- ACRONYMS AND DEFINITIONS
- BMI - Body mass index
- 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, are approved for the treatment of type 2 diabetes - see GLP-1 analogs in diabetes
- In diabetes studies, GLP-1 analogs caused a small amount of weight loss. This observation led to the development of Saxenda for weight loss
- Liraglutide is marketed under the name Victoza® for type 2 diabetes treatment
- 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
- GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation including the hypothalamus. In animal studies, peripheral administration of liraglutide resulted in the presence of liraglutide in these regions. The exact mechanism by which liraglutide regulates appetite is unknown.
- FDA-APPROVED INDICATIONS
- Weight loss in adults with BMI ≥ 30
- Weight loss in adults with BMI ≥ 27 in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
- WEIGHT LOSS
- Overview
- The effects of liraglutide on weight loss were studied in the three large trials presented below
| Liraglutide (Lir) vs placebo in a 56-week weight loss trial | ||
|---|---|---|
| Placebo (N=1244) | Lir 3 mg daily (N=2487) | |
| Weight loss (%) (average % change from baseline at 56 weeks) |
3% | 7.4% |
| Weight loss (pounds) (average pounds lost at 56 weeks) |
7 | 17 |
| Liraglutide (Lir) vs placebo for 3 years in prediabetics | ||
|---|---|---|
| Placebo (N=738) | Lir 3 mg daily (N=1472) | |
| Weight loss (%) (average % change from baseline at 3 years) |
1.9% | 6.1% |
| Weight loss lbs (kg) (average pounds lost at 3 years) |
4.4 lbs (2 kg) | 14.3 lbs (6.5 kg) |
| Liraglutide (Lir) vs placebo for 56 weeks in overweight diabetics | |||
|---|---|---|---|
| Placebo (N=212) | Lir 1.8 mg daily (N=211) | Lir 3 mg daily (N=423) | |
| Weight loss (%) (average % change from baseline at 56 weeks) |
2% | 4.7% | 6% |
| Weight loss (pounds) (average pounds lost at 56 weeks) |
4.8 | 11 | 14 |
- Summary
- When prescribing Saxenda for one year, providers can expect the following:
- About 28% of patients will discontinue the drug
- On average, a 233-pound person will lose about 10 pounds more on Saxenda than if they were not taking it
- SIDE EFFECTS
Gastrointestinal (GI) side effects
Overview
- Gastrointestinal side effects are the most common side effects with Saxenda
- GI side effects likely contribute to some degree to Saxenda's weight-loss properties
- Side effects reported in placebo-controlled trials are presented in the table below
| Side effect | Saxenda | Placebo |
|---|---|---|
| Nausea | 39% | 14% |
| Diarrhea | 21% | 10% |
| Constipation | 19.4% | 8.5% |
| Vomiting | 15.7% | 3.9% |
| Upset stomach | 9.6% | 2.7% |
| Abdominal pain | 5.4% | 3.1% |
| GERD | 4.7% | 1.7% |
| Burping | 4.5% | 0.2% |
| Flatulence | 4% | 2.5% |
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 who have had reactions to other GLP-1 analogs.
Liraglutide antibodies
Overview
- Liraglutide has the potential to induce an immune response
- The immune response can lead to the production of antibodies against liraglutide
- In trials, 2.8% of patients treated with liraglutide developed anti-liraglutide antibodies (1505 patients were tested)
- In vitro studies showed that 43% of these antibodies had a neutralizing effect
Summary
- It is not uncommon for injectable biologic drugs to induce antibodies (insulin is known for this)
- The overall significance of this effect with liraglutide is unknown
- Based on available evidence, a small percentage of liraglutide patients (1.2%) may experience a loss of effect if antibodies develop
Pancreatitis
Overview
- Pancreatitis is a painful condition where the pancreas becomes inflamed. Severe pancreatitis can be life-threatening.
- In clinical trials, acute pancreatitis was confirmed in 0.3% of 3291 Saxenda-treated patients and 0.1% of 1843 placebo-treated patients
- The incidence of pancreatitis was too low to determine causality
Summary
- The FDA reviewed a large amount of information regarding GLP-1 analogs and pancreatitis in diabetes trials and came to the conclusion that no definitive link could be proven. See GLP-1 analogs and pancreatitis for more.
Decreased kidney function
Overview
- In patients receiving Saxenda, decreased kidney function has been reported
- The majority of these cases occurred in patients who were experiencing gastrointestinal side effects. GI side effects can lead to dehydration which affects kidney function.
