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CE: Review of Semaglutide, the First Oral GLP-1 Receptor Agonist

21 Jan 2021 6:30 PM | Anonymous

By: Rachel Kiehne, PharmD; PGY2 Ambulatory Care Resident

Mentor: Justinne Guyton, PharmD, BCACP, PGY2 Ambulatory Care Residency Director, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis/St. Louis County Department of Public Health

Program Number: 2021-01-04

Approval Dates: February 3, 2021 to August 1, 2021

Approved Contact Hours: 1 hour

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Learning Objectives:

  1. Identify appropriate dosing and administration instructions for oral semaglutide
  2. Describe the mechanism of action of oral semaglutide
  3. Compare oral semaglutide to other injectable GLP-1 receptor agonists
  4. Summarize the results of the PIONEER trials

Introduction:

There is a growing need for new and innovative drugs due to the significant prevalence, morbidity, and mortality of type 2 diabetes mellitus. In 2018, 32.6 million people in the United States had this disease, and diabetes mellitus was the seventh leading cause of death.1 The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in clinical practice for the treatment of type 2 diabetes mellitus has steadily increased over the past few years due to its unique mechanism of action, efficacy, and effect on major adverse cardiac events.

According to the 2020 American Diabetes Association (ADA) guidelines, first-line treatment of type 2 diabetes mellitus should be a combination of maximally titrated metformin and lifestyle modifications. The next medication used is then dependent upon clinical characteristics and patient preference. Some considerations include presence of atherosclerotic cardiovascular disease (ASCVD), heart failure, chronic kidney disease (CKD), minimizing hypoglycemia risk, minimizing weight gain/promoting weight loss, and cost. The GLP-1 RA class is a reasonable choice in most of these categories; an exception is cost concerns due to availability as brand name only. Additionally, some GLP-1 RAs provide benefit in reducing cardiovascular disease events (i.e. liraglutide, semaglutide and dulaglutide) and therefore are preferred in patients with established ASCVD. This class has not shown reduction in heart failure hospitalizations, but several agents have shown renal benefits. Additionally, in patients with significant hyperglycemia that require injectable therapy, GLP-1 RAs should be considered prior to insulin in most patients.2

One potential barrier to initiation of a medication in the GLP-1 RA class is administration. Until recently, these medications were only available as subcutaneous injections that ranged from twice daily to once weekly. However, in September 2019, the first oral GLP-1 RA was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.3 Of note, oral semaglutide is available as the brand name Rybelsus®, while subcutaneous semaglutide is available under the brand name Ozempic®. Availability of an oral formulation makes GLP-1 RAs more accessible to patients who are resistant or unable to perform self-administered injections. However, not all GLP-RAs have shown the same degree of A1c lowering, weight loss, or cardiovascular benefit. Therefore, this article will focus on reviewing the pharmacology, pharmacokinetics, and clinical trial data for oral semaglutide.

Pharmacology:

Semaglutide is an analogue with 94% sequence homology to the endogenous hormone, GLP-1. It therefore binds to and activates the GLP-1 receptor. Semaglutide has increased albumin binding compared to endogenous GLP-1, which extends the half-life significantly by reducing renal clearance and protecting the drug from metabolic degradation. Semaglutide is also stabilized against degradation by the DPP-4 enzyme.4

Semaglutide achieves blood glucose reduction by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. It also slightly delays gastric emptying in the early phase after food intake, which reduces the rate at which postprandial glucose appears in blood circulation. Due to its long half-life, both fasting and post-prandial glucose levels are reduced with semaglutide. During induced hypoglycemia, semaglutide does not inhibit counter-regulatory increases in glucagon versus placebo.4

Pharmacokinetics:

Oral semaglutide is co-formulated with salcaprozate sodium. This aids absorption after oral administration, which mainly occurs in the stomach. Maximum concentrations of oral semaglutide occur 1-hour post-dose, and steady state exposure is achieved after 4-5 weeks of administration. Bioavailability of oral semaglutide is 0.4%-1%.4

The volume of distribution of semaglutide is approximately 8 liters. Semaglutide is highly albumin-bound (>99%).4

The elimination half-life is approximately 1 week, and semaglutide will remain in circulation for approximately 5 weeks following the last dose. The primary method of semaglutide metabolism is proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. The primary method of secretion is through the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine unchanged.4

Oral semaglutide does not significantly inhibit or induce CYP enzymes or drug transporters. However, due to it’s ability to delay gastric emptying, there is some potential for increased drug absorption of other medications. A drug interaction study showed that oral semaglutide increased exposure of levothyroxine by 33%.4

