- ACRONYMS AND DEFINITIONS
- BMI - Body mass index
- bpm - Beats per minute
- DM - Diabetes Mellitus
- GI - Gastrointestinal
- GLP-1 - Glucagon-Like Peptide-1
- Lir - Liraglutide
- RCT - Randomized controlled trial
- Thyroid C-cell tumor - same as thyroid medullary tumor
- DRUGS IN CLASS
- Saxenda® (liraglutide)
- Saxenda® (liraglutide) is a GLP-1 analog. GLP-1 analogs, including liraglutide, were originally developed to treat type 2 diabetes (see GLP-1 analogs in diabetes), and liraglutide is marketed under the name Victoza® for this purpose.
- During diabetes studies, it was noted that patients treated with GLP-1 analogs also had significant weight loss. This created interest in using them for the sole purpose of treating obesity. In 2014, Saxenda® became the first GLP-1 analog to be approved for weight loss. In 2021, another GLP-1 analog called semaglutide (Wegovy®) was also approved for this purpose.
- The weight-loss version of liraglutide (Saxenda®) differs from the diabetes formulation (Victoza®) in dosing (3 mg daily vs 1.8 mg daily, respectively)
- MECHANISM OF ACTION
- GLP-1 analogs
- GLP-1 stands for "glucagon-like peptide-1." GLP-1 is a hormone secreted into the bloodstream by special cells in the intestine in response to food consumption. In the pancreas, GLP-1 stimulates insulin release and suppresses glucagon secretion. GLP-1 receptors are also found in parts of the brain that regulate appetite and food intake. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1 and makes it inactive.
- GLP-1 analogs have a similar structure to endogenous GLP-1, and they mimic its actions in the pancreas and brain. They have also been modified so that DPP-4 cannot metabolize them.
- FDA-APPROVED INDICATIONS
- Weight loss (adults)
- As an adjunct to diet and exercise for weight loss in adults with a BMI ≥ 30 or ≥ 27 in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
- Weight loss (children ≥ 12 years old)
- As an adjunct to diet and exercise for weight loss in children with body weight > 60 kg (132 lbs) and an initial BMI corresponding to ≥ 30 kg/m2 for adults (obese) by international cutoffs (see Saxenda PI [sec 2.1] for cutoff values)
- WEIGHT LOSS
- In the first two trials below, Saxenda was compared to placebo for weight loss in adults. The first study was a 56-week trial in overweight nondiabetics. The second trial was a 104-week extension of the first study that only included prediabetics. In the third trial, Saxenda went head-to-head with Wegovy, another GLP-1 analog approved for weight loss.
- The SCALE study enrolled 3731 overweight adults who did not have diabetes
Main inclusion criteria
- BMI ≥ 30; or ≥ 27 with dyslipidemia and/or hypertension
- < 5 kg change in body weight in previous 3 months
- History of failed dieting
Main exclusion criteria
- Type 1 or 2 diabetes
- Use of medications that cause weight gain or loss
- Previous GLP-1 analog therapy
- Previous bariatric surgery
- History of pancreatitis
- History of significant psychiatric disorder
- Average age 45 years
- Female sex - 78%
- Average weight - 233 lbs (106 kg)
- Average BMI - 38
Randomized treatment groups (2:1 ratio)
- Group 1 (2487 patients): Liraglutide 3 mg once daily
- Group 2 (1244 patients): Placebo
- Liraglutide was started at 0.6 mg once daily and increased in 0.6 mg increments at weekly intervals to 3 mg
- All patients received counseling on lifestyle modification
Primary outcome: The three prespecified coprimary endpoints, assessed at week 56, were weight change from baseline, the proportion of patients who lost at least 5% of their baseline body weight, and the proportion of patients who lost more than 10% of their baseline body weight
|Duration: 56 weeks|
|Weight loss||18.5 lbs (8.4 kg)||6.2 lbs (2.8 kg)||p<0.001|
|% weight loss||8%||2.6%||p<0.001|
|Loss ≥ 5% body weight||63.2%||27.1%||p<0.001|
|Loss > 10% body weight||33.1%||10.6%||p<0.001|
Findings: In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (
- This study is a substudy of the SCALE study. Patients who were prediabetics at enrollment to the SCALE study were treated for an additional 104 weeks (160 weeks total). The primary outcome of the extension study was average time to diabetes onset.
