Effect of Oral Semaglutide Compared with Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients with Type 2 Diabetes

Julia Lvovich, Mercer University College of Pharmacy

Worldwide, type II diabetes affects 9% of male population and 7.9% of female population. [1] It has been shown that genetics, lifestyle, and environment factors can predispose adults and children to develop insulin resistance that leads to increased glucose levels in the blood. Overtime, prolonged exposure to high blood glucose levels causes damage to blood vessels and increases risk for coronary artery disease, kidney disease, and obstructive sleep apnea. [2] Treatment of type II diabetes can be targeted with lifestyle modifications (e.g. weight and diet management, exercise) and pharmacotherapy. When considering pharmacotherapy agents, the choices depend on the desired lower blood glucose hemoglobin A1C (HbA1C) reduction, weight gain/loss properties, and other comorbidities. [1]

Glucagon-like peptide -1 (GLP-1) receptor agonists are incretin mimetics and lower HbA1C level by 0.5-1.5%. [3] These drugs also possess weight loss property, which provides an added benefit in type II diabetic patients. However, they are only available in injection formulations due to degradation of the peptides by stomach acid. [4] To overcome the pharmacological limitation, an oral GLP-1 receptor agonist was co-formulated with an absorption enhancer, which increases the local pH to prevent the degradation in the stomach. The efficacy and safety of the new drug, semaglutide, has been evaluated in a phase II trial, which is summarized below.

Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes
Design Phase II, randomized, parallel-group, double-blind (oral semaglutide only), open-label (subcutaneous semaglutide only) dosage-finding trial; N= 632
Objective To determine the dose-response of five different dosages of oral semaglutide compared to placebo and once weekly subcutaneous semaglutide in patients with type II diabetes
Study Groups Daily Oral semaglutide at doses of:

·       2.5mg (n=70)

·       5mg (n= 70)

·       10mg (n= 69)

·       20mg (n= 70)

·       40mg 8 week standard dose escalation (n= 71)

·       40mg 8 week slow dose escalation (n= 70)

·       40mg 8 week fast dose escalation (n= 70)

Oral placebo (n= 71)

Once weekly subcutaneous semaglutide 1.0mg (n=70)

Methods Inclusion Criteria:

18 or older years old with type II diabetes

·       HbA1C level range between 7.0-9.5% with diet and exercise or a stable dose of metformin for at least 30 days.

·       BMI of 25 to 40

Exclusion Criteria:

·       HbA1C outside of 7-10% range

·       Impaired renal function

·       BMI outside of 25-40

Patients were randomized into one of the 9 treatment groups using stratification randomization method. Patients were administered oral semaglutide or placebo in the morning after at least 6 hours of fasting, and did not eat or drink for at least 30 minutes. If fasting glucose exceeded 270mg/dL (week 1-5), 240mg/dL (week 6-11) or 200mg/dL (week 12 to end of trial), rescue medication was offered.

Duration December 2013- December 2014
Primary Outcome Measure Change in hemoglobin A1c from baseline to week 26
Baseline Characteristics
Placebo Group n= 71 2.5 mg

n= 70

5 mg

n= 69

10 mg

n= 70

20 mg

n= 70

40 mg

n= 71

Slow escalation 40mg

N= 70

Fast escalation 40mg

N= 70

1-mg SC

n= 69

Age, mean (SD), y 58.9 (10.3) 56.7 (9.9) 55.7 (11.0) 56.5 (10.1) 58.3 (10.2) 56.5 (10.4) 57.1 (10.5) 57.7 (10.8) 56.8 (11.8)
Body Weight, (SD) kg 93.8 (18.1) 93.6 (15.6) 93.1 (19.0) 91.8 (14.0) 93.8 (17.9) 90.8

(16.5)

93.3 (18.8) 92.0 (15.4) 88.8 (15.4)
BMI 32.6 (4.5) 31.7 (4.1) 31.6 (4.9) 31.9 (4.4) 32.0 (4.5) 31.1 (4.1) 32.3 (4.5) 31.7 (3.8) 30.7 (4.0)
HbA1c level (SD) % 8.0 (0.8) 8.0 (0.7) 7.8 (0.6) 7.8 (0.7) 7.9 (0.7) 8.0 (0.7) 8.0 (0.7) 7.8 (0.8) 7.8 (0.7)
Diabetes duration, years 6.7 (5.1) 6.1 (6.0) 5.3 (4.7) 5.8 (4.8) 7.0 (5.3) 7.7 (5.9) 6.6 (4.9) 5.6 (4.7) 5.6 (5.0)
Metformin use, No. % 58 (87.1) 61 (87.1) 60 (85.7) 58 (84.1) 59 (84.1) 61 (85.9) 60 (85.7) 60 (85.7) 58 (84.1)

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HbA1c, hemoglobin A1c; SC, subcutaneous.