Administration and dosing:

Semaglutide should be administered at 3 mg by mouth once daily for 30 days, then 7 mg by mouth once daily. If further glycemic control is needed after another 30 days, then the dose may be increased to a maximum dose of 14 mg by mouth once daily. In order to achieve full oral absorption, semaglutide should be administered on an empty stomach at least 30 minutes before the first food, beverages, or other oral medications and with a maximum of 4 ounces of plain water. Tablets should also be swallowed whole without splitting, chewing, or crushing.4

Clinical Trial Data:

Novo Nordisk funded a series of ten clinical trials to study the safety and efficacy of oral semaglutide. These trials make up the PIONEER (Peptide InnOvatioN for Early diabEtEs tReatment) series. This series compares oral semaglutide to placebo as well as other standard of care glucose-lowering medications.5-14

Common key inclusion criteria for the PIONEER trials include adults aged 18 and older with type 2 diabetes mellitus, an A1c between either 7.0% to 9.5% or 7.0 to 10.5%, and various background glucose-lowering medications. Common key exclusion criteria included eGFR less than 60 mL/min/1.73m2, history of pancreatitis, history of proliferative retinopathy or maculopathy requiring acute treatment, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and any medication for diabetes or obesity within previous 90 days other than those meeting inclusion criteria or short-term insulin for less than 14 days.5-14

All trials also allowed for use of additional glucose-lowering medication (other than GLP-1 RAs or DPP-4 inhibitors) if the subject discontinued the trial product, or if rescue medication was required as add-on to the trial product due to unacceptable hyperglycemia or elevated A1c. Most of the trials performed two statistical tests using the treatment policy estimand and trial product estimand. The treatment policy estimand was an intention-to-treat analysis that included all subjects regardless of additional glucose-lowering medication use or trial product discontinuation. The trial product estimand was a per-protocol analysis that estimated results using data collected prior to premature discontinuation or initiation of rescue medication. Results will be listed for the treatment policy estimand unless otherwise specified.5-14

Oral semaglutide versus placebo

PIONEER 1 was a 26-week, randomized, double-blind clinical trial comparing the efficacy of daily oral semaglutide versus placebo as monotherapy for type 2 diabetes managed with diet and exercise alone. Patients were randomized in a 1:1:1:1 ratio to oral semaglutide 3 mg, 7 mg, or 14 mg and placebo. The dose of oral semaglutide was increased every 4 weeks until the randomize dose was achieved. Rescue medications could be used if fasting blood glucose levels were greater than 240 mg/dL from weeks 8-13 or greater than 200 mg/dL from week 14 onward. The primary endpoint was change in A1c from baseline to week 26, and the confirmatory secondary endpoint was change from baseline to week 26 in body weight. The estimated treatment differences (ETD) for A1c lowering for oral semaglutide 3 mg, 7 mg, and 14 mg versus placebo were -0.6%, -0.9%, and -1.1% respectively (p<0.001). All results significantly favored oral semaglutide. For change in bodyweight, only the 14 mg dose of oral semaglutide showed significantly more bodyweight reduction than placebo with an ETD of -2.3 kg (p<0.001). The ETDs for the 3 mg and 7 mg doses versus placebo were -0.1 kg (p = 0.87) and -0.9 kg (p = 0.09).5

PIONEER 5 was a 26-week, randomized, double-blind clinical trial to compare the efficacy of oral semaglutide versus placebo as add-on to metformin and/or a sulfonylurea, or basal insulin with or without metformin in patients with type 2 diabetes mellitus and moderate renal impairment (eGFR 30-59 mL/min/1.73m2). Patients were randomized in a 1:1 fashion to either once-daily oral semaglutide 14 mg or placebo. Semaglutide was titrated every 4 weeks until the target dose was reached. Rescue medications could be used if fasting blood glucose levels were greater than 240 mg/dL from weeks 12-16 or greater than 200 mg/dL at week 17 and later. The primary endpoint was change from baseline to week 26 in A1c, with the confirmatory secondary endpoint being change in bodyweight during this timeframe. The ETD for change in A1c for oral semaglutide versus placebo was -0.8%, with an ETD of -2.5 kg for change in body weight (p<0.0001). The eGFR remained unchanged throughout the trial period. This shows that oral semaglutide is safe and effective in patients with moderate renal impairment.6

