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Dr Sanjay Kalra, DM (AIIMS); President-elect, SAFES, Bharti Hospital, Karnal, India; Dr Ashok Kumar Dept. of Endocrinology, Cedar Clinic, Panipat, Haryana, India 07 February 2023
Diabetes is a complex syndrome, with multiple causative factors, complications and confounding situations. Ever widening spectrum of pharmacological evolution is trying to match the complexities in diabetes management with gradual addition of newer class of drugs one after another.
The Gordian Knot of Glucose Control
Many conventional therapies, however, like traditional sulfonylureas, create a Gordian knot which is difficult to disentangle. In a unicentric approach to achieve euglycemia, unwanted side effects like hypoglycemia and weight gain often occur.1 These results of glucose-lowering therapy, which were hitherto considered inevitable, have been addressed in the concepts of the glycemic pentad and the KgA1c paradox. The glycemic pentad suggests that avoidance of hypoglycemia and glycemic variability is as important a therapeutic goal as achievement of normal glucose values.2 The KgA1c paradox reminds us of the deleterious rise in body weight that is often seen when HbA1c is lowered with conventional diabetes control strategies.3
Glucagon-Like Peptide-1 Receptor Agonists
In recent years, injectable glucagon-like peptide-1 receptor agonists (GLP-1RA) have become accepted as first-line injectable therapy in persons with type 2 diabetes, especially those with/at high risk of atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD).4-7 GLP-1RA are a multifaceted class of glucose-lowering drugs, which act at various levels of glucose homeostasis to ensure optimization of glucose levels. The glucose-dependent mechanism of action prevents hypoglycemia, while pharmacological actions on the hypothalamus and gastrointestinal (GI) tract ensure avoidance of weight gain, promote weight loss and prevent the KgA1c paradox from setting into motion.
There still remains, however, a slight reluctance to use injections. This avoidance can lead to clinical inertia, and result in suboptimal control.8 Semaglutide, a novel GLP-1RA, which was earlier available as a once-weekly subcutaneous injectable, has now been formulated as a once daily oral pill.9
Untangling The Pharmaceutical Knot
Formulating an oral preparation of semaglutide posed multiple challenges to drug developers.
The oral administration of semaglutide or other GLP-1RAs alone led to negligible bioavailability of 0.01%. Protein and peptides like semaglutide get degraded by proteolytic enzymes and low pH. Furthermore, due to high molecular weight, these are not able to permeate through the GI epithelium leading to low absorption. This leads to the lower absorption and very low bioavailability.
This Gordian knot was opened using a absorption enhancer, SNAC {sodium N-(8-[2-hydroxybenzoyl]amino)caprylate}. It is a small fatty acid derivative that promotes absorption across gastric epithelium. SNAC increases the localized pH around the tablet and protects it from degradation by proteolytic enzymes and acidic pH. It helps in absorption of semaglutide through GI epithelium via transcellular route. The action of SNAC is time- and concentration-dependent and is fully reversible. Bioavailability of semaglutide has been increased by 100 times when formulated along with SNAC.9
In various pharmacological studies, dose of SNAC has been studied from 150 to 600 mg and it has been found that 300 mg of SNAC is the optimum dose to get the maximum bioavailability. When co-formulated with 300 mg SNAC, 1% of semaglutide usually absorbed in stomach.10
Clinical Trials
A robust phase 3 clinical trial program, based upon results of extensive pre-clinical and early clinical studies, has been published. This supports the easy and effective use of oral semaglutide in diverse patient populations, as monotherapy or in combination with varied concomitant therapy, to achieve a wide-spectrum of desired clinical endpoints (Table 1).
Table 1. Summary of Efficacy Outcome in the PIONEER Clinical Trials11-19 | |||||||||||
Trials (N) | Baseline HbA1c | Time Point | Comparator | % mean reduction in HbA1c | Estimated mean change from baseline SBP (mmHg) (ontreatment period) | ||||||
Semaglutide | Comparator | Semaglutide | Comparator | ||||||||
3 mg | 7 mg | 14 mg | 3 mg | 7 mg | 14 mg | ||||||
PIONEER 2 (822) | 8.1 | Week 52 | Empa 25 mg | −1.3 | −0.9 | −5 | −4 | ||||
PIONEER 3 (1,864) | 8.1 | Week 78 | Sita 100 mg | −0.6 | −1.0 | −1.3 | −0.8 | −2 | −3 | −3 | −0 |
PIONEER 7 (504) | 8.3 | Week 52 | Sita 100 mg | −1.3 | Flex dosing | −0.8 | −4 | Flex dosing | −2 | ||
PIONEER 10 (458) | 8.3 | Week 52 | Dula 0.75 mg | −0.9 | −1.4 | −1.7 | −1.4 | −2 | −2 | −2 | −1 |
PIONEER 9 (243) | 8.2 | Week 52 | Lira 0.9 mg | −0.9 | −1.4 | −1.5 | −1.2 | −1 | −1 | −2 | −1 |
Placebo | −0.1 | −3 | |||||||||
PIONEER 4 (711) | 8.0 | Week 52 | Lira 1.8 mg | −1.2 | −1.1 | −2 | −3 | ||||
Placebo | −0.2 | 0 | |||||||||
PIONEER 1 (703) | 8.0 | Week 26 | Placebo | −0.9 | −1.2 | −1.4 | −0.3 | −4 | −4 | −5 | −2 |
PIONEER 5 (324) | 8.0 | Week 26 | Placebo | −1.0 | −0.2 | −7 | 0 | ||||
PIONEER 8 (731) | 8.2 | Week 52 | Placebo | −0.6 | −0.9 | −1.3 | −0.1 | −1 | −2 | −5 | 0 |
Untangling The Clinical Knot
The diabetes care physician faces multiple challenges while managing his or her patients. Ensuring patient acceptance, adherence and persistence, while offering an effective and efficient therapy that can be administered with minimal intrusion in the individual’s lifestyle, and avoiding adverse events or complications, is a difficult task. Added to these are the needs to ensure vasculo-metabolic and viscera-metabolic safety, and promote cardiovascular health. All these “tasks” are the equivalent of cleaning the Augean stables.
