Endocrine Disorders, Contraception, and Hormone Therapy during Pregnancy
“Bert” Bertis Britt Little in Drugs and Pregnancy, 2022
Semaglutide is a relatively new GLP-1 inhibitor that has not been studied on human pregnancy. The manufacturer reports that in animal studies birth defects and pregnancy losses occurred in pregnancies exposed to the drug during organogenesis. No pregnancy risk categories are assigned to this agent; however, it is noted in the manufacturer’s package literature that the drug should be discontinued two months before conception. No studies of excretion into breast milk are published but the manufacturer states that it is transferred into animal breast milk.
Overweight/Obesity
Charles Theisler in Adjuvant Medical Care, 2023
Bariatric surgery is the gold standard in terms of obesity treatment, but not all patients are good candidates. Phentermine (3.75 mg) plus topirimate (23 mg) is the most prescribed short-term obesity medication.1 Semaglutide (2.4 mg) shows great promise as a long-term treatment.
The Enteroinsular Axis
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
There are six clinically approved GLP-1 mimetics for T2DM (Table 3.2) and one for obesity [34], employing dosing regimens that vary from twice daily to once weekly [35]. The first drug to be approved in this class was exenatide, a synthetically produced peptide based on the structure of a substance originally found in the saliva secretions of the venomous Gila monster lizard [36]. Although only sharing approximately 50% sequence identity with human GLP-1, exenatide represents a potent, long-acting GLP-1 receptor agonist in humans [36]. All drugs in the GLP-1 mimetic class have essentially similar beneficial effects in T2DM, but small differences in efficacy, and particularly tolerability, have been noted [36]. This gives rise to the idea of possible patient stratification in relation to choice of GLP-1 based drugs [37]. In addition to this, there are continuing efforts to develop more potent and longer-acting GLP-1 analogues that can provide further pharmacokinetic and pharmacodynamic advantages beyond what has already been achieved [36]. Notable examples currently undergoing clinical trials include HM11260C an exenatide-derived molecule covalently attached to the non-glycosylated Fc region of an antibody fragment via a short polyethylene glycol (PEG) linker [38; Figure 3.2]. PB1023 is a recombinant GLP-1 analogue genetically fused with an elastin-like protein with the repeated pentapeptide sequence VPGXG [39; Figure 3.2]. Semaglutide shares 94% sequence homology with human GLP-1, but has amino acid substitutions at position 8 (alpha-aminoisobutyric acid for alanine) and position 34 (arginine for lysine), with further C-18 acylation at Lys26 via two 8-amino-3,6-dioxaoctanoic acid (ADO) linker moieties [40; Figure 3.2]. NB-1001 (Xten-GLP-1) is a novel GLP-1 mimetic covalently attached to a hydrophilic, biodegradable protein polymer called Xten [41; Figure 3.2]. In addition, a GLP-1-antithrombin III pentapeptide has been developed by conjugating a stabilized form of GLP-1 to an antithrombin III-binding pentasaccharide, and shown promising preclinical potential in T2DM [42; Figure 3.2]. Although potentially very interesting, all these novel GLP-1 derivatives, similar to the current clinically available drugs in this class, are peptidic in nature and therefore require parenteral delivery [43]. As such, of particular interest is the possible development of an orally available form of semaglutide [44], which could dramatically change the landscape of this specific field of therapeutics. Together, it is envisaged that the ongoing efforts to generate new GLP-1 compounds will ultimately enable clinicians to select the most appropriate GLP-1 drug according to an individual patient's needs [45]. Importantly, the previously reported safety concerns regarding sustained use of GLP-1 mimetics relating to pancreatitis, thyroid cancer, and emergence of neuroendocrine tumors [46,47], have now been fully allayed [48].
