It's all about medicine

1. Journal Club
Vikram Sharma MD
PGY-1 - Internal Medicine

3. Background and Significance
● GLP-1 receptor agonists (semaglutide) are an effective way to achieve glycemic control in
patients with T2DM but have only been available in subcutaneous injection form
○ Well established data in subcutaneous administration
● Research and data regarding effectiveness of oral semaglutide is limited and has not been well
studied
● Oral semaglutide traditionally has very poor oral bioavailability due to extensive degradation via
proteolytic enzymes and poor absorption across the GI mucosa
● For this trial, oral semaglutide was formulated with absorption enhancement and dosages were
based on dose-finding phase 2 trial with 3 doses selected.
● Trial is a phase 3 trial to assess the efficacy and and safety of oral semaglutide monotherapy in
individuals with T2DM managed only with diet and exercise

4. Clinical Questions
● What is the effectiveness of oral semaglutide administration in T2DM compared to placebo in
patients with T2DM?

5. Research Design
● Randomized, double blind, placebo controlled, parallel group trial
○ Randomized: A study in which participants are divided into separate groups that compare different
treatments or interventions.
○ Double blind: A type of clinical trial in which neither the participants nor the researcher knows which
treatment or intervention participants are receiving until the clinical trial is over.
○ Parallel group: an experimental study design in which each subject is randomized to one of two or more
distinct treatment/intervention groups.
● Novo Nordisk A/S designed the trial, monitored sites, and collected and analyzed the data.
● One of the authors (O.K.J) was responsible for the statistical analysis.

6. Research Design Cont.
● A total of 1,006 patients were screened and 703 patients were randomized.
● Conducted at 93 sites across nine countries (Algeria, Bulgaria, Czech Republic, Japan, Mexico,
Russia, Serbia, Turkey, and the U.S.) from September 2016 to December 2017.
● Randomization of patients was stratified by Japanese and non-Japanese patients.
● The primary end point and the confirmatory secondary end point were planned to be tested for
superiority of oral semaglutide 3 mg, 7 mg, and 14 mg versus placebo, with a sample size
calculation (n = 704) to ensure a power of at least 90% to jointly confirm HbA1c superiority of
oral semaglutide versus placebo at each dose level.
● Approximately 50% of randomized patients were female, and mean age was 55 years, diabetes
duration 3.5 years, BMI 31.8 kg/m2, and HbA1c 8.0%

8. Inclusion Criteria
• Informed consent
• Male or female, age ≥18 years (Japan ≥20 years, Algeria ≥19 years)
• Diagnosed with type 2 diabetes mellitus and on treatment with diet/exercise for at least 30
days before screening
• Glycated hemoglobin 7.0–9.5% (both inclusive)

9. Exclusion Criteria
● Treatment with glucose-lowering agent in 90 days prior to screening (short-term [≤14 days]) insulin treatment
excepted)
● History of pancreatitis
● Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2
● Estimated glomerular filtration rate <60 mL/min/1.73 m2
● Acute coronary or cerebrovascular event within 180 days before randomization
● Heart failure New York Heart Association class IV
● Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated
fundoscopy performed within 90 days prior to randomization
● Malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and in-situ carcinomas)

10. Study
● Patients were randomized 1:1:1:1 to receive 3, 7, or 14 mg oral semaglutide or placebo.
● All patients randomized to oral semaglutide initiated treatment with 3 mg once daily with dose
escalations every 4 weeks until the randomized maintenance dose was achieved.
● There was a 5-week follow-up period after the 26-week treatment period
● Two Estimands:
○ The treatment policy estimand evaluates the treatment effect for all randomized patients regardless of trial product
discontinuation and use of rescue medication.
○ The trial product estimand evaluates the treatment effect for all randomized patients under the assumption that all
patients remained on trial product for the entire planned duration of the trial and did not use rescue medication.
● Rescue medication criteria for persistent hyperglycemia were confirmed fasting blood glucose .240
mg/dL from weeks 8-13 or .200 mg/dL from week 14 onward.