Results
Placebo Groupn= 71 2.5 mg n= 70 5 mg

n= 69

10 mg

n= 70

20 mg

n= 70

40 mg

n= 71

1-mg SC

n= 69

HbA1C level at week 26, mean (95%CI), % 7.6 (7.4 to 7.8) 7.2 (7.0 to 7.4) 6.7 (6.5 to 6.9) 6.4 (6.2 to 6.6) 6.2 (6.0 to 6.4) 6.0 (5.8 to 6.2) 6.0 (5.8 to 6.2)
Change from baseline
in HbA1c level to week 26, mean (95% CI), % –0.3 (–0.5 to –0.1) –0.7 (–0.9 to –0.5) –1.2 (–1.4 to –1.0) –1.5 (–1.7 to –1.3) –1.7 (–1.9 to –1.5) –1.9 (–2.1 to –1.7) –1.9 (–2.1 to –1.7)
ETD for comparator vs. placebo for HbA1c level (95% CI), % N/A –0.4 (–0.7 to –0.1) –0.9 (–1.2 to –0.6) –1.2 (–1.5 to –0.9) –1.4 (–1.7 to –1.0) –1.6 (–1.9 to –1.3) –1.6 (–1.8 to –1.3)
p value N/A <0.01 <0.001 <.001 <.001 <.001 <.001
ETD for comparator vs. SC semaglutide for HbA1c level (95% CI), % N/A 1.2 (0.9 to 1.4) 0.7 (0.4 to 1.0) 0.4 (0.1 to 0.7) 0.2 (–0.1 to 0.5) <–0.0 (–0.3 to 0.3) NA
p value N/A < 0.001 < 0.001 0.01 0.24 0.80 NA
Change from baseline in fasting plasma glucose to week 26, mean (95% CI), mg/dL –1.1 (–9.6 to –7.5) –17.3 (–25.6 to –9.1) –27.8 (–36.1 to –19.4) –42.1 (–50.4 to –33.9) –41.9 (–50.6 to –33.1) –51.2 (–60.0 to –42.4) –56.3 (–65.3 to –47.4)
ETD for comparator vs. placebo for fasting plasma glucose (95% CI), mg/dL N/A –16.3 (–28.2 to –4.3) –26.7 (–38.7 to –14.6) –41.0 (–52.8 to –29.2) –40.8 (–52.9 to –28.6) –50.1 (–62.4 to –37.8) –55.3 (–67.6 to –42.9)
p value N/A < 0.01 <0.001 <0.001 <0.001 <0.001 <0.001
Change from baseline in body weight to week 26, mean (95% CI), kg –1.2 (–2.3 to –0.1) –2.1 (–3.1 to –1.0) –2.7 (–3.7 to –1.6) –4.8 (–5.8 to –3.7) –6.1 (–7.3 to –5.0) –6.9 (–8.0 to –5.8) –6.4 (–7.5 to –5.3)
ETD for comparator vs. placebo for body weight (95% CI), kg N/A –0.9 (–2.4 to 0.6) –1.5 (–3.0 to 0.0) –3.6 (–5.1 to –2.1) –5.0 (–6.5 to –3.4) –5.7 (–7.3 to –4.2) –5.2 (–6.8 to –3.7)
p value N/A 0.25 0.06 <0.001 <0.001 <0.001 <0.001

Abbreviations: ETD, estimated treatment difference; NA, not applicable; SC, subcutaneous.

Adverse Events Common Adverse Events: mild- moderate gastrointestinal adverse events (higher in oral and subcutaneous groups than in placebo), nausea, diarrhea,
Serious Adverse Events: two episodes severe hypoglycemia, three events of pancreatitis in the oral and subcutaneous groups
Percentage that Discontinued due to Adverse Events: 6-27% in oral group, and 14% in subcutaneous, vs. 1% in placebo

Placebo Group

n= 71, No. of Patients (%), [No. of events]

2.5 mg

n= 70

5 mg

n= 69

10 mg

n= 70

20 mg

n= 70

40 mg

n= 71

Slow escalation 40mg

N= 70

Fast escalation 40mg

N= 70

1-mg SC

n= 69

Adverse Events 48 (68) [127] 47 (67) [142] 44(63) [169] 52 (75) [233] 57 (81) [289] 56 (79) [230] 55 (79) [233] 60 (86) [245] 56 (81) [218]
Serious adverse events* 5 (7) [8] 1 (1) [1] 2 (3) [2] 2 (3) [5] NR 1 (1) [1] 3 (4) [3] 5 (7) [9] 2 (3) [2]
All gastrointestinal adverse events 20 (28) [32] 22 (31) [44] 2 (31) [49] 37 (54) [101] 39 (56) [127] 43 (61) [128] 38 (54) [116] 54 (77) [111] 37 (54) [86]

* Defined as an experience that at any dose results in any of the following: death; a life threatening experience; in patient hospitalization or prolongation of existing hospitalization; a persistent or significant disability or incapacity.

Study Author Conclusions Oral semaglutide resulted in better glycemic control compared to placebo. The data support progression to a phase III study to assess long-term outcomes and safety.

This phase II study of oral semaglutide provided short-term efficacy and safety data. Although limited by short study duration, the data show that oral semaglutide may be as safe and effective as injectable GLP-1 agonists in lowering HbA1C, especially at higher doses (20-40mg). Such findings suggest that oral therapy may be a viable alternative for patients with poor adherence to injectable medications. Based on the results, conducting a phase III trial to assess long-term outcomes in a larger population may be reasonable to further assess the safety and efficacy of the drug.

References

  1. Zhou B, Lu Y, Hajifathalian K, Bentham J, Di Cesare, M,  Danaei G, Bixby H. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387(10027):1513-30.
  2. Lam DC, Lui MM, Lam JC, Ong LH, Lam KS, Ip MS. Prevalence and recognition of obstructive sleep apnea in Chinese patients with type 2 diabetes mellitus. Chest. 2010;138(5):1101-7.
  3. Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(10):CD006423.
  4. Davies M, Pieber TR, Hartoft-nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: A randomized clinical trial. JAMA. 2017;318(15):1460-1470.

 

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