Oral versus subcutaneous semaglutide for prevention of major adverse cardiovascular events: cost per outcome analysis of SUSTAIN-6 and PIONEER-6
Published in Postgraduate Medicine, 2022
Ariel Hammerman, Candace Makeda Moore, Enis Aboalhasan, Joseph Azuri, Ronen Arbel
Semaglutide is a long-acting GLP1a that can be administered once-weekly when provided subcutaneously or once daily in its oral formulation. The phase 3 pre-approval CV outcome trials (CVOTs), SUSTAIN-6 [4], and PIONEER-6 [5] were planned to evaluate the CV effects of semaglutide subcutaneous and oral formulations, respectively, each against placebo in patients with T2DM and high CV risk. The trials were intended to prove the non-inferiority of semaglutide for the primary endpoint of time to the first occurrence of a three-component MACE outcome (CV death, nonfatal myocardial infarction, or nonfatal stroke). In both trials, there were fewer MACE with semaglutide versus placebo. In SUSTAIN-6, this decrease was significant and mainly driven by a reduction in nonfatal stroke. In PIONEER-6, the small reduction in the occurrence of MACE with oral semaglutide did not reach statistical significance, though a significant reduction in CV mortality was seen.
Introducing an important therapy for obesity to primary care: once-weekly subcutaneous semaglutide 2.4 mg
Published in Postgraduate Medicine, 2022
Janine V. Kyrillos, Patrick M. O’Neil, Sean Wharton
GLP-1RAs were first developed for the treatment of T2D and multiple long-acting GLP-1RAs are approved for this indication [26,27]. With regards to obesity, the first US Food and Drug Administration (FDA)-approved GLP-1RA for weight management was once-daily subcutaneous liraglutide 3 mg, which has been available since 2015 [28–30]. In June 2021, once-weekly subcutaneous semaglutide 2.4 mg was approved by the FDA for the treatment of people with overweight or obesity [31]. Based on the substantial weight loss seen in clinical trials with semaglutide 2.4 mg as an adjunct to lifestyle intervention, it has been proposed to be the first ‘second-generation’ medication for weight management [5,32,33]. Semaglutide lowers energy intake and body weight via multiple mechanisms, including reduction of appetite and food cravings, better control of eating and lower relative preference for fatty foods [25,34]. Semaglutide 2.4 mg has the potential to help more than half of treated patients to achieve ≥15% weight loss, and more than one-third to achieve ≥20% weight loss [5,32,33]. This represents a substantial improvement in effectiveness over that reported for previously approved obesity medications, which lead to <10% weight loss in the majority of patients [5]. As an adjunct to lifestyle intervention, semaglutide may therefore help practitioners and patients in achieving the weight loss targets recommended for amelioration of the complications associated with obesity [5].
Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity
Published in Expert Opinion on Emerging Drugs, 2021
Mathies M. Jepsen, Mikkel B. Christensen
Clinical data: A clinical trial program called STEP aimed at supporting a market authorization approval for semaglutide once weekly for the treatment of obesity [72]. Four STEP studies have been published. STEP 1–3 showed a 68 week mean change in body weight from baseline (99–106 kg) of −9.6 kg to −17.1 kg (−9.6 to −16%) with once-weekly semaglutide 2.4 mg and −6.9 kg (−7%) with semaglutide 1.0 mg, compared to −3.1 kg to −5.9 kg (−2.9 to −5.7%) with placebo [73–75]. STEP 4 showed a 20 week mean change in body weight from baseline (107 kg) of −11.3 kg (−10.6%) with semaglutide 2.4 mg. A 48 week change in mean body weight from ‘week 20 baseline’ (96 kg) was −7.6 kg (−7.9%) with continued semaglutide compared to +6.3 kg (+6.9%) with shift to placebo [76]. Transient and mild-to-moderate in severity nausea and diarrhea were the most common adverse events with semaglutide.
Related Knowledge Centers
- Peptide
- Type 2 Diabetes
- Weight Management
- Diabetes Medication
- Anti-Obesity Medication
- Glucagon-Like Peptide-1
- Subcutaneous Administration
- Oral Administration
- Glp-1 Receptor Agonist
- Indication