Safety profile for once-weekly Ozempic® (semaglutide) injection
The safety of Ozempic® was evaluated across clinical trials1,a
Incidence of severe hypoglycemia was ≤1.5% across placebo-controlled trials, <1% for Ozempic® 1 mg and Ozempic® 2 mg in SUSTAIN FORTE1,2,a,b
- Patients receiving Ozempic® in combination with an insulin secretagogue (eg, sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia
- When initiating Ozempic®, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia
Rates of GI symptoms across placebo-controlled trials1 with Ozempic®
- The most common adverse reactions, reported in ≥5% of patients treated with Ozempic®, are nausea, vomiting, diarrhea, abdominal pain, and constipation
- The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation
- In placebo-controlled trials, discontinuation due to GI adverse reactions was 3.1% and 3.8% for the Ozempic® 0.5 mg and 1 mg dose, respectively, compared with 0.4% for placebo
No new safety signals identified with Ozempic® 2 mg dose1
- In a 40-week, randomized, active-controlled trial with 959 patients treated with Ozempic® 1 mg or Ozempic® 2 mg once weekly as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified1,2
- In the trial with Ozempic® 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving Ozempic® 2 mg (34.0%) vs Ozempic® 1 mg (30.8%)1
- SUSTAIN FORTE: Results are from a 40-week, randomized, active-controlled trial in 959 adult patients with type 2 diabetes on metformin with or without a sulfonylurea, comparing Ozempic® 1 mg with 2 mg.1,2
There were no new serious or severe adverse reactions identified in the FLOW trial.
- In the FLOW trial in patients with type 2 diabetes and chronic kidney disease, safety data collection was limited to serious adverse events and selected predefined categories of adverse events regardless of seriousness1
aIn addition to the CVOT (SUSTAIN 6), glycemic control trials (SUSTAIN 1 through 5), and SUSTAIN FORTE, 2 Japanese trials are incorporated into the pool of safety data within the FDA-approved label. These trials evaluated the use of Ozempic® as monotherapy and add-on therapy to oral medications or insulin. CV safety was assessed in SUSTAIN 6. Occurrence of adverse reactions was evaluated in SUSTAIN 1-5 and 2 Japanese trials.
bSevere hypoglycemia adverse reactions are episodes requiring the assistance of another person.
GI=gastrointestinal; CVOT=cardiovascular outcomes trial.
Adverse events ≥5% in SUSTAIN 4
AEs occurring in ≥5% of participants treated with Ozempic® in SUSTAIN 43
SUSTAIN 4 was not designed to evaluate relative safety between Ozempic® and Lantus®
AE=adverse events; GI=gastrointestinal.
- In placebo-controlled trials, the most common adverse reactions reported in ≥5% of patients treated with Ozempic® are nausea, vomiting, diarrhea, abdominal pain, and constipation1
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice1
- Comparator adverse event rates are not an adequate basis for comparison of safety between products
- Incidence of severe hypoglycemia was ≤1.5% across all placebo-controlled trials1
- Incidence of severe hypoglycemia or blood glucose-confirmed hypoglycemia (% of patients) was 4% with Ozempic® 0.5 mg, 6% with Ozempic® 1 mg, and 11% with Lantus®3,a
aDefined as an event requiring assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions or blood glucose–confirmed symptomatic hypoglycemia (plasma glucose ≤3.1 mmol/L [56 mg/dL]).3
Results are from a 30-week, randomized, open-label, active-controlled trial in 1082 adult, insulin-naïve patients with type 2 diabetes on metformin ± sulfonylurea.1,3
Adverse events ≥5% in SUSTAIN 5
AEs occurring in ≥5% of participants treated with Ozempic® in SUSTAIN 54,5
AE=adverse events; GI=gastrointestinal; MET=metformin.
