Semaglutide - a GLP-1 analogue from a cardiovascular perspective.

GLP-1 analogs are modeled on the natural GLP-1 (glucagon-like peptide 1). In studies, they show potent HbA1C control and weight reduction in patients with type 2 diabetes.^1,2,*Their positive effect on cardiovascular disease in these patients should also be particularly emphasized.^3,4 The SGED therefore recommends early therapy with a GLP-1 analogue such as Semaglutide (^Ozempic®) in type 2 diabetics at cardiovascular risk.^3,*

Cardiovascular aspects as part of diabetes therapy.

For patients with type 2 diabetes, cardiovascular prevention is central: cardiovascular disease is the leading cause of complications and even death in them.⁵ Therefore, according to the guidelines of the Swiss Society of Endocrinology and Diabetology (SGED) , the reduction of cardiovascular burden is of primary importance in diabetes therapy.³ Well-controlled blood glucose reduces the risk of atherosclerotic changes. In parallel, patients with type 2 diabetes are targeted for treatment of known cardiovascular risk factors: Obesity, high blood pressure, dyslipidemia and smoking^.3

Semaglutide exceeds expectations in cardiovascular endpoint study

Since 2008, the U.S. Food and Drug Administration has required new antidiabetic drugs to demonstrate cardiovascular safety. The results of the cardiovascular endpoint study evaluating Semaglutide (^Ozempic®) were positively surprising^.2 3,297 patients with type 2 diabetes and high cardiovascular risk were randomized to receive placebo or ^Ozempic® subcutaneously once weekly for 104 weeks, each in addition to standard therapy°. Included were diabetic patients over 50 years of age with established cardiovascular disease or chronic renal failure (chronic kidney disease stage ≥ 3) and over 60-year-olds with at least one cardiovascular risk factor. Patients in the Ozempic® study ^arm experienced 26% fewer major adverse cardiovascular events (MACE) over the two years of the study compared to the placebo group^.2,* Similarly, 39% fewer non-fatal strokes occurred with ^Ozempic® (HR=0.61, p=0.04)^.2

Semaglutide in the SGED therapy recommendations

The EASD and ESC considered these positive results in the 2019 update of their guidelines.⁴ They advise GLP-1 analogs for patients with type 2 diabetes, cardiovascular disease, or high cardiovascular risk4^,** The same conclusion is found in the current January 2020 SGED recommendation, with the primary goal of limiting cardiovascular burden.³ After initiation of antidiabetic therapy-lifestyle changes and first-line medication such as metformin-early combination with modern antidiabetic agents such as the GLP-1 analog semaglutide is recommended.³ Thus, its positive effect on cardiovascular disease is expected to take effect at an early stage in diabetes therapy.³ This is all the more important because the vast majority of patients with type 2 diabetes belong to the high-risk cardiovascular group.^3,**

Semaglutide (^Ozempic®) in practical application

In the 2 years since its approval, ^Ozempic® has become the most prescribed GLP-1 analogue in Switzerland^.6 Thanks to the optimized active ingredient, it only needs to be applied subcutaneously once a week, independently of meals^.1 This makes ^Ozempic® as easy as it is practical to use. In addition to the convincing HbA1c reduction, it fulfills another crucial concern of patients regarding their diabetes therapy: a support in weight reduction1^,*With the help of ^Ozempic®, patients with insufficiently controlled type 2 diabetes and overweight (BMI≥28) can achieve their therapy goals.^1,* Considering the cardiovascular risk of these patients, the reduction of cardiovascular events is a significant benefit of ^Ozempic®.^5,*

* ^Ozempic® is indicated for the treatment of inadequately controlled type 2 diabetes mellitus in addition to diet and exercise, but is not indicated for weight loss or reduction of cardiovascular events^.1

**current ^ESC/EASD guidelines4:
High cardiovascular risk: patients with diabetes duration of ≥10 years without organ damage plus any other risk factor. Very high cardiovascular risk: patients with diabetes and established cardiovascular disease or other organ damage or three or more risk factors or juvenile-onset type 1 diabetes with disease duration of ≥ 20 years.
Thus, the vast majority of patients with type 2 diabetes have a very high cardiovascular risk^.3