|Duration: 160 weeks|
|Average time to diabetes onset||99 weeks||87 weeks||p<0.0001|
|Weight loss||14.3 lbs (6.5 kg)||4.4 lbs (2 kg)||p<0.0001|
|% weight loss||6.1%||1.9%||p<0.0001|
|Loss ≥ 5% body weight||49.6%||23.7%||p<0.0001|
|Loss > 10% body weight||24.8%||9.9%||p<0.0001|
Findings: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3.0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes.
- The STEP 8 trial enrolled 338 adults with BMI ≥ 30 or ≥ 27 and 1 or more weight-related comorbidities
Main inclusion criteria
- Adults ≥ 18 years
- BMI ≥ 30 or ≥ 27 with one weight-related condition (OSA, hyperlipidemia, CVD, hypertension)
- ≥ 1 self-reported unsuccessful dietary weight loss effort
Main exclusion criteria
- HgA1C ≥ 6.5%
- Weight change ≥ 5 kg in last 90 days
- Average age 49 years
- Female sex - 78.4%
- Average BMI - 38
- Average weight - 231 lbs (105 kg)
Randomized treatment groups
- Group 1 (126 patients): Wegovy (semaglutide) 2.4 mg once weekly
- Group 2 (127 patients): Saxenda (liraglutide) 3 mg once daily
- Group 3 (85 patients): Placebo
- Patients were randomized 3:1 to Wegovy or matching placebo or 3:1 to Saxenda or matching placebo. Wegovy and Saxenda treatment group assignments were not blinded.
- Wegovy was titrated to 2.4 mg over 16 weeks. A 1.7 mg maintenance dose was permitted if 2.4 mg could not be tolerated
- Saxenda was titrated over 4 weeks. If 3.0 mg dose was not tolerated, treatment could be restarted, with reescalation over 4 weeks.
Primary outcome: Percentage change from baseline in body weight at week 68
|Duration: 68 weeks|
|Primary outcome (% weight loss)||15.8%||6.4%||p<0.001|
|People with ≥ 10% weight loss||71%||26%||p<0.001|
|People with ≥ 20% weight loss||39%||6%||p<0.001|
|Actual weight loss||34 lbs (15.3 kg)||15 lbs (6.8 kg)||diff 8.5, 95%CI[11.2 to 5.7]|
Findings: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.
- In the placebo comparison trials above, Saxenda improved weight loss over placebo by about 4 - 6%, and the effect persisted for up to 3 years. In the 68-week head-to-head trial with Wegovy (STEP 8 trial), Saxenda was clearly inferior to Wegovy with weight loss of 6.4% and 15.8%, respectively.