- Incidence of severe hypoglycemia was ≤1.5% across all placebo-controlled trials1
- Incidence of severe hypoglycemia or blood glucose-confirmed hypoglycemia (% of patients) was6:
- 8.3% with Ozempic® 0.5 mg + basal insulin ± metformin
- 10.7% with Ozempic® 1 mg + basal insulin ± metformin
- 5.3% with placebo + basal insulin ± metformin
- Patients receiving Ozempic® in combination with an insulin secretagogue (eg, sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia
Results are from a 30-week, randomized, double-blind, placebo-controlled, parallel-group trial in 397 adult patients with type 2 diabetes evaluating the addition of Ozempic® 0.5 mg and Ozempic® 1 mg to basal insulin ± metformin.1
Adverse events in SUSTAIN 66
- Treatment discontinuation due to adverse events was more frequent in the Ozempic® group than in the placebo group6
- GI disorders were more frequent in the Ozempic® group than in the placebo group6
dThis category was defined according to the system organ class in MedDRA.6
eThis category of hypoglycemic event includes episodes of severe hypoglycemia (defined according the the American Diabetes Association criteria) or symptomatic hypoglycemia as confirmed on plasma glucose testing (<56 mg/dL [3.1 mmoL/l])6
fThis category was based on the group pf preferred terms in MedDRA.6
gThis event was confirmed by the event adjudication committee.6
Adverse events ≥5% in SUSTAIN 7
AEs occurring in ≥5% of participants treated with Ozempic® in SUSTAIN 77
SUSTAIN 7 was not designed to evaluate relative safety between Ozempic® and Trulicity®
- In placebo-controlled trials, the most common adverse reactions reported in ≥5% of patients treated with Ozempic® are nausea, vomiting, diarrhea, abdominal pain, and constipation1
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice1
- Comparator adverse event rates are not an adequate basis for comparison of safety between products
Results are from a 40-week, randomized, open-label, active-controlled trial in 1201 adult patients with type 2 diabetes on metformin comparing Ozempic® 0.5 mg with Trulicity® 0.75 mg and Ozempic® 1 mg with Trulicity® 1.5 mg.7
Adverse events ≥5% in SUSTAIN FORTE
AEs occurring in ≥5% of participants treated with Ozempic® 1 mg and 2 mg in SUSTAIN FORTE2
- In placebo-controlled trials, the most common adverse reactions reported in ≥5% of patients treated with Ozempic® are nausea, vomiting, diarrhea, abdominal pain, and constipation1
- No new safety signals were identified. Gastrointestinal adverse reactions occurred more frequently among patients receiving Ozempic® 2 mg (34.0%) vs Ozempic® 1 mg (30.8%)1
- Incidence of severe hypoglycemia (Level 3) was less than 1% for Ozempic® 1 mg and Ozempic® 2 mg in SUSTAIN FORTE trial4
Safety results are from a 40-week, randomized, active-controlled, parallel-group trial in 961 adult patients with type 2 diabetes in need of treatment intensification comparing Ozempic® 2 mg with Ozempic® 1 mg.1,2
Adverse events ≥5% in FLOW
Prespecified adverse events of special interest8
- In FLOW, the most common adverse event of special interest was diabetic retinopathy8
- The incidence of serious adverse events related to a cardiovascular disorder was approximately 15% with Ozempic® and 18% with placebo8
- In the FLOW trial, safety data collection was limited to serious adverse events and selected predefined categories of adverse events regardless of seriousness. There were no new serious or severe adverse reactions identified in this trial1
hData were from an additional data-collection form; data for all other prespecified events of special interest were collected by means of a Medical Dictionary for Regulatory Activities search.8
STUDY DESIGNS
SUSTAIN 4: Head-to-head vs Lantus® (insulin glargine U-100)1,3
Study design: 30-week, randomized, open-label, active-controlled, parallel-group, multinational, multicenter trial to compare the efficacy and safety of Ozempic® vs insulin glargine U-100.
Patients: A total of 1089 insulin-naïve adult patients with type 2 diabetes inadequately controlled on metformin alone (48%) or in combination with a sulfonylurea (51%) were randomized to receive once-weekly Ozempic® 0.5 mg (n=362), once-weekly Ozempic® 1 mg (n=360), or once-daily insulin glargine U-100 (n=360). Patients assigned to insulin glargine had a baseline mean A1C of 8.1% and were started on a dose of 10 units once daily. Insulin glargine dose adjustments occurred throughout the trial period based on self-measured fasting plasma glucose before breakfast, targeting 71 to <100 mg/dL. In addition, investigators could titrate insulin glargine based on their discretion between study visits. Twenty-six percent of patients had been titrated to goal by the primary endpoint at Week 30, at which time the mean daily insulin dose was 29 units per day.
Primary endpoint: Mean change in A1C from baseline at Week 30.