°Standard therapy included oral antidiabetic medication, insulin, antihypertensives, diuretics, and lipid-lowering agents^.7

Abbreviations: CKD: Chronic Kidney Disease-Stage; EASD: European Association for the Study of Diabetes; ESC: European Society of Cardiology; GLP-1: Glucagon-like peptide 1; HR: hazard ratio; MACE: major adverse cardiovascular event, defined here as first occurrence of cardiovascular-related fatality, nonfatal stroke, or nonfatal myocardial ^infarction1; SGED: Swiss Society of Endocrinology and Diabetology; SU= sulfonylureas.

References

Ozempic® SmPC, www.swissmedicinfo.ch.
Marso et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834-44.
SGED/SSED Working Group. Recommendations of the Swiss Society of Endocrinology and Diabetology (SGED/SSED) for the treatment of type 2 diabetes mellitus (2020). Status: January 23, 2020. Available at: https://www.sgedssed.ch/fileadmin/user_upload/6_Diabetologie/61_Empfehlungen_Facharzt/2020_Swiss_Recomm_Medis_DE_def.pdf, last accessed 05/2020.
Cosentino et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2019;41(2):255-23.
Low Wang et al. 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):2459-502.
Novo Nordisk Data basis IQVIA Switzerland, 2016-2019.
Marso et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(suppl 1)S1:108.

Limitatio: For the treatment of patients with type 2 diabetes, in exclusive combination therapy with metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea, when adequate glycemic control is not achieved with these oral antidiabetic agents. For treatment as combination therapy with a basal insulin alone or a combination of a basal insulin with metformin when adequate glycemic control is not achieved with these treatments. Minimum BMI 28. Additional weight loss medications are not covered by health insurance.

Summary of product information ^Ozempic® Z: Semaglutide 1.34 mg/ml. I: ^Ozempic® is used to treat adults with inadequately controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when contraindicated or intolerant to metformin; in combination with other antihyperglycemic drugs. D: The starting dose of ^Ozempic® is 0.25 mg once weekly. After 4 weeks, the dose should be increased to 0.5 mg once weekly. To improve blood glucose control, after at least 4 more weeks at a dose of 0.5 mg once per week, the dose may be increased to 1 mg once per week. Dose adjustment is not required in the elderly, in patients with impaired renal or hepatic function. ^Ozempic® is used once a week at any time and independently of meals. AI: Hypersensitivity to the active substance or to one of the excipients according to “Composition”. VM: ^Ozempic® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. The use of GLP-1 receptor agonists may be associated with adverse gastrointestinal effects. If pancreatitis is suspected, ^Ozempic® should be discontinued. Patients receiving ^Ozempic® in combination with a sulfonylurea or insulin may be at increased risk for hypoglycemia. ^Ozempic® should be used in patients with diabetic retinopathy only under close ophthalmologic control. IA: Gastric emptying delayed by semaglutide may affect absorption of concomitant oral medications. UW: Very common: hypoglycemia when used with insulin or sulfonylurea, nausea, diarrhea. Common: hypoglycemia when used with other OAD’s, decreased appetite, dizziness, complications of diabetic retinopathy, vomiting, abdominal pain, abdominal tightness, constipation, dyspepsia, gastritis, gastroesophageal reflux, belching, flatulence, cholelithiasis, increased lipase, increased amylase, weight loss, fatigue. Occasional: dysgeusia, increased heart rate, injection site reactions, acute pancreatitis. Rare: Anaphylactic reaction. P: ^Ozempic® DualDose 0.25 mg or 0.5 mg: 1 prefilled pen of 1.5 ml; ^Ozempic® FixDose 1 mg: 2 prefilled pens of 1.5 ml, 1 prefilled pen of 3 ml (B). V4.0. For detailed information, please visit www.swissmedicinfo.ch.