Oral semaglutide versus placebo as add-on to insulin

PIONEER 8 was a 52-week, randomized, double-blind clinical trial comparing the efficacy of oral semaglutide to placebo as add-on to insulin with or without metformin for treatment of type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1 ratio to either semaglutide (3 mg, 7 mg, or 14 mg) or placebo. Oral semaglutide was titrated every 4 weeks until target dose was achieved. The baseline insulin dose was reduced by 20% at randomization and maintained until week 8. The dose of insulin could then be altered from weeks 8 to 26 without exceeding pre-trial dosing and was freely adjustable from weeks 26 to 52. The dose of insulin could be lowered at any time if deemed appropriate. Basal insulin doses were adjusted based on self-monitored blood glucose readings measured 3 days leading up to the visit. The recommended target fasting blood glucose was 71-99 mg/dL and A1c was less than 7.0%. Adjustments were made in 2-unit increments if fasting blood sugars were 100-126 mg/dL and up to 8 units if over 162 mg/dL. Increases in insulin doses met rescue medication criteria if the dose was increased by at least 20% and maintained for 2 visits. Other criteria for rescue medication were fasting blood glucose greater than 200 mg/dL at week 16 and later, and an A1c > 8.5% at week 26 and later. The primary endpoint was change in A1c from baseline to week 26, and the confirmatory secondary endpoint was change in bodyweight at week 26. Oral semaglutide was more effective for A1c lowering at week 26, with an ETD of -0.5%, -0.9%, and -1.2% for the 3 mg, 7 mg, and 14 mg doses respectively (p<0.0001). The 3 mg, 7 mg, and 14 mg doses of oral semaglutide had significantly larger reductions in bodyweight than placebo, with an ETD of -0.9 kg (p = 0.0.0392), -2.0 kg (p = 0.0001) and -3.3 kg (p = <0.0001). At 52 weeks, all three doses of oral semaglutide demonstrated significant decreases in total daily insulin dosage versus placebo, with an ETD of -8 units (p = 0.0450), -16 units (p<0.0001), and -17 units (p<0.0001) for the 3 mg, 7 mg, and 14 mg doses respectively.7

Oral semaglutide versus SGLT-2 Inhibitor

PIONEER 2 was a 52-week, randomized, open-label clinical trial comparing the efficacy of daily oral semaglutide versus empagliflozin as add-on to metformin for type 2 diabetes mellitus. Patients were randomized in a 1:1 ratio to oral semaglutide 14 mg daily versus oral empagliflozin 25 mg daily. Empagliflozin was titrated every 4 week until the treatment dose was achieved, while empagliflozin was started at 10 mg daily then increased to 25 mg daily at week 8. Rescue medications could be used if fasting blood glucose levels were above 260 mg/dL from weeks 8 to 13, greater than 240 mg/dL from weeks 14 to 25, and greater than 200 mg/dL or A1c greater than 8.5% weeks 26 and later. The primary outcome was change in A1c while the confirmatory endpoint was change in bodyweight, both from baseline to week 26. Oral semaglutide 14 mg significantly reduced A1c more than empagliflozin 25 mg at week 26, with an ETD of -0.4% (p<0.0001). However, there was no significant difference between the two groups for bodyweight lowering at 26 weeks, with an ETD of -0.1 kg (p = 0.7593).8

Oral semaglutide versus DPP-4 Inhibitor

PIONEER 3 was a 78-week, randomized, double-blind, double-dummy clinical trial comparing the efficacy of daily oral semaglutide versus sitagliptin as add-on to metformin with or without a sulfonylurea for treatment of type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1 ratio to daily oral semaglutide (3 mg, 7 mg, or 14 mg) or daily oral sitagliptin (100 mg). Oral semaglutide was titrated every 4 weeks until the treatment dose was achieved, while sitagliptin was initiated and maintained at 100 mg daily. The primary outcome was change in A1c while the confirmatory endpoint was change in bodyweight, both from baseline to week 26. Semaglutide 3 mg significantly reduced the A1c compared to oral sitagliptin at 26 weeks with an ETD of 0.2% (p = 0.008). However, the 7 mg and 14 mg doses demonstrated significantly more A1c lowering, with an ETD of -0.3% and -0.5% respectively (p<0.001). All three doses of oral semaglutide significantly reduced bodyweight, with ETDs of -0.6 kg (p = 0.02), -1.6 kg (p<0.001), and -2.5 kg (p<0.001) for the 3 mg, 7 mg, and 14 mg doses respectively when compared to sitagliptin 100 mg daily.9