Secondary endpoints: Mean change in body weight from baseline at Week 30; proportion of patients achieving A1C <7% at Week 30.
SUSTAIN 5: As add-on to basal insulin vs placebo4
Study design: 30-week, randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter trial to compare the efficacy and safety of Ozempic® in combination with basal insulin vs volume-matched placebo in combination with basal insulin.
Patients: A total of 397 adult patients inadequately controlled on basal insulin with or without metformin were randomized to once-weekly Ozempic® 0.5 mg (n=132), Ozempic® 1 mg (n=131), or placebo (n=133). Randomization was stratified according to A1C at screening. Patients with A1C ≤8% at screening reduced the insulin dose by 20% at the start of the trial to reduce the risk of hypoglycemia.
Primary endpoint: Mean change in A1C from baseline at Week 30.
Secondary endpoints: Mean change in body weight from baseline at Week 30; proportion of patients achieving A1C <7% at Week 30; change in mean fasting plasma glucose (FPG) at Week 30.
SUSTAIN 6: Cardiovascular outcomes trial6
Study design: 2-year, randomized, multicenter, multinational, placebo-controlled, double-blind cardiovascular outcomes trial designed to assess noninferiority of Ozempic® vs placebo, both in addition to standard of care, for time to first MACE using a risk margin of 1.3.
Patients: A total of 3297 adult patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to once-weekly Ozempic® 0.5 mg (n=826), Ozempic® 1 mg (n=822), or placebo (n=1649), all in addition to standard of care treatments for diabetes and CVD such as oral antidiabetic treatments, insulin, antihypertensives, diuretics, lipid-lowering therapies, and antithrombotic medications at investigator discretion.
Primary composite endpoint: Time from randomization to first occurrence of a 3-part composite MACE, defined as CV death, nonfatal myocardial infarction, or nonfatal stroke.
Secondary endpoints: Time from randomization to event onset for each of the following components of the 3-part composite MACE: CV death, nonfatal myocardial infarction, and nonfatal stroke.
SUSTAIN 7: Head-to-head vs Trulicity® (dulaglutide)6
Study design: 40-week, multinational, multicenter, randomized, open-label, 4-armed, pairwise, active-controlled, parallel-group trial to compare the efficacy and safety of Ozempic® vs dulaglutide.
Patients: A total of 1201 adult patients with type 2 diabetes inadequately controlled on metformin were randomized to receive Ozempic® 0.5 mg (n=301), Ozempic® 1 mg (n=300), dulaglutide 0.75 mg (n=299), or dulaglutide 1.5 mg (n=299) once weekly.
Primary endpoint: Mean change in A1C from baseline at Week 40.
Secondary endpoints: Mean change in body weight from baseline at Week 40; proportion of patients achieving A1C <7% at Week 40.
SUSTAIN FORTE: Ozempic® 1 mg vs 2 mg2
Study design: 40-week, randomized, active-controlled, parallel-group, double-blind, phase 3B efficacy and safety trial of Ozempic® 2 mg vs Ozempic® 1 mg in patients with type 2 diabetes in need of treatment intensification.
Patients: A total of 961 adult patients with inadequately controlled type 2 diabetes (A1C 8.0%-10.0%) on metformin with or without a sulfonylurea were randomized 1:1 to 2.0 mg (n=480) or 1.0 mg (n=481) of once-weekly Ozempic®.
Primary endpoint: Mean change in A1C from baseline at Week 40.
Secondary endpoints: Mean change in body weight from baseline at Week 40; proportion of patients achieving A1C <7.0% at Week 40.
FLOW: Kidney outcomes trial1,8
Study design: A randomized, double-blind, placebo-controlled, event-driven trial in adults with type 2 diabetes and chronic kidney disease. Median duration of follow-up was 41 months.
Patients: A total of 3533 adult patients with a mean eGFR of 47 mL/min/1.73 m2 (11% of patients having an eGFR <30 mL/min/1.73 m2, and median UACR 568 mg/g with 69% of patients with UACR >300 mg/g at baseline) were randomized 1:1 to receive Ozempic® 1 mg (n=1767) or placebo (n=1766) once-weekly, both in addition to standard-of-care treatments, including a maximum tolerated labeled dose of a renin-angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment was contraindicated or not tolerated. At baseline, 95% of patients were treated with an ACE inhibitor or ARB, 16% were on sodium-glucose co-transporter 2 (SGLT-2) inhibitors, 76% were on a statin, and 50% were on an antiplatelet agent.
