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Injectable Semaglutide Approved for Weight Loss

A higher dose of once-weekly, injectable semaglutide was approved by the Food and Drug Administration (FDA) in June 2021 for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure [BP], type 2 diabetes [T2D], or high cholesterol), in addition to a reduced-calorie diet and increased physical activity.¹ This approval was based on a series of clinical trials known as the STEP trials. Four STEP trials have been published to date and are summarized in Table 1.^2-5

The STEP-1 trial evaluated semaglutide 2.4 mg once weekly as an adjunct to lifestyle modification in overweight or obese patients without T2D.² Semaglutide resulted in significant and sustained weight loss over 68 weeks compared to placebo (-14.9% vs -2.4%; p < 0.001). 86.4% of patients taking semaglutide achieved at least 5% weight loss compared to 31.5% of those taking placebo (p < 0.001). Those taking semaglutide also had better improvements in cardiometabolic risk factors and physical functioning. The most common adverse effects were gastrointestinal (GI) in nature, were transient, typically rated as mild to moderate in severity, and occurred in more patients taking semaglutide compared to placebo (nausea 44.2% vs 17.4%, diarrhea 31.5% vs 15.9%, vomiting 24.8% vs 6.6%).²

The STEP-2 trial compared semaglutide 2.4 mg weekly with semaglutide 1 mg weekly (the T2D maximum treatment dose) or placebo in overweight or obese people with T2D.³ Weight loss was greater in people taking the higher dose compared to the lower dose or placebo (9.6% vs 7.0% vs 3.4%, respectively; p < 0.0001). A higher percentage of patients taking the higher dose were able to achieve ≥5% weight loss (68.6% vs 57.1% vs 28.5%, respectively, p < 0.0001). The most common adverse effects were GI, which were described as mild to moderate, and occurred more commonly in the higher-dose group.³

The STEP-3 trial compared semaglutide 2.4 mg weekly with placebo in overweight or obese patients without T2D.⁴ This trial differed from the STEP-1 trial in that the study drug was evaluated as an adjunct to intensive behavioral therapy with an initial low-calorie diet. Results indicated that semaglutide led to more weight loss than placebo (-16% vs -5.7%; p < 0.001) and more patients were able to achieve a ≥ 5% weight loss (86.6% vs 47.6%; p < 0.001). GI adverse effects were more common with semaglutide vs placebo (82.8% vs 63.2%).⁴

The STEP-4 trial evaluated the continued use of semaglutide 2.4 mg weekly vs a switch to placebo after 20 weeks of semaglutide titrated to 2.4 mg weekly.⁵ After 20 weeks of semaglutide, with an initial weight loss of 10.6%, continued use of semaglutide 2.4 mg weekly for 48 more weeks resulted in additional weight loss of 7.9% while those switched to placebo had an average weight gain of 6.9% (p < 0.001).⁵

The STEP trials mark a major advancement in the treatment of overweight and obesity with the addition of a once-weekly treatment option that demonstrates significant reductions in weight. We now have two injectable GLP-1 RAs at higher doses approved for use in overweight and obesity; liraglutide 3 mg once daily (Saxenda)⁶ and semaglutide 2.4 mg once weekly (Wegovy).¹ These agents can be used for weight loss in patients with or without T2D.

This also marks the third FDA-approved brand name semaglutide product, in addition to once weekly injectable semaglutide (Ozempic)⁷ and once-daily oral semaglutide (Rybelsus)⁸, both of which are approved for the treatment of T2D.

Tirzepatide: A Dual GIP and GLP-1 RA

Tirzepatide is a novel dual agonist at both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide receptor agonists (GLP-1 RAs) and is currently being studied for the treatment of T2D. Currently available GLP-1 RAs affect only GLP receptors, but GIP is another incretin hormone that plays an important role in stimulating meal-time insulin secretion, which is diminished in T2D.⁹ The combined GLP and GIP effect may also have improved weight loss effects.

The Phase 3 SURPASS clinical study program evaluates tirzepatide against a variety of comparators including placebo, semaglutide, dulaglutide, insulin degludec, and insulin glargine and also includes a cardiovascular (CV) outcome trial. To date, three of the SURPASS studies have been published.^9-11 Table 2 provides a summary of the design and results of the studies published to date. A trial of tirzepatide for obesity (SURMOUNT-1) is also currently underway (https://clinicaltrials.gov/ct2/show/NCT04184622).