12. Data Collected
Changes from baseline to week 26:
● HbA1c
● Body weight (kg)
● Fasting plasma glucose
● SMBG
● BMI
● Pulse
● Systolic blood pressure
● Diastolic blood pressure

13. Data Collected Contd.
● Fasting pro-insulin
● Fasting glucagon
● Fasting C peptide
● Fasting insulin
● C-reactive protein
● HOMA-B
● HOMA-IR
● Total cholesterol
● Low-density lipoprotein cholesterol
● High-density lipoprotein cholesterol
● Triglycerides

14. Study End Points
● The primary end point was change in HbA1c from baseline to week 26.
● The confirmatory secondary end point was change from baseline to week 26 in body weight.
● Supportive secondary end points included:
○ Changes in measures of glucose control (including fasting plasma glucose, C-peptide, insulin, proinsulin,
glucagon, self-monitored blood glucose [SMBG] profile, and achievement of an HbA1c target of <7% or
≤6.5%)
○ Achievement of weight loss of at least 5% or 10%, as well as C-reactive protein and fasting lipid levels—all
from baseline to week 26.
● Composite End Points:
○ 1) HbA1c <7% without severe or blood glucose–confirmed (<56 mg/dL symptomatic hypoglycemia and no
weight gain
○ 2) at least an absolute reduction in HbA1c of 1% and body weight loss of 3% or more.

15. Study End Points: Statistical Analysis
● The primary end point and the confirmatory secondary end point were planned to be tested for superiority of oral
semaglutide 3 mg, 7 mg, and 14 mg versus placebo, with a sample size calculation (n = 704) to ensure a power of
at least 90% to jointly confirm HbA1c superiority of oral semaglutide versus placebo at each dose level.
● The confirmation of efficacy of oral semaglutide on change in HbA1c and in body weight both from baseline to
week 26 was based on a weighted Bonferroni closed-testing strategy to control the overall type 1 error for the
hypotheses evaluated by the treatment policy estimand
○ Bonferroni allows for test of all endpoints
● Imputation was done within groups defined by trial product and treatment status at week 26.
○ Both the imputation and the analysis were based on ANCOVA models.
● The treatment policy estimand was estimated by a pattern mixture model using multiple imputation to handle
missing week-26 data for both confirmatory end points.
● The trial product estimand was estimated by a mixed model for repeated measurements (MMRM) that used data
collected prior to premature trial product discontinuation or initiation of rescue medication from all randomized
patients.
○ MMRM: Reduces bias involving missing data due to trials having repeated outcome measures over time.
■ Unbiasedness for data which are missing completely at random (MCAR) or missing at random (MAR) vs. t-test
which can lead to bias.

26. Results: Glycemic Control
All three doses of oral semaglutide resulted in clinically meaningful and superior reductions in HbA1c compared with
placebo for the treatment policy estimand (regardless of rescue medication use and trial product discontinuation) and
statistically significant reductions for the trial product estimand (on treatment without the use of rescue medication)
Placebo-adjusted estimated treatment differences at week 26 for oral semaglutide 3, 7, and 14 mg: (P < 0.001 for all):
Treatment Policy:
● 3 mg: −0.6% (95% CI −0.8 to −0.4) (–6 mmol/mol [95% CI –9 to –4])
● 7 mg: −0.9% (−1.1 to −0.6) (–9 mmol/mol [–12 to –7])
● 14 mg: −1.1% (−1.3 to −0.9) (–12 mmol/mol [–15 to –9])

27. Results: Glycemic Control
Trial Product:
● 3 mg: −0.7% (−0.9 to −0.5) (–7 mmol/mol [–10 to –5])
● 7 mg: −1.2% (−1.5 to −1.0) (–14 mmol/mol [–16 to –11])
● 14 mg: −1.4% (−1.7 to −1.2) (–16 mmol/mol [–18 to –13])
● The observed proportion of patients achieving the HbA1c targets (<7.0% and ≤6.5%) were
greater with oral semaglutide compared with placebo. The odds of achieving each target were
statistically significantly greater with oral semaglutide than with placebo (P < 0.001 for all doses).
● Oral semaglutide also reduced fasting plasma glucose significantly more than placebo (P < 0.001
for the trial product estimand)

