mental confusion. MASLD is initially suspected if blood tests show high levels of liver enzymes with an absence of chronic alcohol intake. However, other liver diseases are first ruled out through additional tests (e.g., Wilson's disease, hepatitis).(19,20,21)

The presence of MASLD is tightly linked to type 2 diabetes (T2D), obesity and other cardiometabolic risk factors. Studies suggest that one-third to two-thirds of people with type 2 diabetes have MASLD. Research suggests that MASLD is present in up to 75% of people who are overweight and in more than 90% of people who have severe obesity. MASLD is associated with an increased risk of cardiovascular events, chronic kidney disease, hepatic and extrahepatic malignancies, and liver-related outcomes, including liver failure and hepatocellular carcinoma (HCC). Therefore, the high socio-economic burden of MASLD poses a global health challenge that needs to be addressed by medical societies and policymakers.(19,27,28)

The following are the adult cardiometabolic risk factors (at least 1 out of 5) in the definition of MASLD:(27,28)

• Weight (BMI or WC) Overweight or Obesity Body mass index(BMI): 
  • Greater than or equal to 25 kg/m^2 (greater than or equal to 23 kg/m^2 in people of Asian ethnicity) OR
  • Waist Circumference (WC): 94 cm (male), 80 cm (female) or ethnicity adjusted equivalent
• Prediabetes or type 2 diabetes:
  • Fasting serum glucose greater than or equal to 5.6 mmol/L (100mg/dL) OR
  • 2-hour post load glucose levels greater than or equal to 7.8 mmol/L (greater than or equal to 140 mg/dL) OR
  • HbA1c greater than or equal to 5.7% OR
  • Type 2 diabetes OR
  • Treatment for type 2 diabetes
• Plasma triglycerides:
  • Greater than or equal to 1.7 mmol/L (greater than or equal to 150 mg/dL) OR
  • Lipid-lowering treatment
• HDL cholesterol:
  • Less than or equal to 1.0 mmol/L (less than or equal to 39 mg/dL) in men and less than or equal to 1.3 mmol/L (less than or equal to 50 mg/dL) in women OR
  • Lipid-lowering treatment
• Blood pressure:
  • Greater than or equal to 130/85 mmHG OR
  • Specific antihypertensive drug treatment

The 2021 AACE and 2023 AASLD practice guidelines suggest the following: Clinicians should identify individuals with obesity, metabolic syndrome traits, pre-diabetes, or type 2 diabetes, as well as those showing hepatic steatosis on imaging or persistently high plasma aminotransferase levels (over six months) as "high risk" and recommend screening for NAFLD/MASLD and advanced fibrosis. Metabolic syndrome is characterized by any three of the following: obesity, hypertension, high blood triglycerides, low HDL cholesterol, and insulin resistance.(19,21)

An initial evaluation for individuals suspected of having hepatic steatosis based on imaging findings should include tests to rule out other causes of liver disease (e.g., hepatitis B and C serology, autoantibody panels, and metabolic syndrome evaluations). It's important to note that many laboratory normal ranges are higher than the accepted thresholds for NAFLD/MASLD, where normal alanine aminotransferase (ALT) levels typically range from 29 to 33 U/L in men and from 19 to 25 U/L in women.(19,21,22)

The American Gastroenterology Association (AGA) guidelines recommend best practices for diagnosing MASH/MASLD:(24)

• A Fibrosis 4 Index score below 1.3 is linked with a strong negative predictive value for advanced hepatic fibrosis and may be helpful in ruling out advanced fibrosis in NAFLD/MASLD patients
• A combination of two or more NITs, incorporating serum biomarkers and/or imaging biomarkers, should be used for staging and risk assessment
• In patients with a Fibrosis 4 Index score above 1.3. FIB-4 risk categories from low risk (<1.3) to intermediate risk (1.3–2.67) to high risk (>2.67) can be used to evaluate clinical progression
• NITs should be evaluated in the context of relevant clinical data (e.g., physical examination, biochemical tests, and imaging) to enhance positive predictive value in identifying patients with advanced fibrosis
• Liver biopsy should be considered for patients with indeterminate or conflicting NIT results, discrepancies with other clinical or laboratory findings, or when other liver disease causes are suspected

