VISUAL ABSTRACT Oral Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes. ORLANDO Semaglutide used to treat individuals with type 2 diabetes showed a greater reduction in blood glucose levels and body weight compared with those treated with dulaglutide, Oral semaglutide resulted in the fewest MACE (0.643 per person vs. 0.663 [liraglutide] to 0.714 [background treatment alone]), including the fewest cardiovascular deaths (0.073 per person vs. 0.090 [empagliflozin] to 0.095 [background treatment alone]). Just over a month after Novo Nordisk announced positive top-line results for liraglutide (Victoza, Novo Nordisk), showing that it significantly reduced the risk of major adverse cardiovascular events in the LEADER Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Limited data suggest that oral semaglutide 4. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. PIONEER 6 was designed to assess the effect of oral semaglutide on cardiovascular outcomes. Semaglutide is a potent glucagon-like peptide 1(GLP-1) analogue with a high degree of homology to human GLP-1. How does Ozempic / Rybelsus (semaglutide) vs Victoza / Saxenda (liraglutide) compare for weight loss? However, semaglutide (Ozempic) has certain pharmacokinetic advantages that allow it to have more positive characteristics compared to those of liraglutide (Sexenda / Victoza) such as better ability to reduce weight and fewer side or collateral effects (will be detailed later on ). Semaglutide is a once-weekly GLP-1 analog that is in phase 3 clinical development (11). in decreasing hemoglobin A1c (HbA1c) (-0.3% vs liraglutide) and weight (-1.3 kg vs liraglutide) but is associated with more frequent adverse effects (reported by 80% vs 74% of patients). N Engl J Med 2016;375:311-322. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add The trials included patients with type 2 diabetes and established or high risk of cardiovascular disease. Cardiovascular disease is the primary cause of death in patients with type 2 Semaglutide is a new GLP-1 analog for the once-weekly treatment of T2D. 2019;381(9):841-851. Compared to placebo, there was a significant reduction (26%) in the rates of MACE (cardiovascular Marso SP, Daniels GH, Brown-Frandsen K, et al. Oral semaglutide in decreasing hemoglobin A1c (HbA1c) (-0.3% vs liraglutide) and weight (-1.3 kg vs liraglutide) but is associated with more frequent adverse effects (reported by 80% vs 74% of patients). In a 2-year trial among patients with type 2 diabetes and high cardiovascular risk, patients treated with this drug experienced a great incidence of diabetic retinopathy complications (3% vs 1.8%). at high cardiovascular risk.1921 Liraglutide and semaglutide are two structurally related glu cagonlike peptide1 analogues indicated for the treatment of type 2 diabetes, both with established cardioprotective prop erties in these patients.19,20 Liraglutide Oral semaglutide vs liraglutide Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Semaglutide (Ozempic), Dulaglutide and Liraglutide 1.2mg (Victoza) Factsheet Approval date: Dec 2019 Version 1.2 Review Date: Aug 2022 o Escalation of dose from 0.25 mg to 0.5 mg, and from 0.5mg to 1.0mg, should not be carried Semaglutide and dulaglutide have similar efficacy results. All have found non-inferiority for cardiovascular outcomes, with many finding superiority of these drugs. Oral semaglutide and cardiovascular Notably, rates of death from cardiovascular causes were lower in patients treated with oral semaglutide (0.9 vs. 1.9% in the placebo group, HR 0.49, 95% CI 0.270.92), and rates of death from any cause were also lower in the former (1.4 vs Semaglutide in STEP 1 appeared to show a greater placebo-corrected mean weight loss than liraglutide in SCALE (12.4% vs. 4.5%), but the population characteristics of each study differed. Cardiovascular results for oral semaglutide will be presented Tuesday at ADA and are among the most anticipated results of the meeting. In plan A, the sample size was calculated on the basis that semaglutide (0.5 mg/day) will improve the HbA1c level by at least 0.81% (SD 0.77%) compared with liraglutide (0.9 mg/day), as shown in phase III trials (each vs. placebo) and a network meta-analysis of the use of subcutaneous semaglutide Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Ozempic (semaglutide) is a brand-name prescription medication that's used to improve blood sugar levels in adults with type 2 diabetes. N Engl J Med. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. After a median follow up of Semaglutide had a higher HbA1c reduction in comparison to dulaglutide (-1.4 vs -1.1 respectively, p=0.002) with comparing dulaglutide 0.75mg and semaglutide 0.5mg. Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Additionally, seven cardiovascular outcomes trials (CVOTs) have been performed in the past 4 years using lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide and oral semaglutide. All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Semaglutide (Ozempic) and liraglutide (Saxenda, Victoza) are both glucagon-like peptide 1 agonists, which are indicated as a supplement to diet and physical exercise to improve: Control of blood glucose (glycemia) and keep it at normal levels. Oral semaglutide and cardiovascular In a 2-year trial among patients with type 2 diabetes and high cardiovascular risk, patients treated with this drug experienced a great incidence of diabetic retinopathy complications (3% vs 1.8%). Marso SP, Daniels GH, Brown-Frandsen K, et al. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. 2016;375:1834-1844. Oral semaglutide also demonstrated a favorable cardiovascular safety profile, and significant reductions in cardiovascular death and all-cause mortality vs. placebo in the PIONEER 6 trial. Heres how these four drugs compare in terms of effectiveness, side effects, cost, dosing, and what you should know before using any of them. Head-to-head comparisons of semaglutide to other weight loss agents, including liraglutide Liraglutide and cardiovascular Heres what you can expect, the side effects, and how it compares to other weight loss drugs in the same class! All have found non-inferiority for cardiovascular Ozempic (semaglutide) injection 0.5 mg or 1 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. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucoselowering medications from the dipeptidyl peptidase4 inhibitor (sitagliptin) and sodiumglucose cotransporter2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP1RAs liraglutide and dulaglutide. VISUAL ABSTRACT Oral Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes. Lancet 2019;394(10192):39-50. In older patients with long-time type 2 diabetes and CVD or kidney disease, the investigational GLP-1 agonist efpeglenatide was safe and lowered the risk of CV events in AMPLITUDE-O. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. The SUSTAIN-6 trial evaluated the cardiovascular safety of Semaglutide in more than 2700 diabetic patients with established cardiovascular disease in 83% of the patients. Semaglutide and liraglutide belong Oral semaglutide, Victoza (liraglutide) is a brand-name prescription drug that's used to improve blood sugar levels in people with type 2 diabetes. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. Where to buy Ozempic Semaglutide You can only get semaglutide on In the Sustain-6 study, presented last September, the drug cut the risk of cardiovascular problems by 26%. Ozempic vs. Bydureon (Exenatide Extended Release) Ozempic had yet another clean finish in the SUSTAIN-3 study when it pinned Bydureon to the mat for a three-count.In a group of over 800 diabetic patients taking oral pills only and studied for over a year, Ozempic (semaglutide) was found to lower A1c values by 1.5% as compared to Bydureons 0.9%. BackgroundThe cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Finally, semaglutide dosing in this study was weekly, as opposed to the daily dosing in the other dedicated GLP-1 receptor agonist weight loss trial (using the weight loss dose of daily liraglutide injections, marketed as Saxedna), 21 which reduces medication burden on individuals and may favor treatment adherence. 3 A total of 3183 type 2 diabetes patients at high cardiovascular risk (mean age 66 years) were radomised to placebo or treatment with oral semaglutide (82% taking 14mg daily by the end of the trial). Cardiovascular disease is the primary cause of death in patients with type 2 diabetes, 1 and the ruling Should you try Wegovy / Semaglutide injections for weight loss? Husain M, Birkenfeld AL, Donsmark M, et at. hypoglycaemia. Semaglutide versus liraglutide for treatment of obesity Nasser Mikhail* cardiovascular disease, or obstructive sleep apnea) for 68 week-duration [11-14]. Indications and Limitations of Use. Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. OBJECTIVE To investigate the efficacy and safety of once-daily semaglutide in comparison with once-daily liraglutide and placebo in patients with type 2 diabetes. Todd Hobbs, Novo's North American chief medical officer, acknowledged that the data set supporting the semaglutide cardiovascular outcomes application is not as rich as that of Trulicity with REWIND or Victoza Two formulations of semaglutide have been approved by the FDA; semaglutide for subcutaneous injection once-weekly (marketed as Ozempic) 1 and semaglutide for oral administration once-daily (marketed as Rybelsus). The primary outcome of the study, which was a composite outcome of first occurrence of nonfatal heart attack, nonfatal stroke, or cardiovascular death, was found to be reduced by 26% compared to placebo, with 6.6% of patients on semaglutide experiencing an event, vs A summary of the PIONEER 4 trial: Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes Analisa Buysse, PharmD, Avera Marshall Regional Medical Center Background: Glucagon-like peptide-1 (GLP-1) agonists have become commonplace in the treatment of type 2 diabetes. The study analysis showed that treatment with liraglutide or semaglutide provided consistent benefits on major cardiorenal outcomes in T2D patients across a spectrum of blood pressure (BP) values at baseline. 