28. Results: Body Weight
● Treatment Policy Estimand: Oral semaglutide (14 mg only) provided superior reductions in body
weight compared with placebo.
● Trial Policy Estimand: Oral semaglutide (7 and 14 mg) provided statistically significant reductions
in body weight compared with placebo.
● Significantly more patients achieved body weight loss of at least 5% with oral semaglutide at 7
mg and 14 mg compared with placebo

29. Results: Body Weight
Treatment Policy:
−3 mg: 0.1 kg (95% CI −0.9 to 0.8) (P = 0.87),
−7 mg: 0.9 kg (−1.9 to 0.1) (P = 0.09)
− 14 mg: 2.3 kg (−3.1 to −1.5) (P < 0.001)
Trial Product:
− 3 mg: 0.2 kg (−1.0 to 0.6) (P = 0.71),
− 7 mg: 1.0 kg (−1.8 to −0.2) (P = 0.01)
− 14 mg: 2.6 kg (−3.4 to −1.8) (P < 0.001)

30. Results: Other Outcomes
● The observed proportion of patients who achieved the triple composite end point of HbA1c
<7%) without severe or blood glucose–confirmed symptomatic hypoglycemia or weight gain was
higher with oral semaglutide (all doses) versus placebo.
● The observed proportion of patients who achieved the composite end point of an HbA1c
reduction of 1% or more and body weight loss of 3% or more was also higher with oral
semaglutide versus placebo in the trial product estimand.

31. Significance: Clinical vs. Statistical?
● Glycemic Control
○ Statistically significant reduction in glycemic control across two estimands and all pre-selected doses
○ Clinically significant reduction in HbA1c with 0.6% - 1.4% decrease throughout
● Body Weight
○ Statistically significant only in higher doses (7 mg and 14 mg)
○ Clinically modest weight reduction (maximum of 2.6 kg weight lost)
■ Diet and exercise?
● Overall
○ The highest dose of oral semaglutide studied (14 mg daily) resulted in a mean reduction of 1.5%, from a
baseline HbA1c of 8.0% to a final HbA1c of 6.5%, and a body weight reduction of 4.1 kg, with 80% of
patients achieving an HbA1c target of <7% (trial product estimand).
■ Significant decrease in HbA1c into target HbA1c ranges

32. External Validity
● Broad demographics of subjects enrolled in study with large age range (18/19+)
○ Male and Female subjects (50% each)
○ Mean age: 55
○ Diverse population of subjects enrolled - international
○ Similar to Fresno’s diverse population
● History of DMII as inclusion criteria along with given range of HbA1c levels
○ Large population of patient encounters at SAMC involve those with a history of DMII with HbA1c levels in
elevated ranges
○ However, the mean duration of DMII in this study was relatively short at 3.5 years and only controlled via
diet and exercise
● Exclusion criteria of those with CKD (GFR <60) may have limited effect on outcome
● Based on inclusion and exclusion criteria, this has acceptable external validity

33. Internal Validity
● This study has high internal validity as results showed statistically significant reduction in HbA1c
and body weight from baseline at week 26 of oral semaglutide therapy as was its aim

34. Limitations
● Only enrolled patients whose diabetes was being managed only with diet and exercise at trial
entry
○ Many patients, including our population, have DMII requiring management with other modalities
● The mean duration of diabetes in study participants was only 3.5 years
○ Difficult to extrapolate information to patients who have established DMII diagnoses
● Oral semaglutide was given as first-line monotherapy, while metformin is usually recommended
as first-line pharmacotherapy in the management of type 2 diabetes.
○ Similar decreases in HbA1c may be possible with Metformin therapy
● Relatively shorter duration of trial (26 weeks)
● HbA1c baseline was 8% for study

35. Future
● Longer term trials:
○ Currently underway at time of publication
● Oral semaglutide in conjunction with other glucose lowering medications
○ Safety and efficacy
○ Including testing in conjunction with Metformin
● Testing in those with high level heart failure or renal impairments

36. Questions?

37. Various Statistical Issues
● Weighted Bonferroni closed testing:
● Imputation of Missing Data:
● ANCOVA models and Rubin’s rules:
● Mixed models for Repeated Measurements: