- 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, a drug class originally developed to treat type 2 diabetes. Patients receiving GLP-1 analogs sometimes saw significant weight loss, creating interest in using them as an obesity treatment. In 2014, Saxenda® became the first GLP-1 analog approved for weight loss, and in 2021, semaglutide (Wegovy®), became the second GLP-1 analog to receive this indication.
- Liraglutide is also marketed as a diabetes drug under the name Victoza®.
- MECHANISM OF ACTION
- GLP-1 analogs
- Glucagon-like peptide-1 (GLP-1) is a hormone secreted into the bloodstream by special cells in the intestine in response to food consumption. GLP-1 has the following actions: (1) slows gastric emptying; (2) stimulates insulin release and suppresses glucagon secretion in the pancreas; (3) suppresses appetite in the brain. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1, rendering it inactive.
- GLP-1 analogs have a similar structure to endogenous GLP-1, mimicking its actions in the pancreas, stomach, 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)
- WEIGHT LOSS
- The SCALE study detailed below compared Saxenda to placebo for weight loss in nondiabetic adults. Results from a 104-week extension of SCALE that only included prediabetics are also presented. Lastly, a head-to-head trial of Saxenda and Wegovy is reviewed.
- 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 (N=2254 | liraglutide - 1505, placebo 749) 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 trials above, Saxenda enhanced weight loss by 4 - 6% compared to placebo, and the effect persisted for up to 3 years. In the 68-week 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 it was only slightly better than Victoza (difference of 1.3%). [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]
- 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 a year 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 side effects are the most common type of complaint 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
- Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with Saxenda and other GLP-1 analogs. Discontinue Saxenda if a hypersensitivity reaction occurs and use caution in patients with a history of reactions to other GLP-1 analogs.
- Liraglutide antibodies
- Liraglutide has the potential to induce an immune response, which can lead to the production of anti-liraglutide antibodies, and in some cases, antibodies that cross-react with endogenous GLP-1.
- In adult trials, 2.8% of liraglutide-treated patients developed anti-liraglutide antibodies, and 1.2% developed neutralizing antibodies. In a pediatric study, 12% of liraglutide-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, while 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 most cases, symptoms of nausea, vomiting, and/or diarrhea were present. These symptoms are common side effects of liraglutide, and when severe, they can lead to dehydration and worsening kidney function.
- Caution should be used when prescribing liraglutide to patients with renal impairment, and kidney function should be monitored in patients 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 type 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, Saxenda-treated patients had a higher incidence of cholelithiasis (1.5% vs 0.5%) and cholecystitis (0.6% vs 0.2%) than placebo-treated patients. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, even after accounting for the degree of weight loss, gallbladder disease was more common in Saxenda-treated patients.
- If patients experience symptoms of gallbladder disease, appropriate workup should be initiated
- Heart rate increase
- In adult and pediatric trials, Saxenda-treated patients had an average increase in resting heart rate of 2 - 7 bpm compared to placebo. 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 did increases of > 20 bpm (5% vs 2%). These effects may be related to Saxenda-induced dehydration.
- 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 study, 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, with levels ≥ 3 X ULN occurring 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).
- History of serious hypersensitivity reaction to liraglutide or any of the excipients in Saxenda
- 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.
- Liver disease
- Saxenda has not been studied extensively in liver disease. Use caution.
- Diabetics should be aware that Saxenda will likely lower their blood sugars, and adjustments in diabetes medications may be necessary. Diabetics should monitor blood sugars closely when starting Saxenda, particularly if they use insulin or insulin secretagogues (e.g. sulfonylureas, meglitinides).
- Stomach disorders
- Stomach disorders that slow gastric emptying (ex. diabetic gastroparesis) may be worsened by Saxenda. Use caution in affected patients.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Liraglutide (Saxenda®)
- Insulin and insulin secretagogues - when combined with insulin or insulin secretagogues (e.g. sulfonylureas, meglitinides), liraglutide increases the risk of hypoglycemia. Monitor blood sugars closely 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
- Medications are partially digested in the stomach before being emptied into the small intestine, where most drug absorption occurs. GLP-1 analogs slow the process of gastric emptying, potentially altering the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
- 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 multi-dose prefilled 3 ml pen that contains 6 mg/ml of liraglutide for a total of 18 mg/pen
- The pen can be dialed to doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, and 3 mg
- The pens come in packages that contain 3 pens (54 mg total) or 5 pens (90 mg total). The 3-pen package covers the first 4 weeks of titration plus 4 doses of 3 mg. The 5-pen pack covers the first 4 weeks of titration plus 16 doses of 3 mg or 30 days of the 3 mg dose.
- Pens are compatible with NovoFine® and NovoTwist® disposable pen needles up to a length of 8 mm
- 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. Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis.
- 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 have been shown 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)