NITs (non-invasive tests) derived from clinical variables can estimate the presence of advanced fibrosis. Several have been developed (e.g., FIB-4, NAFLD/MASLD Fibrosis Score, AST Platelet Ratio Index); however, FIB-4 is the most validated. FIB-4 is calculated using a simple algorithm based upon age, ALT, AST, and platelet count and outperforms other calculations in its ability to identify patients with a low probability of advanced fibrosis. The FIB-4 index can be calculated from age and three parameters obtained in routine laboratory assessments: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet count. A change in FIB-4 status category from low risk (<1.3) to intermediate risk (1.3–2.67) to high risk (>2.67) may be used to assess clinical progression. Although FIB-4 is statistically inferior to other serum-based fibrosis markers such as the Enhanced Liver Fibrosis (ELF) panel, FIBROSpect II, and imaging-based elastography methods to detect advanced fibrosis, FIB-4 is still recommended as a first-line assessment for general practitioners and endocrinologists based on its simplicity and minimal added cost.(19,23,24)

Those who may have a moderate or high risk of advanced disease based on FIB-4 should undergo secondary risk assessment. Vibration-controlled transient elastography (VCTE) (e.g., FibroScan) is the most commonly used method to assess liver stiffness and can be used to exclude significant hepatic fibrosis. Magnetic resonance elastography (MRE) is more sensitive than VCTE in the detection of fibrosis stage greater than 2 and is considered to be the most accurate noninvasive imaging-based biomarker of fibrosis in NAFLD/MASLD. Although MRE is not a first-line approach to risk stratification in a patient with NAFLD/MASLD, it can be an important tool if clinical uncertainty exists, if there is a need for concomitant cross-sectional imaging, or when other elastography techniques are unavailable. Among patients with cirrhosis, a baseline liver stiffness measure (LSM) by MRE predicts future risk of incident hepatic decompensation and death. Controlled Attenuation Parameter (CAP) as a point-of-care technique may also be used to identify steatosis. A liver biopsy is the optimal approach to confirm the diagnosis and stage of the severity of liver fibrosis. However, it is recognized that this may not be feasible or acceptable to several individuals.(19,23,24)

Research findings have suggested that patients with NAFLD/MASLD exhibit lower levels of biologically active incretin hormones when compared to healthy individuals and this may be attributed to either an increased degradation of these hormones by dipeptidyl peptidase-4 (DPP-4) or a diminished production of these hormones. GLP-1RAs can exert control over energy intake and weight gain through mechanisms such as prolonging gastric emptying and suppressing appetite. These effects help regulate food consumption and contribute to weight management. Additionally, GLP-1RAs have shown the ability to enhance liver enzyme functions, alleviate liver steatosis, and notably reduce liver fat content. Semaglutide, a second-generation GLP-1-RA, is available in both oral (daily administration) and subcutaneous (weekly administration) formulations. Clinical studies have provided evidence of the favorable effects of semaglutide in patients with NAFLD/MASLD. Nevertheless, there is a lack of comprehensive systematic reviews or meta-analyses that have extensively summarized and quantified these effects. Hence, this systematic review and meta-analysis aimed to evaluate the influence of a 24-week administration of semaglutide in patients with NAFLD/MASLD or NASH/MASH.(18)

A systematic review and meta-analysis was conducted (six hundred studies were screened and eight were included) to evaluate the efficacy and safety of 24 weeks of semaglutide treatment in patients with NAFLD/MASLD or NASH/MASH. The following were concluded:(18)

• Semaglutide could be used in patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis
• It significantly improves liver enzymes, reduces liver stiffness, and improves metabolic parameters in these patients
• Gastrointestinal adverse effects and gallbladder-related diseases could be a major concern

The 2024 European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) guidelines suggest in adults with MASLD, lifestyle modification which includes weight loss, dietary changes, physical exercise and discouraging alcohol consumption. In addition, they recommend optimal management of comorbidities, including use of incretin-based therapies (e.g., semaglutide, tirzepatide) for type 2 diabetes or obesity, if indicated. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage greater than or equal 2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.(27)