Summary
- Saxenda does not appear to directly affect kidney function
- Saxenda may indirectly affect kidney function if GI side effects lead to dehydration
Thyroid cancer
- In toxicology studies, liraglutide was found to cause malignant and benign thyroid C-cell tumors (also called medullary thyroid cancer) in rats and mice
- It is unknown if liraglutide increases the risk of thyroid cancer in humans
- See GLP-1 analogs and thyroid cancer for more information
Gallbladder disease
- In trials, 1.5% of Saxenda-treated patients reported cholelithiasis vs 0.5% of placebo-treated patients
- In trials, 0.6% of Saxenda-treated patients reported cholecystitis vs 0.2% of placebo-treated patients
- Rapid weight loss can increase the risk of cholelithiasis, however, the risk was still elevated in Saxenda-treated patients after accounting for weight loss
- If symptoms of gallbladder disease develop (e.g. right upper quadrant pain, nausea, vomiting), appropriate workup should be performed
Heart rate increase
- In trials, Saxenda-treated patients had an average increase in resting heart rate of 2 - 3 beats per minute when compared to placebo
- The clinical significance of this effect is unknown
Breast cancer
- In trials, 0.6% of 2379 Saxenda-treated patients developed breast cancer compared to 0.2% of 1300 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 were seen in 5.3% of Saxenda-treated patients and 2.2% of placebo-treated patients
- Lipase levels ≥ 3 X ULN were seen in 2.1% of Saxenda-treated patients and 1% of placebo-treated patients
- See pancreatitis above
Calcitonin increases
- Calcitonin levels ≥ 2 X ULN were seen in 1.2% of Saxenda-treated patients and 0.6% of placebo-treated patients
- Significantly elevated calcitonin levels may be seen in medullary thyroid carcinoma (see thyroid cancer above)
- CONTRAINDICATIONS
- Known hypersensitivity
- Pregnancy
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- PRECAUTIONS
Kidney disease
- Saxenda has not been studied extensively in kidney disease. Use with caution.
- Manufacturer makes no dosage recommendations
Liver disease
- Saxenda has not been studied extensively in liver disease. Use with caution.
- Manufacturer makes no dosage recommendations
Diabetes
- Diabetics should be aware that Saxenda will likely lower their blood sugars and adjustments in diabetes medications may be necessary
- When adding liraglutide to diabetes medications, diabetics should monitor blood sugars closely, particularly when taking medications that can cause hypoglycemia (e.g. sulfonylureas, meglitinides, insulin)
- The manufacturer states that Saxenda should not be used in diabetics who are using insulin
- See GLP-1 analog blood sugar effects for a review of the blood sugar-lowering effects of liraglutide
Stomach disorders
- Stomach disorders that slow gastric emptying (ex. diabetic gastroparesis) may be worsened by Saxenda
- Caution should be used in 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®)
- Diabetes medications - When Saxenda is taken with diabetes medications, the risk for low blood sugar is increased. High-risk medications include sulfonylureas, meglitinides, and insulin. Diabetics should watch their blood sugars closely when starting Saxenda and make adjustments if necessary. See GLP-1 analog blood sugar effects for a review of the blood sugar-lowering effects of liraglutide.
- 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
- Insulin - Saxenda should not be used in diabetics who are using insulin because of the high risk of hypoglycemia
Gastric emptying
Overview
- When a person consumes food or medications, they are partially digested in the stomach
- The stomach then "empties" food and medications into the small intestine
- GLP-1 analogs slow the process of stomach emptying
- Since most medications are absorbed in the small intestine, slowing of stomach emptying by GLP-1 analogs may affect the absorption of some medications
- In many cases, the overall effect on the drug's therapeutic effect is not significant
- The large number of possible interaction has not been studied extensively
- The effect of the medications listed below may be altered by decreased gastric emptying caused by GLP-1 analogs
Antibiotics
- Antibiotics require rapid absorption to achieve their desired therapeutic effect
- GLP-1 analogs may alter their absorption
- Antibiotics should be taken at least 1 hour before GLP-1 analogs
Drugs with a narrow therapeutic index
- Drugs with narrow therapeutic index may be affected by GLP-1 analogs
- Taking these drugs at least 1 hour before GLP-1 analogs may help prevent an interaction
- Examples of drugs with a narrow therapeutic index:
- Carbamazepine (Tegretol®)
- Cyclosporine (Neoral®)
- Digoxin
- Levothyroxine (Synthroid®)
- Lithium
- Phenytoin (Dilantin®)
- Tacrolimus (Prograf®)
- Theophylline (Theo-24®)
- Warfarin (Coumadin®) [9]
Metabolism and clearance
- Saxenda does not undergo significant liver metabolism
- DOSING
- 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
- Dosing
- Saxenda is injected once daily
- 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
| Saxenda titration schedule | |
|---|---|
| Week | Saxenda dose |
| 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 |
|
|
- Other
- Efficacy of doses < 3 mg a day has not been established
- Evaluate weight loss at 16 weeks. Discontinue Saxenda if weight loss is < 4% of baseline weight.
- If 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 above
- Saxenda solution should be clear and colorless without particles. Otherwise, it should be discarded.
- Storage
- 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
- GLP-1 analogs, including Saxenda, are relatively new medications
- Saxenda was FDA-approved in December 2014
- There is no long-term safety information for Saxenda
- BIBLIOGRAPHY
- 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)