In adult patients with type 2 diabetes (T2D) and established CVD,
for the composite primary endpoint
After 2 years, Ozempic® significantly reduced the risk of MACE (CV death, nonfatal MI, or nonfatal stroke)1,a
aResults apply to Ozempic® 0.5 mg and 1 mg plus standard of care vs placebo plus standard of care.
CV=cardiovascular; CVD=cardiovascular disease; MACE=major adverse cardiovascular event; MI=myocardial infarction.
Atherosclerotic cardiovascular disease is the #1 cause of death
and disability in patients with T2D2
bBased on a retrospective cohort study using claims to identify adults with (n=379,003) and without (n=9,018,082) T2D living in Ontario, Canada, on or before April 1, 1994. Individuals were followed up to record CVD events until March 31, 2000.5
cPatients aged 50 years with T2D and a history of MI and stroke at baseline.4
dAn analysis of individual patient data from the Emerging Risk Factors Collaboration (n=689,300; years of baseline surveys: 1960-2007) and the UK Biobank, a prospective cohort study, (n=499,808; years of baseline surveys: 2006-2010). Patient-level data were analyzed to determine the associations of cardiometabolic multimorbidity with mortality and reductions in life expectancy. Cumulative survival was estimated by applying calculated age-specific hazard ratios for mortality to contemporary United States age-specific death rates.3,4
T2D=type 2 diabetes.
eStandard of care included, but was not limited to, oral antidiabetic treatments, insulin, antihypertensives, diuretics, lipid-lowering therapies, and antithrombotic medications.1
fResults apply to Ozempic® 0.5 mg and 1 mg plus standard of care vs placebo plus standard of care.6
gEstimated cumulative risk of MACE at Week 104 was 6.2% with Ozempic® 0.5 mg and 1 mg and 8.4% with placebo.7
ARR=absolute risk reduction; CI=confidence interval; NNT=number needed to treat; RRR=relative risk reduction.
SUSTAIN 6: cardiovascular outcomes 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 1.3.6,8
Additional SUSTAIN 6 study information
Patients:
32976
Inclusion criteria:
A1C ≥7%
Previously on 0 to 2 OADs ± basal or premixed insulin
≥50 years of age and established CVDh
OR
≥60 years of age with at least 1 CV risk factori
Treatment duration: 2 yearsj
Treatment duration: 2 yearsr
Treatment duration: 2 yearsj
Primary composite outcome6,k
Time from randomization to first occurrence of MACE:
CV death
Nonfatal
MI
Nonfatal
stroke
hEstablished CV disease (previous CV, cerebrovascular, or peripheral vascular disease) or chronic heart failure (New York Heart Association class II or III) or chronic kidney disease stage 3 or higher.6
iDefined as persistent microalbuminuria (30-299 mg/g) or proteinuria, hypertension and left ventricular hypertrophy by electrocardiogram or imaging, left ventricular systolic or diastolic dysfunction by imaging, or ankle/brachial index <0.9 of those in the trial.8
jTrial consisted of 104 weeks of treatment (including a 4- to 8-week dose escalation period), with a subsequent 5-week follow-up period.6
kFor the primary analysis, a Cox proportional-hazards model was used to test for noninferiority of Ozempic® to placebo for time to first MACE using a risk margin of 1.3.6,9
CV=cardiovascular; CVD=cardiovascular disease; MACE=major adverse cardiovascular event; MI=myocardial infarction; OAD=oral antidiabetic drug.
At baseline, 83% of patients had established CVD6,l,m
lPrior CV disease was defined as age ≥60 years with at least 1 CV risk factor (persistent microalbuminuria [30-299 mg/g] or proteinuria, hypertension and left ventricular hypertrophy by electrocardiogram or imaging, left ventricular systolic or diastolic dysfunction by imaging, or ankle/brachial index <0.9) or age ≥50 years with established CVD (previous CV, cerebrovascular, or peripheral vascular disease; chronic heart failure [New York Heart Association class II of III); or chronic kidney disease of stage 3 or higher).6,8
mIn total, 1940 patients (58.8%) had established CV disease without CKD, 353 (10.7%) had CKD only, and 442 (13.4%) had both CV disease and CKD; 562 patients (17%) had CV risk factors without established CV disease or CKD. In the trial, 453 patients (13.7%) had peripheral artery disease.6
BMI=body mass index; CKD=chronic kidney disease.