While an initial study with liraglutide indicated a histological benefit in MASH, drugs that are being developed for MASH now include semaglutide, and dual GLP1-GIP (e.g., tirzepatide), dual GLP1-glucagon (e.g., cotadutide, survodutide, efinopegdutide) or triple GLP1-GIP-glucagon (e.g., retatrutide) agonists. The largest available trial on semaglutide in MASH (vs. placebo over an 18-month treatment period) demonstrated resolution of steatohepatitis but no fibrosis improvement. A large registrational, phase III study with semaglutide is ongoing. Combining semaglutide with lipogenesis inhibitors may provide additional benefit and such approaches are being tested in larger trials. Histology data are not yet available for the newer dual and triple agonists. Tirzepatide (GLP1-GIP RA) has been shown to significantly reduce both liver and visceral fat in those with type 2 diabetes, in association with major weight loss (comparable to bariatric surgery), and promising results on steatohepatitis resolution from a phase II study in MASH have been communicated. Dual GLP1-glucagon RAs (cotadutide and efinopegdutide) have also been shown to improve liver steatosis, liver enzymes and indexes of fibrosis in individuals with MASLD.(17,27)

Efficacy

SELECT Trial (Wegovy)

Study 1 (NCT03574597) was a multi-national, multi-center, placebo-controlled, double-blind trial to determine the effect of Wegovy relative to placebo on major adverse cardiovascular events (MACE) when added to current standard of care, which included management of CV risk factors and individualized healthy lifestyle counseling (including diet and physical activity). The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. All patients were 45 years or older, with an initial BMI of 27 kg/m2 or greater and established cardiovascular disease (prior myocardial infarction, prior stroke, or peripheral arterial disease). Patients with a history of type 1 or type 2 diabetes were excluded.(2)

In this trial, 17,604 patients were randomized to Wegovy or placebo. At baseline, the mean age was 62 years and 12,732 patients (72.3%) were male. The mean BMI was 33 kg/m^2, and 12,580 patients (71.5%) met the BMI criterion for obesity (≥30). The mean glycated hemoglobin level was 5.8%, and 11,696 patients (66.4%) met the glycated hemoglobin criterion for prediabetes (defined as a mean level of 5.7 to 6.4%). At baseline, prior myocardial infarction was reported in 76% of randomized individuals, prior stroke in 23%, and peripheral arterial disease in 9%. Heart failure was reported in 24% of patients. At baseline, cardiovascular disease and risk factors were managed with lipid lowering therapy (90%), platelet aggregation inhibitors (86%), angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (74%), and beta blockers (70%). A total of 10% had moderate renal impairment (eGFR 30 to <60 mL/min/1.73m2 ) and 0.4% had severe renal impairment eGFR <30 mL/min/1.73m2.(2,16)

Patients were randomly assigned, with the use of a centralized system in a double-blind manner and in a 1:1 ratio without stratification, to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The starting dose of semaglutide was 0.24 mg once weekly, and the dose was increased every 4 weeks (to once weekly doses of 0.5, 1.0, 1.7, and 2.4 mg) until the target dose of 2.4 mg was reached after 16 weeks. If dose escalation led to unacceptable adverse effects, the dose-escalation intervals could be extended, treatment could be paused, or maintenance doses below the 2.4 mg per week target dose could be used.(16)

Among the 17,604 patients with a BMI of 27 or greater and preexisting cardiovascular disease but without diabetes, treatment with once-weekly subcutaneous semaglutide at a dose of 2.4 mg for a mean duration of 33 months reduced the risk of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by 20% (hazard ratio, 0.80; 95% CI, 0.72 to 0.90).

NASH Trial

A 72-week, double-blind phase 2 trial (NCT02970942) involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3 patients were randomly assigned to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.(25)

In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group.(17,25,26)

This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage.(25)

Safety

Liraglutide has the following:(1)

• Contraindications:
  • Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components.
  • Pregnancy
• Boxed warnings:
  • Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Saxenda causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.
  • Saxenda is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Saxenda and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Saxenda.