- Two other studies have shown enhanced weight loss with Saxenda. In the 56-week SCALE Diabetes trial that enrolled overweight diabetics, Saxenda increased weight loss by 4% when compared to placebo, but weight loss was only enhanced by 1.3% compared to Victoza (liraglutide 1.8 mg). [PMID 26284720] In another trial, patients who lost an average of 29 pounds after an 8-week low-calorie diet were randomized to Saxenda or placebo +/- exercise for 1 year. Patients in the Saxenda + exercise group lost an additional 7.5 pounds, whereas patients in the placebo + exercise group gained back 4.4 pounds. [PMID 33951361]
- With the introduction of Wegovy (semaglutide), Saxenda will likely become a second-line choice in patients hoping to lose weight with GLP-1 analogs
- WEIGHT LOSS IN ADOLESCENTS
- The study detailed below compared Saxenda to placebo in overweight adolescents aged 12 - 17 years
- The trial enrolled 251 obese adolescents aged 12 - 17 years
Main inclusion criteria
- 12 - 17 years old
- BMI ≥ 30
- No weight change ≥ 11 lbs within 90 days
- Poor response to lifestyle therapy
Main exclusion criteria
- Body weight ≤ 132 lbs (60 kg)
- Type 1 diabetes
- Average age 14.5 years
- Female sex - 75%
- Average body weight - 222 lbs (101 kg)
- Average BMI - 35
- Diabetes or prediabetes - 26%
Randomized treatment groups
- Group 1 (125 patients): Liraglutide 3 mg subcutaneously once daily for 56 weeks
- Group 2 (126 patients): Placebo
- Dosing was started at 0.6 mg/day and titrated on a weekly basis to 3 mg/day (82% of patients in the liraglutide group achieved 3 mg/day)
- There was a 12-week run-in period where all participants received lifestyle therapy
- At the end of the 56 week treatment period, there was a 26-week follow-up period without treatment
Primary outcome: Change from baseline in the BMI standard-deviation score at week 56. The BMI standard-deviation score is a measure of the number of standard deviations from the population mean BMI, matched for age and sex
|Duration: 56 weeks|
|Primary outcome||-0.23||0||difference −0.22 (−0.37 to −0.08)|
|BMI (absolute change)||-1.39||+0.19||difference −1.58 (−2.47 to −0.69)|
|Body weight||-4.97 lbs (2.26 kg)||+4.95 lbs (2.25 kgs)||difference −9.9 (−15.7 to −4.0)|
Findings: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy.
- Saxenda caused modest weight loss over 56 weeks in obese adolescents. On average, an adolescent weighing 222 pounds can expect to lose about 5 lbs over 56 weeks with liraglutide as opposed to gaining 5 lbs without it. If the drug is stopped, the weight will likely be gained back within 26 weeks. Gastrointestinal side effects are common.
- SIDE EFFECTS
- Gastrointestinal (GI) side effects
- Gastrointestinal complaints are the most common type of side effect seen with Saxenda. The table below gives the incidence of GI side effects from Saxenda trials. To minimize the risk, Saxenda should be started at low doses and titrated gradually.
- Saxenda by itself does not pose a significant risk of hypoglycemia. When combined with diabetes medications, particularly insulin and insulin secretagogues, the risk of hypoglycemia is increased.
- In the SCALE Study that only enrolled nondiabetics, hypoglycemia was reported in 1.3% of Saxenda-treated patients and 1% of placebo-treated patients.
- Patients who are taking concomitant diabetes medications should monitor their blood sugars appropriately and be prepared to treat hypoglycemia if needed (see hypoglycemia for more)
- Injection site reactions
- In trials, injection site reactions including redness, itching, and rash were reported in 14% of Saxenda-treated patients and 10.5% of placebo-treated patients
- Hypersensitivity reactions
- Hypersensitivity reactions including anaphylaxis and angioedema have been reported with other GLP-1 analogs. Use caution in patients with a history of reactions to GLP-1 analogs.
- Liraglutide antibodies
- Liraglutide has the potential to induce an immune response. The immune response can lead to the production of antibodies against liraglutide, and in some cases, the antibodies cross-react with endogenous GLP-1.
- In adult trials, 2.8% of Saxenda-treated patients developed anti-liraglutide antibodies, and 1.2% developed neutralizing antibodies. In a pediatric trial, 12% of Saxenda-treated patients developed anti-liraglutide antibodies, and 0.9% had antibodies that cross-reacted with endogenous GLP-1. The presence of antibodies may be associated with a higher risk of injection site reactions. Their effect on efficacy is unknown.