At baseline, 98% of patients were receiving CV medications6,8
nHistory at baseline among subjects enrolled in the trial (Ozempic® and placebo groups).
oCompromised of asymptomatic (silent) cardiac ischemia (8.6%), stable angina pectoris (14.6%), unstable angina (7.3%), non-ST-segment elevation (11%), ST-segment elevation MI (2.1%) and unknown (6.7%).7
pThe ACC defines ASCVD as: a history of an acute coronary syndrome or myocardial infarction, stable or unstable angina, coronary heart disease with or without revascularization, other arterial revascularization, stroke, or peripheral artery disease assumed to be atherosclerotic in origin.10
ACC=American College of Cardiology; ACE=angiotensin-converting enzyme; ASCVD=atherosclerotic cardiovascular disease; PAD=peripheral artery disease.
Ozempic®: significant reduction in risk of MACE,
driven by rate of nonfatal stroke1,6
In adult patients with T2D and established CVD, when added to standard of care for the composite
primary endpoint after 2 years vs placebo plus standard of careu
This study was not powered to detect a difference in the individual endpoints of the composite MACE. Absolute rates for the combined endpoint of “fatal or nonfatal stroke”: 1.8% (n=30 of 1648) with Ozempic® and 2.8% (n=46 of 1649) with placebo. HR, 0.65 (95% CI, 0.41-1.03); P=NS. There was no significant change in the rate of nonfatal MI or CV death.
Overall MACE occurred in 108 patients of 1648 (6.6%) on Ozempic® (0.5 mg and 1 mg) and 146 patients of 1649 (8.9%) on placebo (HR, 0.74 [95% CI, 0.58-0.95] P<0.001 for noninferiority, P=0.02 for superiority, not prespecified); nonfatal stroke occurred in 27 patients (1.6%) on Ozempic® and 44 patients (2.7%) on placebo; nonfatal Ml occurred in 47 patients (2.9%) on Ozempic® and 64 patients (3.9%) on placebo; CV death occurred in 44 patients (2.7%) on Ozempic® and 46 patients (2.8%) on placebo.6
uStandard of care included, but was not limited to, oral antidiabetic treatments, insulin, antihypertensives, diuretics, lipid-lowering therapies, and antithrombotic medications.6
vResults apply to Ozempic® 0.5 mg and 1 mg plus standard of care vs placebo plus standard of care.
wHazard ratio vs placebo (95% CI). Median study observation time of 2.1 years. Cox proportional-hazards models with treatment as fixed factor and stratified by evidence of cardiovascular disease, insulin treatment, and renal impairment. P values other than for the primary hypothesis (noninferiority) are unadjusted for multiplicity and test null hypotheses of no difference.6,8
xP value is not adjusted for multiplicity and tests null hypotheses of no difference (post hoc).6,8
yThe primary endpoint in the SUSTAIN 6 CVOT was time to first occurrence of a 3-part composite MACE that included CV death, nonfatal MI, or nonfatal stroke.1
HR=hazard ratio; NS=nonsignificant; SOC=standard of care.
WHAT A CARDIOLOGIST IS SAYING ABOUT OZEMPIC®
"As a cardiologist, you either prescribe or recommend to your colleagues a medication with proven CVD benefit and label indication for patients with T2D and established CVD. So you have to know about Ozempic®."