PIONEER 7 was a 52-week, randomized, open-label clinical trial comparing the efficacy of flexibly dosed oral semaglutide versus sitagliptin as add-on to stable doses of one or two glucose-lowering medications (metformin, sulfonylureas, SGLT-2 inhibitors, or thiazolidinediones for treatment of type 2 diabetes. Patient were randomized in a 1:1 ratio to either flexibly dosed oral semaglutide or sitagliptin 100 mg daily. Oral semaglutide was started at 3 mg daily, then every 8 weeks the dose could be adjusted. The current dose was continued if the A1c was less than 7.0%, and increased if 7.0% or greater. However, if moderate-to-severe nausea or vomiting occurred 3 or more days during the week prior to the visit, oral semaglutide was maintained or decreased regardless of glycemic control. Rescue medication was offered to patients with an A1c of 8.5% or higher from week 32 onward. The primary outcome was achievement of an A1c target less than 7.0% at week 52. The confirmatory secondary endpoint was change in bodyweight during the same time period. The use of flexibly dosed oral semaglutide significantly increased the proportion of patients achieving an A1c of <7.0% versus sitagliptin, with an odds ratio (OR) of 4.40 (p<0.0001). Oral semaglutide also significantly reduced bodyweight at 52 weeks, with an ETD of -1.9 kg (p<0.0001).10

Oral semaglutide versus other GLP-1 RA

PIONEER 4 was a 52-week, randomized, double-blind, double-dummy clinical trial comparing the efficacy of daily oral semaglutide versus subcutaneous liraglutide as add-on to metformin with or without an SGLT-2 inhibitor. Patients were randomized in a 2:2:1 ratio to daily oral semaglutide (14 mg) versus daily subcutaneous liraglutide (1.8 mg) vs placebo. The dose of oral semaglutide was increased at 4 week intervals until the target dose was reached, while liraglutide was started at 0.6 mg daily, then increased to 1.2 mg daily at week 1, then increased and maintained at 1.8 mg daily at week 2. Rescue medication could be used if fasting blood glucose levels were above 240 mg/dL from weeks 8 to 13, greater than 200 mg/dL from weeks 14 and later, and an A1c greater than 8.5% weeks 26 and later. The primary outcome was change in A1c from baseline to week 26, while the confirmatory endpoint was change in bodyweight. The use of oral semaglutide 14 mg daily demonstrated no difference in A1c lowering at 26 weeks with an ETD of -0.1% (p = 0.0645), but had significantly more bodyweight lowering at 26 weeks versus liraglutide 1.8 mg daily with an ETD of -1.2 kg (p = 0.0003). There was significantly more A1c and bodyweight lowering with oral semaglutide compared to placebo, with ETDs of -1.1% and -3.3 kg respectively (p<0.0001).11

PIONEER 9 was a 52-week, randomized, double-blind clinical trial to study the efficacy of oral semaglutide versus subcutaneous liraglutide as monotherapy in Japanese patients with type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1:1 ratio to receive oral semaglutide daily (3 mg, 7 mg, or 14 mg) or subcutaneous liraglutide daily (0.9 mg) or placebo. The dose of oral semaglutide was titrated every 4 weeks. Subcutaneous liraglutide was started at 0.3 mg daily, then increased by 0.3 mg at weeks 1 and 2 to achieve the 0.9 mg dose, which is the maximum approved dose in Japan. The liraglutide injections were open-label, but all oral doses were blinded. Rescue medication could be added if patients had blood glucose levels above 240 mg/dL from weeks 8-13, or greater than 200 mg/dL from week 14 onwards. Rescue medication could also be given from week 26 and later if A1c was greater than 8.5%. The primary outcome was change in A1c from baseline to week 26. A secondary endpoint included change in bodyweight at week 26. At week 26, oral semaglutide demonstrated significantly more A1c reduction than placebo at all three doses, with ETDs of -1.1%, -1.5%, and -1.7% for the 3 mg, 7 mg, and 14 doses respectively (p<0.0001). Compared to liraglutide, oral semaglutide showed no difference in A1c reduction at the 3 mg and 7 mg doses, with respective ETDs of 0.3% (p = 0.0799) and -0.1% (p = 0.3942). However, there was more A1c lowering with oral semaglutide 14 mg than liraglutide with and ETD of -0.3% (p = 0.0272). At 26 week, oral semaglutide did not reduce bodyweight versus placebo at 3 mg and 7 mg doses. However, there was significantly more bodyweight reduction with the 14 mg dose, with an ETD of -1.2 (p = 0.0073). When compared to liraglutide, the 3 mg dose of oral semaglutide did not demonstrate more bodyweight reduction, but the 7 mg and 14 doses did, with respective ETDs of -0.4 kg (p = 0.3233), -0.9 kg (p = 0.0312), and -2.3 kg (p<0.0001).12