Semaglutide has the following:(2)

• Contraindications:
  • Personal or family history of  medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • Known hypersensitivity to semaglutide or any of the excipients in Wegovy.
• Boxed warnings:
  • In rodents, semaglutide causes thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Wegovy causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined
  • Wegovy is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors

Tirzepatide has the following:(3)

• Contraindications:
  • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.
  • Known serious hypersensitivity to tirzepatide or any of the excipients in Zepbound.
• Boxed warnings:
  • In rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Zepbound causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.
  • Zepbound is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Zepbound and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Zepbound.

Co-Administration

None of the FDA approved weight loss agents have approval for co-administration with another weight loss agent. New guidelines do not support the use of co-administration of weight loss pharmacological agents.(4,5,10) Use of non-approved drug combinations for obesity treatment should be limited to clinical trials, and patients should be informed when drugs are being used off label alone or in combination.(6)

1

Saxenda prescribing information. Novo Nordisk Inc. April 2023.

2

Wegovy prescribing information. Novo Nordisk Inc. March 2024.

3

Zepbound prescribing information. Lilly USA, LLC. March 2024.

4

Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Feb;100(2):342–362.

5

American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr Pract. 2016 Jul:22(Suppl 3):1-203.

6

Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102–S138.

7

Yanovski SZ, Yanovski JA. Long-Term Drug Treatment for Obesity: A Systematic and Clinical Review. JAMA. 2014 Jan;311(1):74-86.

8

Styne DM, Arslanian SA, Connor EL, et al. Pediatric Obesity - Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017 Jan;102(3):709–757.

9

Barlow SE, et al. Expert Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity: Summary Report. Pediatrics. 2007 Dec;120(Suppl 4):S164-S192.

10

American Academy of Pediatrics (AAP) Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity. Pediatrics. 2023 Jan;151(2):1-100.

11

American Gastroenterological Association (AGA) Clinical Practice Guideline on Pharmacological Interventions for Adults with Obesity. Gastroenterology. 2022 Nov;163(5):1198-1225.

12

Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design. American Heart Journal. 2020;229:61-69. doi:10.1016/j.ahj.2020.07.008.

13

Smith SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update. Circulation. 2011;124(22):2458-2473. doi:10.1161/cir.0b013e318235eb4d.

14

Kleindorfer D, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients with stroke and Transient Ischemic Attack: A Guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7). doi:10.1161/str.0000000000000375.

15

Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients with Chronic Coronary Disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9). doi:10.1161/cir.0000000000001168.

16

Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563.

17

Harrison SA, Loomba R, Dubourg J, Ratziu V, Noureddin M. Clinical trial landscape in NASH. Clinical Gastroenterology and Hepatology. 2023;21(8):2001-2014. doi:10.1016/j.cgh.2023.03.041.

18

Bandyopadhyay S, Das S, Samajdar SS, Joshi SR. Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Diabetes Metab Syndr. 2023;17(10):102849. doi:10.1016/j.dsx.2023.102849.

19

Rinella, Mary E, Neuschwander-Tetri, Brent A, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77(5):p 1797-1835, May 2023. DOI: 10.1097/HEP.0000000000000323.

20

Nash causes & risk factors. American Liver Foundation. (2023, November 1). https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-causes-risk-factors/.

21

Cusi K, Isaacs S, Barb D, et al., American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022 May;28(5):528-562. doi: 10.1016/j.eprac.2022.03.010.

22

U.S. Department of Health and Human Services. (2023). Drinking levels defined. National Institute on Alcohol Abuse and Alcoholism. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking.

23

Blanco-Grau A, et al., Assessing Liver Fibrosis Using the FIB4 Index in the Community Setting. Diagnostics (Basel). 2021 Nov 29;11(12):2236. doi: 10.3390/diagnostics11122236.

24

Wattacheril J, Abdelmalek MF, Lim JK, Sanyal AJ. AGA Clinical Practice Update on the Role of noninvasive biomarkers in the evaluation and management of nonalcoholic fatty liver Disease: Expert review. Gastroenterology. 2023;165(4):1080-1088. doi:10.1053/j.gastro.2023.06.013.

25

Newsome PN, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395

26

Investigation of Efficacy and Safety of Three Dose Levels of Subcutaneous Semaglutide Once Daily Versus Placebo in Subjects With Non-alcoholic Steatohepatitis. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02970942.