- Acute pancreatitis has been reported in patients receiving GLP-1 analogs, including liraglutide. In trials, acute pancreatitis occurred in 0.3% of Saxenda-treated patients and 0.1% of placebo-treated patients. If symptoms of pancreatitis occur (e.g. abdominal pain, nausea, vomiting), discontinue Saxenda and initiate appropriate care. Saxenda has not been studied in patients with a history of pancreatitis.
- Decreased kidney function
- There have been case reports of decreased kidney function in patients receiving liraglutide. In a majority of the cases, symptoms of nausea, vomiting, and/or diarrhea were present. These symptoms are common side effects of liraglutide, and they can lead to dehydration and worsening kidney function.
- Caution should be used when prescribing liraglutide to patients with renal impairment. Monitor renal function in patients who are experiencing significant gastrointestinal reactions.
- Thyroid cancer
- In toxicology studies, a dose-dependent and treatment-duration-dependent increase in the incidence of malignant and benign thyroid medullary tumors (C-cell tumors) was observed in rats and mice receiving clinically relevant doses of liraglutide. This prompted the FDA to place a boxed warning about medullary thyroid cancer on liraglutide. It is unknown if liraglutide increases the risk of tumors in humans as the incidence of these events is too low to establish causality.
- Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, a condition that increases the risk for medullary thyroid cancer. Patients should be aware of the potential risk and report any thyroid symptoms if they occur. Medullary thyroid cancer usually causes elevations in calcitonin levels above 50 ng/L.
- Gallbladder disease
- In trials, cholelithiasis occurred in more patients treated with Saxenda than placebo (1.5% vs 0.5%), as did cholecystitis (0.6% vs 0.2%). Substantial or rapid weight loss can increase the risk of cholelithiasis; however, even after accounting for the degree of weight loss, Saxenda-treated patients still had a higher incidence of acute gallbladder disease.
- If patients experience symptoms of gallbladder disease, appropriate workup should be initiated
- Heart rate increase
- In adult trials, Saxenda-treated patients had an average increase in resting heart rate of 2 - 3 bpm when compared to placebo. In a pediatric trial, Saxenda-treated patients had an average increase in resting heart rate of 3 - 7 bpm. In adults, maximum increases of > 10 bpm from baseline at two consecutive visits occurred in more Saxenda-treated patients than placebo-treated patients (34% vs 19%), as were increases of > 20 bpm (5% vs 2%).
- Monitor heart rates in Saxenda-treated patients and discontinue therapy if sustained increases occur
- Suicidal behavior and ideation
- In adult trials, 0.3% of Saxenda-treated patients reported suicidal ideation compared to 0.1% of placebo-treated patients. In a pediatric trial, 1 (0.8%) Saxenda-treated patient died by suicide.
- Monitor patients for depression, suicidal thoughts, or other unusual changes in mood. Avoid use in patients with a history of suicidal behavior, and discontinue therapy in patients who develop suicidal ideation.
- Breast cancer
- In trials, 0.6% of Saxenda-treated patients developed breast cancer compared to 0.2% of placebo-treated patients. The incidence of breast cancer was too low to determine causality.
- An observational study published in the BMJ in 2016 found no increased risk of breast cancer among GLP-1 analog users when compared to DPP-4 inhibitor users (HR 1.40 (95%CI [0.91 to 2.16]). The average follow-up in the study was 3.5 years. [PMID 27797785]
- Lipase increases
- In trials, lipase increases occurred in 5.3% of Saxenda-treated patients and 2.2% of placebo-treated patients, and levels ≥ 3 X ULN occurred in 2.1% and 1%, respectively. The significance of these effects is unknown.
- Calcitonin increases
- In trials, calcitonin levels ≥ 2 X ULN were seen in 1.2% of Saxenda-treated patients and 0.6% of placebo-treated patients. The significance of this effect is unknown. Calcitonin levels > 50 ng/L may be seen in medullary thyroid carcinoma (see thyroid cancer above).
- Known hypersensitivity
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- Kidney disease
- Saxenda has not been studied extensively in kidney disease. Use caution.