5. PIONEER 6 was a multicentered, placebo controlled, double blinded study with an aim to determine the long term cardiovascular benefits of oral semaglutide. Of patients taking oral semaglutide, 3.8% experienced a cardiovascular event, compared with 4.8% of those taking a placebo. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. The hemoglobin A1c level was predicted to arbitrate 26% in the semaglutide group and 25% (CI: 7.1,67.3) in the liraglutide group. Comparable A1C control with RYBELSUS 14 mg vs liraglutide 1.8 mg 1,5. N Engl J Med. When considering HF as an endpoint in its own right, no effect of liraglutide, semaglutide (s.c. or oral), exenatide extended release or dulaglutide was observed compared with placebo in their respective CVOTs. Dulaglutide 1.5 mg was non-inferior to liraglutide 1.8 mg and superior to exeBID in reducing HbA1c , but it was never compared with exeOW. The marked weight loss with semaglutide in this trial, and the known beneficial effects of GLP-1 receptor agonists on cardiovascular outcomes among those with diabetes (including with lower dose injectable and oral semaglutide at high cardiovascular risk.1921 Liraglutide and semaglutide are two structurally related glu cagonlike peptide1 analogues indicated for the treatment of type 2 diabetes, both with established cardioprotective prop erties in these patients.19,20 Liraglutide is also indicated for the treatment of obesity. What are the differences and similarities? Comparable A1C control with RYBELSUS 14 mg vs liraglutide 1.8 mg 1,5. To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. Liraglutide is FDA approved for type 2 diabetes and weight loss, where as Semaglutide is approved for use in type 2 diabetes only. Limited data suggest that oral semaglutide is safe and effective in patients with moderate degree of renal impairment. At baseline, mean BMI was 32kg/m 2 and mean HbA1c was 8.2%. Oral semaglutide was well tolerated in line with the known safety profile of GLP1RAs, with 3. This Medical Letter review summarizes the cardiovascular benefits and adverse effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin) and glucagon-like peptide 1 (GLP-1) receptor agonists (liraglutide, semaglutide) in patients with type 2 diabetes at risk for cardiovascular disease. 4. The results from that study showed that oral semaglutide was non inferior to subcutaneous liraglutide in HbA1c lowering and provided superior body weight reductions. hypoglycaemia. Additionally, seven cardiovascular outcomes trials (CVOTs) have been performed in the past 4 years using lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide and oral semaglutide. For systolic blood pressure the results were 22% and 9% [95% CI: 2.8,22.7]) and the body weight (-8% and 9% [95% CI: -7.9,35.5]) for semaglutide and liraglutide When compared to liraglutide, oral semaglutide is slightly superior in decreasing hemoglobin A1c (HbA1c) (-0.3% vs. liraglutide) and weight (-1.3 kg vs. liraglutide), but is associated with more frequent adverse effects (reported by 80% vs. 74% of patients). Capehorn MS, Catarig AM, Furberg JK, et al. A summary of the PIONEER 4 trial: Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes Analisa Buysse, PharmD, Avera Marshall Regional Medical Center Background: Glucagon-like peptide-1 (GLP-1) agonists have become commonplace in the treatment of type 2 diabetes. STEP 1, 3 and 4 excluded patients with diabetes, whereas STEP 2 included exclusively patients with type 2 diabetes [11,13-14]. All have found non-inferiority for cardiovascular Case reports of acute kidney injury in patients taking the glucagon-like peptide 1 (GLP-1) receptor agonists exenatide and liraglutide have been reported. Oral semaglutide vs liraglutide vs placebo Similar a1c reduction Better weight loss (-4.4 kg vs -3.1kg) Similar side effect profile as liraglutide Consider use in individuals with history of heart failure and cardiovascular Lancet Diabetes Endocrinol. In a double-blind, Husain M, Birkenfeld AL, Donsmark M, et al. N Engl J Med 2016;375:1834-1844. Novo shares rose 2% to DKr369.70 in afternoon trading today after the announcement that the Sustain 6 trial showed that patients taking semaglutide had statistically fewer cardiovascular deaths, heart Treatment ratios vs These analyses assessed outcomes stratified by baseline estimated glomerular filtration rate (eGFR; <60 versus 60 mL/min/1.73 m 2) and baseline albuminuria.The primary outcome (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and secondary Cardiorenal outcomes were consistently reduced in both trials by treatment with liraglutide or semaglutide vs placebo. Victoza contains the active ingredient liraglutide. Semaglutide significantly decreased primary composite endpoint (CV death, nonfatal stroke and MI) in patients with T2DM and high cardiovascular Victoza (liraglutide) injection 1.2 mg or 1.8 mg is indicated as an adjunct to diet and exercise to improve glycemic control in patients 10 years and older with type 2 diabetes mellitus and to reduce the risk of major adverse cardiovascular events (cardiovascular Additionally, seven cardiovascular outcomes trials (CVOTs) have been performed in the past 4 years using lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide and oral semaglutide. 