27

Tacke F, Horn P, Wong VWS, et al. EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology. Published online June 1, 2024. doi:10.1016/j.jhep.2024.04.031.

28

Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. Metabolic dysfunction–associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology. 2023;79(5):1212-1219. doi:10.1097/hep.0000000000000670.

Saxenda

liraglutide (weight mngmt) soln pen-inj

18 MG/3ML

M ; N ; O ; Y

N

Wegovy

semaglutide (weight mngmt) soln auto-injector

0.25 MG/0.5ML ; 0.5 MG/0.5ML ; 1 MG/0.5ML ; 1.7 MG/0.75ML ; 2.4 MG/0.75ML

M ; N ; O ; Y

N

Zepbound

tirzepatide (weight mngmt) soln

2.5 MG/0.5ML ; 5 MG/0.5ML

M ; N ; O ; Y

N

Zepbound

tirzepatide (weight mngmt) soln auto-injector

10 MG/0.5ML ; 12.5 MG/0.5ML ; 15 MG/0.5ML ; 2.5 MG/0.5ML ; 5 MG/0.5ML ; 7.5 MG/0.5ML

M ; N ; O ; Y

N

Saxenda

Liraglutide (Weight Mngmt) Soln Pen-Inj 18 MG/3ML (6 MG/ML)

18 MG/3ML

15

mLs

30

DAYS

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

0.25 MG/0.5ML

8

Pens

180

DAYS

*This strength is not approvable for maintenance dosing

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

0.5 MG/0.5ML

8

Pens

180

DAYS

*This strength is not approvable for maintenance dosing for pediatric patients

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

1 MG/0.5ML

8

Pens

180

DAYS

*This strength is not approvable for maintenance dosing for pediatric patients

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

1.7 MG/0.75ML

4

Pens

28

DAYS

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

2.4 MG/0.75ML

4

Pens

28

DAYS

Zepbound

tirzepatide (weight mngmt) soln

2.5 MG/0.5ML

4

Vials

180

DAYS

*This strength is not approvable for maintenance dosing

Zepbound

tirzepatide (weight mngmt) soln

5 MG/0.5ML

4

Vials

28

DAYS

Zepbound

tirzepatide (weight mngmt) soln auto-injector

2.5 MG/0.5ML

4

Pens

180

DAYS

*This strength is not approvable for maintenance dosing

Zepbound

tirzepatide (weight mngmt) soln auto-injector

5 MG/0.5ML

4

Pens

28

DAYS

Zepbound

tirzepatide (weight mngmt) soln auto-injector

7.5 MG/0.5ML

4

Pens

28

DAYS

Zepbound

tirzepatide (weight mngmt) soln auto-injector

10 MG/0.5ML

4

Pens

28

DAYS

Zepbound

tirzepatide (weight mngmt) soln auto-injector

12.5 MG/0.5ML

4

Pens

28

DAYS

Zepbound

tirzepatide (weight mngmt) soln auto-injector

15 MG/0.5ML

4

Pens

28

DAYS

6125207000D520

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

0.25 MG/0.5ML

*This strength is not approvable for maintenance dosing

6125207000D525

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

0.5 MG/0.5ML

*This strength is not approvable for maintenance dosing for pediatric patients

6125207000D530

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

1 MG/0.5ML

*This strength is not approvable for maintenance dosing for pediatric patients

61252580002018

Zepbound

tirzepatide (weight mngmt) soln

2.5 MG/0.5ML

*This strength is not approvable for maintenance dosing

6125258000D520

Zepbound

tirzepatide (weight mngmt) soln auto-injector

2.5 MG/0.5ML

*This strength is not approvable for maintenance dosing

Saxenda

liraglutide (weight mngmt) soln pen-inj

18 MG/3ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Wegovy

semaglutide (weight mngmt) soln auto-injector

0.25 MG/0.5ML ; 0.5 MG/0.5ML ; 1 MG/0.5ML ; 1.7 MG/0.75ML ; 2.4 MG/0.75ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln

2.5 MG/0.5ML ; 5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

10 MG/0.5ML ; 12.5 MG/0.5ML ; 15 MG/0.5ML ; 2.5 MG/0.5ML ; 5 MG/0.5ML ; 7.5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Saxenda