The Place of Oral Semaglutide
Oral semaglutide, with its unique pharmaco-clinical properties, seems well-poised to be a game changer in glucose control.
In India, oral semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus as monotherapy when metformin is considered inappropriate due to intolerance or contraindications or in combination with other medicinal products for the treatment of diabetes. Its use is endorsed by expert guidance from professional bodies across the world (Table 2).
Table 2. Recent Guidelines on the Use of GLP-1RAs6,20-24 | |||
Organization | Year | Indication for GLP-1RA | Mention of Semaglutide |
ADA | 2022 | Among individuals with type 2 diabetes who have established ASCVD or indicators of high CV risk, established kidney disease, or heart failure, a SGLT2 inhibitor and/or GLP-1RA with demonstrated CVD benefit. | Yes (Inj. Semaglutide 2.4 OW for obesity management in patients with type 2 diabetes) |
ADA-EASD | 2020 | GLP-1RA or SGLT2 inhibitor in patients with established or high risk of ASCVD independently of baseline HbA1c levels and glycemic targets, but also independently of baseline metformin use. | NA |
ESC | 2021 | In persons with T2DM and ASCVD, the use of a GLP-1RA or SGLT2 inhibitor with proven outcome benefits is recommended to reduce CV and/or cardiorenal outcome. | NA |
AACE/ACE | 2018 | GLP-1RA is recommended as monotherapy in individuals with HbA1c <7.5%. In addition, GLP-1RA is recommended in prediabetic patients if glycemia is not normalized with medications such as metformin and acarbose. | No |
NICE | 2015 | If triple therapy with metformin and two other oral drugs is not effective, not tolerated or contraindicated, consider combination therapy with metformin, a sulfonylurea and a GLP-1 mimetic for adults with type 2 diabetes who: ●have a BMI of 35 kg/m2 or higher (adjust accordingly for people from Black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or ●have a BMI <35 kg/m2 and: ⮚ for whom insulin therapy would have significant occupational implications or ⮚ weight loss would benefit other significant obesity-related comorbidities. Only continue GLP-1 mimetic therapy if the person with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months). | NA |
South Asian Task Force | 2019 | As an adjunct to diet and exercise in adults with T2DM. Recommended as monotherapy in a few countries (e.g., dulaglutide in India). Indicated in adults (liraglutide) with established CVD to reduce the risk of major adverse CV events. | Yes (indicated in adults with T2DM as an adjunct to diet and exercise to improve glycemic control; Lowers fasting and postprandial glucagon concentrations; Delays early postprandial gastric emptying) |
ADA = American Diabetes Association; ASCVD = Atherosclerotic cardiovascular disease; CV = Cardiovascular; SGLT2 = Sodium-glucose cotransporter 2; GLP-1RA = Glucagon-like peptide-1 receptor agonists; CVD = Cardiovascular disease; ADA-EASD = American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD); HbA1c =Glycated hemoglobin; ESC = European Society of Cardiology; T2DM = Type 2 diabetes mellitus; AACE-ACE = American Association of Clinical Endocrinology/American College of Endocrinology; NICE = National Institute for Health and Care Excellence; BMI = Body mass index.
Posology
Based on various pharmacological studies, dosing conditions have been optimized. Oral semaglutide has to be given after overnight fasting (~6 hours) with up to 120 mL water. As food affects the absorption of semaglutide, post-dose fasting of 30 minutes is recommended before eating, drinking or taking any other medications. Oral semaglutide has to be initiated with the lowest dose of 3 mg and a 4-week dose escalation to 7 mg and then to 14 mg (if needed) is recommended to reduce the risk of GI adverse events.25
A Game Changer, A Life Changer
The availability of GLP-1RA in an oral formulation, a peptide in a pill, opens the possibility of untangling the glucose Gordian knot, and achieving safe and effective glucose as well as weight control. This baro-glycemic optimization should prove to be a game changer for all stakeholders in diabetes care, and a life changer for those who live with type 2 diabetes.
References
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