- Manufacturer makes no dosage recommendations
- Liver disease
- Saxenda has not been studied extensively in liver disease. Use caution.
- Manufacturer makes no dosage recommendations
- Diabetics should be aware that Saxenda will likely lower their blood sugars and adjustments in diabetes medications may be necessary. When adding Saxenda to diabetes medications, diabetics should monitor blood sugars closely, particularly when taking medications that can cause hypoglycemia (e.g. sulfonylureas, meglitinides, insulin).
- Stomach disorders
- Stomach disorders that slow gastric emptying (ex. diabetic gastroparesis) may be worsened by Saxenda. Use caution when prescribing to these patients.
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Liraglutide (Saxenda®)
- Insulin and insulin secretagogues - When liraglutide is used with insulin and insulin secretagogues (e.g. sulfonylureas, meglitinides), the risk for hypoglycemia is increased. Monitor blood sugars closely when combining and adjust medications as needed.
- Drugs affected by decreased gastric emptying - see gastric emptying below
- Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of GLP-1 analogs
- Drugs affected by gastric emptying
- After consumption, food and medications are partially digested in the stomach. The stomach then "empties" them into the small intestine. GLP-1 analogs slow the process of stomach emptying, and since most medications are absorbed in the small intestine, this may alter the absorption of some drugs. In many cases, the overall effect on the drug's therapeutic action is not significant, but many drugs have not been studied extensively.
- The medications listed below could potentially be affected by delayed gastric emptying
- Antibiotics require rapid absorption to achieve their desired therapeutic effect
- Drugs with a narrow therapeutic index
- Drugs with narrow therapeutic index may have their steady-state altered by delayed gastric emptying
- Metabolism and clearance
- Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination
- Dosage forms
- Saxenda comes in a 3ml pen that contains 6 mg/ml of liraglutide
- The pen can be dialed to doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3 mg
- The pens come in packages that contain 3 pens (18 doses at 3 mg) or 5 pens (30 doses at 3 mg)
- Pens are compatible with NovoFine® and NovoTwist® disposable pen needles up to a length of 8mm
- No generic. Cost > $150/month.
- Dosing (adults and children ≥ 12 years old)
- Recommended titration schedule and dosing are provided in the table below
- Saxenda is injected subcutaneously in the abdomen, thigh, or upper arm
- Saxenda can be injected at any time during the day without regard to meals or food
- Adults: Efficacy of doses < 3 mg a day has not been established. If patient cannot tolerate 3 mg dose, discontinue Saxenda. Evaluate weight loss at 16 weeks after initiation. Discontinue Saxenda if weight loss is < 4% of baseline weight.
- Children: Recommended maintenance dose is 3 mg once daily. If patient cannot tolerate 3 mg dose, 2.4 mg dose may be used. If patient cannot tolerate 2.4 mg dose, discontinue Saxenda. Evaluate change in BMI after 12 weeks on the maintenance dose. Discontinue Saxenda if the patient has not had a reduction in BMI of at least 1% from baseline.
- Missed doses: If a dose is missed, resume as prescribed at the next scheduled dose. If more than 3 days elapse since the last dose, restart Saxenda at 0.6 mg and use the titration schedule below.
|Saxenda titration schedule for adults and children ≥ 12 years old|
|1||0.6 mg once daily|
|2||1.2 mg once daily|
|3||1.8 mg once daily|
|4||2.4 mg once daily|
|5 and on||3 mg once daily|
- Unopened pens
- Store in refrigerator
- Good until expiration date
- Punctured/used pens
- May be stored in refrigerator or room temperature
- Good for 30 days
- LONG-TERM SAFETY
- The first GLP-1 analog (exenatide) was FDA-approved in 2005. When used appropriately, GLP-1 analogs appear to be safe.
- 1 - Saxenda PI
- 2 - Saxenda NDA
- 3 - PMID 26284720 - SCALES study
- 4 - PMID 28237263 - 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet (2017)