Liraglutide (Weight Mngmt) Soln Pen-Inj 18 MG/3ML (6 MG/ML)

18 MG/3ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

0.25 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

1.7 MG/0.75ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

0.5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

1 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Wegovy

Semaglutide (Weight Mngmt) Soln Auto-Injector

2.4 MG/0.75ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln

5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln

2.5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

10 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

2.5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

7.5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

12.5 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Zepbound

tirzepatide (weight mngmt) soln auto-injector

15 MG/0.5ML

Blue Partner ; Commercial ; GenPlus ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL the following are met:

1. ONE of the following:
   1. The requested use is to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and the patient is either obese or overweight AND ALL of the following: 
      1. The requested agent is FDA labeled for the requested indication and route of administration AND
      2. The patient has a history of ONE of the following: 
         1. Myocardial infarction OR
         2. Stroke OR
         3. Peripheral artery disease as defined by intermittent claudication with ankle-brachial index less than 0.85 at rest, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease AND
      3. The patient has a BMI greater than or equal to 27 kg/m^2 AND
      4. The patient will use optimized pharmacotherapy for established cardiovascular disease in combination with the requested agent OR
   2. The patient is overweight or obese and is using the requested agent for weight management and ALL of the following:
      1. Obesity is NOT restricted from coverage under the patient's benefit AND
      2. The patient is new to therapy, new to Prime, or attempting a repeat weight loss course of therapy AND
      3. ONE of the following:
         1. The patient is an adult (18 years of age or over) AND has ONE of the following:
            1. A BMI greater than or equal to 30 kg/m^2 OR
            2. A BMI greater than or equal to 25 kg/m^2 if the patient is of South Asian, Southeast Asian, or East Asian descent OR
            3. A BMI greater than or equal to 27 kg/m^2 with at least one weight-related comorbidity/risk factor/complication (e.g., hypertension, type 2 diabetes mellitus, obstructive sleep apnea, cardiovascular disease, dyslipidemia) OR
         2. The patient is pediatric (12 to 17 years of age) AND has ONE of the following:
            1. A BMI greater than or equal to 95th percentile for age and sex OR
            2. A BMI greater than or equal to 30 kg/m^2 OR
            3. A BMI greater than or equal to 85th percentile for age and sex AND at least one weight-related comorbidity/risk factor/complication AND
      4. The patient has been on a weight loss regimen of a low-calorie diet, increased physical activity, and behavioral modifications for a minimum of 6 months AND​​​​
      5. ONE of the following:
         1. The patient has NOT tried a targeted weight loss agent (e.g., Saxenda, Wegovy, Zepbound) in the past 12 months OR
         2. BOTH of the following:
            1. The patient has tried a targeted weight loss agent for a previous course of therapy in the past 12 months AND
            2. The prescriber anticipates success with repeating therapy with any targeted weight loss agent AND
      6. If the requested agent is Saxenda, then ONE of the following:
         1. The patient is an adult (18 years of age or over) AND ONE of the following:
            1. The patient is newly starting therapy OR
            2. The patient is currently being treated and has received less than 16 weeks (4 months) of therapy OR
            3. The patient has achieved and maintained a weight loss of greater than or equal to 4% from baseline (prior to initiation of pharmacotherapy) OR
         2. The patient is pediatric (12 to 17 years of age) AND BOTH of the following:
            1. The requested agent is NOT being used to treat type 2 diabetes AND
            2. ONE of the following:
               1. The patient is newly starting therapy OR
               2. The patient is currently being treated and has received less than 20 weeks (5 months) of therapy OR
               3. The patient has achieved and maintained a reduction in BMI of greater than or equal to 1% from baseline (prior to initiation of pharmacotherapy) AND
      7. If the requested agent is Wegovy, then ONE of the following:
         1. The patient is newly starting therapy OR
         2. The patient is currently being treated and has received less than 52 weeks (1 year) of therapy OR
         3. The patient is an adult (18 years of age or over) AND has achieved and maintained a weight loss of greater than or equal to 5% from baseline (prior to initiation of pharmacotherapy) OR
         4. The patient is pediatric (12 to 17 years of age) AND has achieved and maintained a reduction in BMI of at least 5% from baseline (prior to initiation of pharmacotherapy) AND
      8. If the requested agent is Zepbound, then ONE of the following:
         1. The patient is newly starting therapy OR
         2. The patient is currently being treated and has received less than 52 weeks (1 year) of therapy OR
         3. The patient has achieved and maintained a weight loss of greater than or equal to 5% from baseline (prior to initiation of pharmacotherapy) OR
   3. The patient has another FDA labeled indication for the requested agent and route of administration AND
2. The patient will NOT be using the requested agent in combination with another weight loss agent (e.g., Contrave, phentermine, Qsymia, Xenical) for the requested indication AND
3. BOTH of the following:
   1. The patient is currently on a weight loss regimen of a low-calorie diet, increased physical activity, and behavioral modifications AND
   2. The patient will continue the weight loss regimen in combination with the requested agent AND
4. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
5. The patient will NOT be using the requested agent in combination with another GLP-1 receptor agonist (e.g., Saxenda, Wegovy, Zepbound, Mounjaro, Ozempic, Trulicity) AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:            