PIONEER 10 was a 52-week randomized, open-label clinical trial to compare the safety and efficacy of subcutaneous dulaglutide as add-on to monotherapy (sulfonylurea, glinide, TZD, alpha-glucosidase inhibitor, or SGLT-2 inhibitor) in Japanese patients with type 2 diabetes mellitus. Patients were randomized in a 2:2:2:1 ratio to receive either oral semaglutide (3 mg, 7 mg, or 14 mg) or subcutaneous dulaglutide weekly (0.75 mg). The dose of oral semaglutide was increased every 4 weeks until the target dose was reached. Subcutaneous dulaglutide was initiated and maintained at 0.75 mg once weekly, which is the maximum approved dose in Japan. Rescue medication could be added if fasting blood glucose levels were greater than 240 mg/dL during weeks 14-25, greater than 200 mg/dL after week 26, or an A1c greater than 8.5% at week 26 and later. The primary endpoint was number of treatment-emergent adverse events during exposure to the study drug (Table 3). Change in A1c and bodyweight from baseline to week 26 were also measured as secondary outcomes. Compared to dulaglutide, oral semaglutide 3 mg demonstrated less A1c lowering with an ETD of 0.4% (p = 0.0026), similar A1c lowering for the 7 mg dose with an ETD of -0.1% (p = 0.2710), and more A1c lowering at the 14 mg dose with an ETD of -0.4% (p = 0.0006). There was no significant difference in bodyweight lowering for the 3 mg dose of oral semaglutide, but there was significant decreases in bodyweight compared to dulaglutide for the 7 mg and 14 mg doses, with ETDs of -0.5 kg (p = 0.2632), -1.3 kg (p = 0.0023), and -2.5 kg (p<0.0001) respectively.13

Oral Semaglutide and Cardiovascular Outcomes

PIONEER 6 was an event-driven, randomized, double-blind, placebo-controlled clinical trial to investigate cardiovascular outcomes on treatment with once-daily oral semaglutide versus placebo as add-on to standard of care for patients with type 2 diabetes mellitus. Patients were included in this study if they were 50 years of age or older and had established cardiovascular disease (CVD) or CKD or if they were 60 years of age or older and had cardiovascular risk factors only. Key exclusion criteria were treatment with an GLP-1 RA, DPP-4 inhibitor, or pramlintide within 90 days prior to screening; New York Heart Association class 4 heart failure; planned coronary-artery, carotid-artery, or peripheral-artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within 60 days before screening; long-term or intermittent hemodialysis or peritoneal dialysis, or severe renal impairment (eGFR <30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment. The primary outcome was time from randomization to the first occurrence of a major adverse cardiovascular event (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The hazard ratio for the primary outcome was 0.79 (p<0.0001 for noninferiority, p = 0.17 for superiority). Therefore, oral semaglutide has shown cardiovascular safety, but has not demonstrated cardiovascular benefit.14 However, an additional trial is currently underway to further investigate the cardiovascular effects of oral semaglutide with a larger patient population for a longer follow-up period. This trial is titled “A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL).” However, the study completion is not expected until 2024.15

Side effects

A summary of adverse effects is reported in table 3. The most common reported adverse events were consistent with those seen by the injectable GLP-1 RAs, including gastrointestinal upset (nausea, vomiting, diarrhea). Rates of severe or blood-glucose confirmed hypoglycemia were low, with most events occurring in trials where patients were receiving background glucose-lowering agents with known risk of hypoglycemia (sulfonylureas, insulin).2,5-14

Conclusions

Oral semaglutide benefits include A1c and bodyweight reduction, both in comparison to placebo and other standard of care treatment regimens. The reductions in A1c and bodyweight are dose-dependent, and based on the results of the PIONEER series, all patients should be titrated up to a minimum effective dose of 7 mg. Small benefit from the 3 mg may still be seen during the titration period, which is used to minimize GI side effects. The results of the PIONEER 7 trial also showed that based on tolerability and blood glucose control, flexible dosing of semaglutide is a reasonable treatment strategy.5-14