SURPASS-1 compared 3 doses of tirzepatide to placebo in 478 adults with T2D inadequately controlled with diet and exercise and naïve to injectable therapy.⁹ After 40 weeks, all doses of tirzepatide lowered A1C, fasting glucose levels, and weight. The most common adverse effects were nausea (12-18% vs 6%), diarrhea (12-14% vs 8%), and vomiting (2-6% vs 2%) and were described as mild to moderate and transient.⁹

SURPASS-2 compared 3 doses of tirzepatide to semaglutide 1 mg in 1879 adults with T2D inadequately controlled on metformin.¹⁰ After 40 weeks, all doses of tirzepatide (5 mg, 10 mg, 15 mg) were noninferior and superior to semaglutide for change in A1C from baseline (-2.01%, -2.24%, -2.3%, -1.86%, respectively; p < 0.001). Weight loss was also significantly better with all doses of tirzepatide compared to semaglutide (-7.6kg, -9.3kg, -11.2kg, -5.7kg; p < 0.001). The most common adverse effects with tirzepatide and semaglutide were GI related (nausea 17-22% vs 18%, diarrhea 13-16% vs 12%, and vomiting 6-10% vs 8%, respectively).¹⁰

SURPASS-3 compared 3 doses of tirzepatide to insulin degludec in 1437 adults with T2D inadequately controlled on metformin with or without a SGLT2 inhibitor.¹¹ After 40 weeks, all 3 doses of tirzepatide were superior to titrated insulin degludec for change in A1C from baseline (-1.93%, -2.2%, -2.37%, -1.34%, respectively; p < 0.0001). Weight loss was also significantly better with all doses of tirzepatide compared to insulin degludec (-7.5kg, -10.7kg, -12.9kg, +2.3kg; p < 0.0001). Tirzepatide led to higher rates of GI adverse effects (nausea 12-24% vs 2%, diarrhea 15-17% vs 4%, vomiting 6-10% vs 1%) but lower rates of hypoglycemia (1-2% vs 7%).¹¹

The results of the SURPASS trials indicate A1C and weight-lowering effects of tirzepatide are superior to both semaglutide and insulin degludec, making tirzepatide a much anticipated and promising treatment option. It has not yet been approved by the FDA, but the company is expected to file for approval by the end of 2021.

New and Upcoming Cardiovascular and Renal Outcomes Data

Another GLP-1 RA that is currently being investigated is efpeglenatide, an exendin-based, once-weekly, injectable agent. The AMPLITUTE-O study evaluated efpeglenatide vs placebo in subjects with T2D and either a history of cardiovascular disease (CVD) or current chronic kidney disease (CKD); eGFR 25-59.9 mL/min/1.73m²) plus one additional CV risk factor.¹² After a median follow-up of 1.81 years, the primary outcome of major adverse cardiovascular event (MACE) was lower in subjects taking efpeglenatide compared to placebo (7.0% vs 9.2%; hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.58-0.92; p < 0.007 for superiority). The secondary, composite kidney outcome of decrease in kidney function or macroalbuminuria was also lower in subjects taking efpeglenatide (13.0% vs 18.4%; HR 0.69; 95% CI, 0.57-0.79; p < 0.001). Efpeglenatide is not FDA approved at this time, but if it does receive approval, it will be the first exendin-based GLP-1 RA with demonstrated CV and kidney benefit. Currently available GLP-1 RAs that have demonstrated CV and kidney benefit are human-based GLP-1 RA analogs (dulaglutide, liraglutide, and semaglutide).¹²

Currently, the ongoing FLOW study is evaluating the impact of once-weekly, injectable semaglutide on CKD progression in patients with T2D (https://clinicaltrials.gov/ct2/show/NCT03819153). The primary outcome is time to first occurrence of a composite of eGFR decline of ≥ 50% from baseline, end-stage kidney disease (ESKD), or death from kidney or CVD. This study will better elucidate the effects of GLP-1 RAs, particularly semaglutide, on kidney-related outcomes and is anticipated to be completed in 2024.

Added Benefit with Higher Doses

In addition to higher doses of GLP-1 RAs being evaluated for weight loss indications, higher doses are also being studied for added glycemic and weight benefits in the treatment of T2D. Two studies were recently published evaluating the effects of higher doses of the GLP-1 RA agents, dulaglutide and semaglutide.

The AWARD-11 study evaluated weekly dulaglutide 3.0 mg and 4.5 mg vs weekly dulaglutide 1.5 mg in 1842 patients with T2D on metformin.¹³ Change in A1C from baseline to 36 weeks was significantly better in the 4.5 mg and 3.0 mg groups compared to the 1.5 mg group (-1.77% vs
-1.64% vs 1.54%, respectively; p < 0.001 for 4.5 mg vs 1.5 mg and p = 0.003 for 3.0 mg vs 1.5 mg). Weight was also incrementally improved with the 4.5 mg and 3.0 mg groups compared to the 1.5 mg group (-4.6 kg vs -3.8 kg vs -3.0 kg, respectively; p < 0.001 for 4.5 mg vs 1.5 mg and p < 0.05 for 3.0 mg vs 1.5 mg). GI adverse effects were most common including nausea (17.3% vs 16.1% vs 14.2%, respectively), diarrhea (11.6% vs 12.0% vs 7.7%, respectively), and vomiting (10.1% vs 9.1% vs 6.4%, respectively). Based on the results of this trial, the FDA approved both the 3.0 mg and 4.5 mg doses.¹³ Dulaglutide should be initiated at 0.75 mg once weekly and increased to 1.5 mg once weekly for additional glycemic control. The dose can be increased to 3.0 mg if needed after at least 4 weeks on the 1.5 mg dose and increased again to 4.5 mg if needed after at least 4 weeks on the 3.0 mg dose.¹⁴