• For Wegovy, Zepbound: 12 months
• For Saxenda: Pediatric patients (12 to 17 years of age): 5 months; Adults: 4 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. The requested use is to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease AND ALL of the following: 
      1. The requested agent is FDA labeled for the requested indication and route of administration AND
      2. The patient will use optimized pharmacotherapy for established cardiovascular disease in combination with the requested agent AND
      3. The patient has had clinical benefit with the requested agent OR
   2. The patient is overweight or obese and is using the requested agent for weight management and ALL of the following:
      1. Obesity is NOT restricted from coverage under the patient's benefit AND
      2. The patient is continuing a current weight loss course of therapy AND
      3. If the patient is pediatric (12 to 17 years of age), then the current BMI is greater than 85th percentile for age and sex AND
      4. The patient meets ONE of the following:
         1. The patient has achieved and maintained a weight loss greater than or equal to 5% from baseline (prior to the initiation of requested agent) OR
         2. If the requested agent is Saxenda, then ONE of the following:
            1. The patient is pediatric (12 to 17 years of age) AND BOTH of the following:
               1. The requested agent is NOT being used to treat type 2 diabetes AND
               2. The patient has achieved and maintained a reduction in BMI of greater than or equal to 1% from baseline (prior to initiation of pharmacotherapy) OR
            2. The patient is an adult (18 years of age or over) AND has achieved and maintained a weight loss greater than or equal to 4% from baseline (prior to initiation of pharmacotherapy) OR
         3. If the requested agent is Wegovy, then ONE of the following:
            1. The patient has received less than 52 weeks of therapy on the maximum-tolerated dose OR
            2. The patient is pediatric (12 to 17 years of age) AND has achieved and maintained a reduction in BMI of at least 5% from baseline (prior to initiation of pharmacotherapy) AND
         4. If the requested agent is Zepbound, the patient has received less than 52 weeks of therapy on the maximum-tolerated dose OR
   3. The patient has another FDA labeled indication for the requested agent and route of administration AND has had clinical benefit with the requested agent AND 
3. The patient will NOT be using the requested agent in combination with another weight loss agent (e.g., Contrave, phentermine, Qsymia, Xenical) for the requested indication AND
4. BOTH of the following:
   1. The patient is currently on a weight loss regimen of a low-calorie diet, increased physical activity, and behavioral modifications AND
   2. The patient will continue the weight loss regimen in combination with the requested agent AND
5. The patient will NOT be using the requested agent in combination with another GLP-1 receptor agonist (e.g., Saxenda, Wegovy, Zepbound, Mounjaro, Ozempic, Trulicity) AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria

QL

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. If requested agent is Wegovy 0.5 mg or 1 mg AND the intended use is for maintenance therapy, then ALL of the following:
      1. The patient is an adult AND
      2. The patient has an inability to use an FDA labeled strength indicated for maintenance therapy AND
      3. The patient has achieved weight loss on the lower requested strength from baseline (prior to initiation of pharmacotherapy) OR
   2. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   3. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   4. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication

Length of Approval: up to 12 months