DR JOSHUA STOLKER | CARDIOLOGIST
A paradigm shift in the management of CV risk in patients with T2D and established atherosclerotic cardiovascular disease10
Major medical societies support use of GLP-1 RAs with proven CVD benefit (label indication)10-14,q
American Diabetes Association
American Association of Clinical Endocrinology
American College of Cardiology
American Heart Association
American Stroke Association
A division of the American Heart Association
In patients with T2D and established atherosclerotic cardiovascular disease,r the use of a GLP-1 RA or SGLT-2i with proven CVD benefit is recommended independently of baseline A1C, individual A1C target, or metformin use10,13,15,s
In addition, in patients with an ischemic stroke or TIA and T2D, treatment of diabetes should include glucose-lowering agents with proven CV benefits to reduce the risk of future MACE (eg, stroke, MI, CV death).14,t
qAccording to the ADA, GLP-1 RAs with proven CVD benefit in adults with T2D that have demonstrated an effect on MACE risk reduction in a CVOT include those with an FDA label indication for MACE (CV death, nonfatal Ml, or nonfatal stroke) risk reduction.12,15
rThe ACC defines atherosclerotic cardiovascular disease as a history of an acute coronary syndrome or MI, stable or unstable angina, coronary heart disease with or without revascularization, other arterial revascularization, stroke, or peripheral artery disease assumed to be atherosclerotic in origin.10
sPlease refer to the ADA Standards of Care in Diabetes—2024, the AACE Clinical Practice Guideline 2022 Update, and the 2020 ACC Expert Consensus Decision Pathway.
tRefer to AHA/ASA Stroke 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack for full recommendations.
AACE=American Association of Clinical Endocrinology; ADA=American Diabetes Association; AHA=American Heart Association; ASA=American Stroke Association; CVOT=cardiovascular outcomes trial; GLP-1 RA=glucagon-like peptide-1 receptor agonist; SGLT-2i=sodium-glucose cotransporter-2 inhibitor; TIA=transient ischemic attack.
Ozempic® has once-weekly dosing1
More ways to help your patients with T2D
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 Limitations of Use
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 mellitus and to reduce the risk of major adverse cardiovascular (CV) events (CV death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes mellitus and established CV disease.
- Ozempic® has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Ozempic® is not indicated for use in patients with type 1 diabetes mellitus.
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 referred to an endocrinologist for further evaluation if serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging.
- Pancreatitis: Acute and chronic pancreatitis have been reported in clinical studies. 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® promptly, and if pancreatitis is confirmed, do not restart.
- 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 (eg, 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: There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of Ozempic® in patients reporting severe adverse gastrointestinal reactions.
- Hypersensitivity: Serious hypersensitivity reactions (eg, 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.
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.
- Low Wang CC, Hess CN, Hiatt WR, Golfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus-mechanisms, management, and clinical considerations. Circulation. 2016;133(24):2459-2502. doi:10.1161/CIRCULATIONAHA.116.022194
- Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, et al. Association of Cardiometabolic Multimorbidity With Mortality (supplemental appendix). JAMA. 2015;314(1):52-60. doi:10.1001/jama.2015.7008
- Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52-60. doi:10.1001/jama.2015.7008
- Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet. 2006;368(9529):29-36. doi:10.1016/S0140-6736(06)68967-8
- Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844. doi:10.1056/NEJMoa1607141
- 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 (supplemental appendix). N Engl J Med. 2016;375:1834-1844. doi:10.1056/NEJMoa1607141
- Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720-1732. doi:10.1056/NEJMoa1504347
- Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(9):1117-1145. doi:10.1016/j.jacc.2020.05.037
- Joseph JJ, Deedwania P, Acharya T, et al; American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022;145(9):e722-e759. doi:10.1161/CIR.0000000000001040
- American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S158-S178. doi:10.2337/dc24-S009
- Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022;28(10):923-1049. doi:10.1016/j.eprac.2022.08.002
- Kleindorfer DO, 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):e364-e467. doi:10.1161/STR.0000000000000375
- American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S179-S218. doi:10.2337/dc24-S010