At 26 weeks, oral semaglutide at the maximum dose of 14 mg daily was more effective for A1c reduction than placebo, oral empagliflozin 25 mg daily, oral sitagliptin 100 mg daily, titration of current insulin regimen, subcutaneous liraglutide 0.9 mg daily in Japanese patients, and subcutaneous dulaglutide 0.75 mg weekly in Japanese patients. Oral semaglutide 14 mg daily had similar A1c lowering when compared to subcutaneous liraglutide 1.8 mg daily.5-14

Oral semaglutide 14 mg daily significantly reduced bodyweight at 26 weeks when compared to placebo, oral sitagliptin 100 mg daily, further titration of background insulin regimen, subcutaneous liraglutide 1.8 mg daily, subcutaneous liraglutide 0.9 mg daily in Japanese patients, and subcutaneous dulaglutide 0.75 mg weekly in Japanese patients. Similar bodyweight reductions were seen with oral semaglutide 14 mg daily and oral empagliflozin 25 mg daily at 26 weeks.5-14

One major limitation of implementation of this new dosage form is the lack of demonstrated cardiovascular benefit that has been seen in other injectable GLP-1 RAs, including injectable semaglutide.2 However, use may increase significantly if the SOUL trial shows cardiovascular benefit.15 Currently, oral semaglutide should be considered in patients who are averse to injectable formulations. While oral semaglutide demonstrated cardiovascular safety in the PIONEER 5 trial, the injectable GLP-1 RAs and oral SGLT-2 inhibitors that have demonstrated cardiovascular risk reduction would be preferred in patients with clinical ASCVD. Cost considerations are also important, as use is limited to patients with good insurance coverage or those that qualify for patient assistance programs. Patients started on oral semaglutide should be counseled on potential gastrointestinal side effects and its unique administration instructions.



*Exact results not reported for change in bodyweight or change in A1c

Abbreviations: AGI, alpha-glucosidase inhibitors; BAS, basal; BMI, body mass index; BOL, bolus; DUL, dulaglutide; EMP, empagliflozin; ETD, estimated treatment difference; FLEX, flexible-dosing; GLI, glinides; INS, insulin; LIR, liraglutide; MET, metformin; PLA, placebo; SEM, semaglutide; SGLT-2i, Sodium-glucose co-transporter-2 inhibitor; SIT, sitagliptin; SU, sulfonylureas; TZD, Thiazolidinediones; T2DM, type 2 diabetes mellitus

Abbreviations: MAX, maximally tolerated dose; PLA, placebo; SEM, semaglutide



Abbreviations: AGI, alpha-glucosidase inhibitors; BAS, basal; BMI, body mass index; BOL, bolus; DUL, dulaglutide; EMP, empagliflozin; ETD, estimated treatment difference; FLEX, flexible-dosing; GLI, glinides; INS, insulin; LIR, liraglutide; MET, metformin; PLA, placebo; SEM, semaglutide; SGLT-2i, Sodium-glucose co-transporter-2 inhibitor; SIT, sitagliptin; SU, sulfonylureas; TZD, Thiazolidinediones

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References:

  1. American Diabetes Association. Statistics about Diabetes. https://www.diabetes.org/resources/statistics/statistics-about-diabetes. Accessed: Oct 2020.
  2. American Diabetes Association. Standards of Medical Care in Diabetes – 2020. Diab Care. 2020;43(Suppl. 1):S3-S212.
  3. Novo Nordisk A/A [press release]. FDA approves Rybelsus® (semaglutide), the first GLP-1 analog treatment available in a pill for adults with type 2 diabetes. Sept 2020. https://www.novonordisk-us.com/media/news-releases.html?122973. Accessed: Nov 2020.
  4. Rybelsus (semaglutide tablets) [package insert]. Plainsboro, NJ: Novo Nordisk Inc; January 2020
  5. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019;42(9):1724-1732.
  6. Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):515-527.
  7. Zinman B, Aroda VR, Buse JB, et al. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019;42(12):2262-2271.
  8. Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019;42(12):2272-2281.
  9. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019;321(15):1466-1480.
  10. Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):528-539.
  11. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.
  12. Yamada Y, Katagiri H, Hamamoto Y, et al. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020;8(5):377-391.
  13. Yabe D, Nakamura J, Kaneto H, et al. Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 2020;8(5):392-406.
  14. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-851.
  15. ClinicalTrials.gov [Internet]. National Library of Medicine. Nov 2020. NLM identifier: NCT03914326, A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). https://clinicaltrials.gov/ct2/show/NCT03914326. Accessed: Nov 2020.


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