Primary composite endpoint: Time to first occurrence of ≥50% sustained (≥28 days) eGFR decline, kidney failure (sustained eGFR <15 mL/min/1.73 m2, or initiation of long-term dialysis or kidney transplant), or renal or CV death.
Secondary confirmatory endpoints: Total eGFR slope (the annual rate of change in eGFR); MACE (a composite of nonfatal myocardial infarction, nonfatal stroke, and death from CV causes), assessed in a time-to-first-event analysis; and death from any cause.
More ways to help your patients with T2D
Ozempic® has proven glycemic control1
View A1C Results »
Once-weekly dosing
Start your patients »
Important Safety Information for Ozempic® (semaglutide) injection
WARNING: RISK OF THYROID C-CELL TUMORS
- In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Ozempic® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined
- Ozempic® 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 for MTC with the use of Ozempic® and inform them of symptoms of thyroid tumors (eg, 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 Ozempic®
Indications and Usage
Ozempic® (semaglutide) injection 0.5 mg, 1 mg, or 2 mg is indicated:
- as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
- to reduce the risk of major adverse cardiovascular (CV) events (CV death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes and established CV disease
- to reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease
Important Safety Information cont.
Contraindications
- Ozempic® is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with a hypersensitivity reaction to semaglutide or to any of the excipients in Ozempic®. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with Ozempic®
Warnings and Precautions
- Risk of Thyroid C-Cell Tumors: Patients should be further evaluated if serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging
- Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including semaglutide. Observe patients carefully for signs and symptoms of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back with or without vomiting). If pancreatitis is suspected, discontinue Ozempic® and initiate appropriate management
- Diabetic Retinopathy Complications: In a 2-year trial involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with Ozempic® (3.0%) compared with placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline than among patients without a known history of diabetic retinopathy.
Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy - Never Share an Ozempic® Pen Between Patients: Ozempic® pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens
- Hypoglycemia: Patients receiving Ozempic® in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia
- Acute Kidney Injury Due to Volume Depletion: There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with semaglutide. The majority of reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea. Monitor renal function in patients reporting adverse reactions to Ozempic® that could lead to volume depletion, especially during dosage initiation and escalation
- Severe Gastrointestinal Adverse Reactions: Use of Ozempic® has been associated with gastrointestinal adverse reactions, sometimes severe. In Ozempic® clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving Ozempic® (0.5 mg 0.4%, 1 mg 0.8%) than placebo (0%). Ozempic® is not recommended in patients with severe gastroparesis
- Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with Ozempic®. If hypersensitivity reactions occur, discontinue use of Ozempic®; treat promptly per standard of care, and monitor until signs and symptoms resolve. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist
- Acute Gallbladder Disease: Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients treated with Ozempic® 0.5 mg and 1 mg, respectively, and not reported in placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated
- Pulmonary Aspiration During General Anesthesia or Deep Sedation: Ozempic® delays gastric emptying. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking Ozempic®
Adverse Reactions
- The most common adverse reactions, reported in ≥5% of patients treated with Ozempic® are nausea, vomiting, diarrhea, abdominal pain, and constipation
Drug Interactions
- When initiating Ozempic®, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia
- Ozempic® causes a delay of gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications, so caution should be exercised
Use in Specific Populations
- There are limited data with semaglutide use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Discontinue Ozempic® in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide
Please click here for Ozempic® Prescribing Information, including Boxed Warning.
References:
- Ozempic® [package insert]. Plainsboro, NJ: Novo Nordisk Inc.
- Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 2021;9(9):563-574.
- Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naïve patients with type 2 diabetes (SUSTAIN 4): a randomized, open-label, parallel-group, multicenter, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017:5(5):355-366.
- Rodbard HW, Lingvay I, Reed J, et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomised, controlled trial. J Clin Endocrinol Metab. 2018;103(6):2291-2301.
- Data on file. Novo Nordisk Inc., Plainsboro, NJ.
- Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. Supplementary appendix. N Engl J Med. 2016;375(19):1834-1844.
- Pratley RE, Aroda VR, Lingvay I, et al. on behalf of the SUSTAIN 7 investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275-286.
- Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 Diabetes. N Engl J Med. 2024;391:109-121.