The SUSTAIN-FORTE study evaluated weekly semaglutide 2.0 mg vs weekly semaglutide 1 mg in 961 patients with T2D on metformin with or without a sulfonylurea.¹⁵ Change in A1C from baseline to 40 weeks was significantly better in the 2.0 mg group compared to the 1 mg group
(-2.2% vs -1.9%; p = 0.003). Mean change in body weight was also significantly better in the 2.0 mg group (-6.9kg vs -6.0kg; p = 0.015). GI side effects occurred in 34% of those taking 2.0 mg and 31% in those taking 1 mg.¹⁵ The higher dose of semaglutide for the treatment of T2D is not yet FDA approved but has been submitted to the agency for approval.

A New Option for Children and Adolescents

Prior to 2019, treatment options for children and adolescents with T2D were limited to metformin and insulin. In 2019, liraglutide was added to this list, marking the first approval for a glucose-lowering medication in this population since 2000. In July 2021, exenatide extended-release (XR) was also approved by the FDA for use in pediatric patients aged 10 and older, making it the first once-weekly GLP-1 RA to be approved in this patient population.¹⁶ Approval was based on a Phase 3 trial evaluating the safety and efficacy of exenatide XR compared to placebo in 82 youth (10-17 years old). Patients taking exenatide XR achieved a greater mean change in A1C from baseline compared to placebo (-0.25% vs +0.45%; p < 0.05). Adverse effects were consistent with those observed in the adult population. Persistent glycemic control is challenging in this patient population and while the results of this study were modest; any addition to the treatment armamentarium for this population is welcomed.¹⁷

Conclusion

Many new agents in the GLP-1 RA class are currently under investigation and will continue to be developed. New indications, additional benefits, and higher doses are also being studied. The evidence with GLP-1 RAs continues to mount and the implications related to clinical practice are vast. It’s crucial that pharmacists stay abreast of the emerging evidence in order to care for and collaborate effectively with their patients.

References

1. Wegovy (semaglutide) [package insert], Plainsboro, NJ: Novo Nordisk; 2021.
2. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
3. Davies M, Faerch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (Step 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397:971-984.
4. Wadden TA, Bailey TS, Billings LK, et al. Effects of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The Step 3 randomized clinical trial. JAMA. 2021;325:1403-1413.
5. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The Step 4 randomized clinical trial. JAMA. 2021;325:1414-1425.
6. Saxenda (liraglutide) [package insert], Plainsboro, NJ: Novo Nordisk; 2021.
7. Ozempic (semaglutide) [package insert], Plainsboro, NJ: Novo Nordisk; 2021.
8. Rybelsus (semaglutide) [package insert], Plainsboro, NJ: Novo Nordisk; 2021.
9. Rosenstock J, Wysham C, Frias JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomized, phase 3 trial. Lancet. 2021;398:143-155.
10. Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-515.
11. Ludvik B, Giorgino F, Jodar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomized, open-label, parallel-group, phase 3 trial. Lancet. Published online August 6, 2021. https://doi.org/10.1016/S0140-6736(21)01443-4. Accessed October 14, 2021.
12. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385:896-907.
13. Frias JP, Bonara E, Ruiz LN, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. Published online Jan 4, 2021. https://doi.org/10.2337/dc20-1473. Accessed October 14, 2021.
14. Trulicity (dulaglutide) [package insert], Indianapolis, IN: Eli Lilly; 2021.
15. Frias 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, randomized, phase 3B trial. Lancet Diabetes Endocrinol. 2021;9:563-574.
16. Bydureon BCise (exenatide extended-release) [package insert], Wilmington, DE: AstraZeneca; 2020.
17. AstraZeneca US Press Release. BYDUREON BCise (exenatide extended-release) approved in the US for the treatment of type 2 diabetes in pediatric patients ages 10 years and older. Available at: https://www.astrazeneca-us.com/content/az-us/media/press-releases/2021/bydureon-bcise-exenatide-extended-release-approved-in-the-us-for-the-treatment-of-type-2-diabetes.html. Accessed October 14, 2021.

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