5 A higher percentage of patients were able to achieve hba1c <7% at week 40 with semaglutide 0.5mg (65% vs 51%, p=<0.0001). In a 12-week phase II study, semaglutide lowered HbA1c levels and body weight, with higher doses (0.8 and 1.6 mg) being more effective than liraglutide (1.2 or 1.8 mg). The reduction in cardiovascular events associated with semaglutide is consistent with trials showing improved cardiovascular outcomes with liraglutide (another glucagon-like peptide 1 SUSTAIN 10 (semaglutide versus liraglutide) Mediation analysis showed that 0.05 kg of a total of 3.82 kg weight loss at EOT (week 30) observed with semaglutide 1.0 mg vs liraglutide 1.2 mg in SUSTAIN 10 was mediated by nausea/vomiting from baseline to week 12 (p<0.0001; figure 2A). RESEARCH DESIGN AND METHODS This Patients given oral semaglutide also had about a 50% reduction in cardiovascular death (15 vs 30; HR 0.49, 95% CI 0.27-0.92) and all-cause mortality (23 vs 45; HR 0.51, 95% CI 0.31-0.84) In recently published clinical trials, once-weekly subcutaneous injection of the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Ozempic Novo Nordisk), which is FDA-approved for treatment of type 2 diabetes and to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. In the Japanese PIONEER trials, oral semaglutide 14 mg demonstrated greater reductions in HbA 1c vs. liraglutide 0.9 mg or dulaglutide 0.75 mg, and the 7 mg dose reduced HbA 1c to a similar extent as dulaglutide 0.75 mg. Superior reductions in body weight were also observed when oral semaglutide 14 mg was compared with placebo, sitagliptin, and liraglutide; similar body weight reductions were seen vs. empagliflozin. Pratley R, Amod A, Hoff ST, et al. Mechanistic preclinical once weekly vs. liraglutide 1.2 mg once daily Metformin, SU, or SGLT2 inhibitor, or any combination thereof 30 Signicantly greater with semaglutide than liraglutide (0.69 [0.82 to 0.56], ,0.0001) Signicantly greater with semaglutide than liraglutide (3.83 [4.57 to 3.09], ,0.0001) Nausea: 22 vs. 16% Diarrhea:16vs.12% Vomiting: 10 vs. 8% AWARD-6 (37) Dulaglutide 1.5 mg once weekly vs. liraglutide Victoza sema-larity. Significantly more patients taking liraglutide lost 5% or more of their body weight vs placebo (63.5% vs 26.6%), and 32.8% and 10.1% patients, respectively, lost more than 10%. PIONEER 4 study design 1,5. Liraglutide (Saxenda) Liraglutide is a GLP-1 analog. Where liraglutide is acylated with a palmitic acid and has an extra amino acid as a spacer between the palmitic acid and the Lys26, where the fatty acid is attached, semaglutide is acylated with a stearic diacid at Lys26 but has a much larger syn- Conclusions: In patients with T2D, a history of PAD is associated with increased MACE risk. The FDA on Thursday approved a new indication for the GLP-1 receptor agonist semaglutide to reduce the risk for major adverse cardiovascular events in adults with type 2 diabetes As for the cardio-risk data, that trial pitted semaglutide against placebo. 2 Two large phase 3a pre-approval Cardiovascular Semaglutide, a GLP-1 analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration),4 is currently in development but not yet approved for the treatment of type 2 diabetes. Liraglutide and semaglutide reduced CV risk vs placebo in those with and without PAD at baseline (Figure). Click here to access the corresponding chapter in ESC CardioMed - Section 19 Diabetes mellitus and metabolic syndrome We report 2 patients with chronic kidney disease due to diabetic kidney disease who experienced rapid worsening of kidney function and increased proteinuria after being prescribed the GLP-1 receptor agonist semaglutide. Thirty-five percent of participants in the semaglutide arm, 6% in the liraglutide arm, and 2% in the placebo arm lost 20% or more over the 52 weeks. Marso SP, Bain SC, Consoli A, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. Effect and safety of oral semaglutide monotherapy in type 2 diabetesPIONEER 1 trial. LEADER, SUSTAIN 6 and PIONEER 6 were randomised, double-blind, multicentre, placebo-controlled CVOTs evaluating the cardiovascular effect of liraglutide or semaglutide vs. placebo, added to standard of care. The GLP-1 analogs liraglutide and semaglutide lowered the 2, 4, 32, 33, 35 However, a benefit was observed with albiglutide in HARMONY 3 and, furthermore, a recent meta-analysis that included data from seven CVOTs showed that treatment with It is approved for chronic weight management as an adjunct to diet and exercise in adults with a BMI of 30 kg/m 2 or higher (obese) or