Effects of Cinnamon Supplementation on Glucose Metabolism in Patients With Pre-diabetes

BACKGROUND: The transition from normal glucose tolerance and insulin sensitivity to overt
type 2 diabetes (T2D) encompasses a variety of glycemic abnormalities that are commonly
referred to as 'prediabetes'. In 2003, 314 million people (8.2% of the adult population) had
prediabetes, and this number is projected to increase to 472 million (9.0% of the adult
population) by 2025. Approximately 40-50% of individuals with prediabetes have been reported
to develop T2D within 10 years.

While intensive lifestyle interventions remain the cornerstone of T2D prevention, targeted
pharmacotherapy has been shown to be effective and may be considered in high-risk patients.
Several antidiabetic medications prevent or, at least, delay the progression from prediabetes
to diabetes, including metformin, α-glucosidase inhibitors or pioglitazone. However, cost,
potential adverse effects, and secondary failure in the long-term have often limited the
widespread use of these and other newer antidiabetic drugs in patients with prediabetes. For
instance 10 to 20% of metformin-treated patients experience gastrointestinal side effects
(nausea, vomiting, and diarrhea) leading to its discontinuation, whereas the use pioglitazone
is often complicated by weight gain and increased risk of fractures.

In this context, efficacious, cost-effective, and safe adjunct therapeutics for T2D
prevention are highly desirable. The present trial proposes to test the effects of cinnamon
in patients with prediabetes.

RATIONALE: Several randomized controlled studies have addressed the effects of cinnamon on
changes in glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) in adult patients
with T2D. Almost all studies showed a significant 10-20% decrease in FPG from baseline and
improvements in HbA1c, although the latter change often did not achieve statistical
significance. These findings in patients with T2D provide the rational to test whether
cinnamon exerts similar beneficial effects in patients with prediabetes.

STUDY DESIGN: This is a multi-center placebo-controlled, randomized (1:1), double masked
trail to assess the effects of cinnamon (cinnamomum burmannii) on glucose homeostasis over a
12- week period. FPG, HbA1c, and other measures of glucose metabolism will be collected at
baseline, after 6 weeks, and at the end of the 12-week study period. Participants will be
prompted to report Adverse Events (AE) at the study visits or anytime during the study
period.

OUTCOMES: The primary outcome for the Cinnamon Trial is a change in the FPG level from
baseline to week 12 of treatment, as compared to placebo. Secondary outcomes include change
in the FPG from baseline to week 6 of treatment, and change from baseline in plasma glucose
at 2 hours and area under the curve-glucose during a 75-gram oral glucose tolerance test to
week 12. Data will be analyzed using the "intent-to-treat" approach, which includes all
randomized subjects with at least one post-baseline FPG measurement; the supplementation
group assignment will not be altered based on the subject's adherence to the regimen.

SAMPLE SIZE DETERMINATION: Anticipating an absolute change in FPG smaller than what observed
in previous studies in patients with T2D, 10 patients with prediabetes in total entering a
two-treatment parallel-design study will provide 90% probability of detecting a true
between-treatment difference in FPG means of 22 mg/dl with standard deviation of 10 mg/dl,
using a paired two-sided comparison with type 1 error of 0.05. To allow for up to 20%
dropout, 12 patients in total will be recruited.

Inclusion Criteria:

1. Ages 20 - 70 years old at screening

2. Meet at least one of the following criteria of Prediabetes according to the 2016
American Diabetes Association criteria:

1. Impaired Fasting Glucose (IFG [100-125 mg/dL])

2. Impaired Glucose Tolerance (IGT [2-h plasma glucose: 140-199 mg/dL based on 75-g
OGTT])

3. HbA1c between 5.7-6.4%

3. Willingness to provide informed consent and follow all study procedures, including
attending all scheduled visits.

Exclusion Criteria:

1. Documented diabetes mellitus diagnosed by a physician and confirmed by other clinical
data.

2. Previous use of any antidiabetic medication.

3. Cardiovascular disease within 6 months of the study commencement including arrhythmia,
congestive heart failure, myocardial infarction or pacemaker placement.

4. History of uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg or
diastolic blood pressure > 95 mmHg on three or more assessments on more than 1 day).
If the patient is on blood pressure medications, dosing should be stable for at least
4 weeks prior to randomization.

5. Cancer diagnosis requiring treatment in the past 5 years

6. Chronic kidney disease stage 3-5 (estimated glomerular filtration rate < 60; based on
MDRD formula or creatinine ≥ 1.4 for men or >1.3 mg/dL for women, or a urine protein ≥
2+)

7. Known liver disease or elevation of AST, ALT, or GGT > 2.50 × upper limit of normal at
screening.

8. Other gastrointestinal diseases (including pancreatitis and inflammatory bowel
disease)

9. Participation in other clinical trials within 2 months.

10. Surgery within 30 days prior to screening.

11. Pulmonary disease with dependence on oxygen or daily use of bronchodilators.

12. Chronic infections (e.g., human immune-deficiency virus (HIV) or active tuberculosis)

13. Allergy or hypersensitivity to any of the ingredients in the test products.

14. Cognitive impairment or any other reason to expect the patient would have difficulty
complying with study protocol

15. Excessive alcohol intake defined as greater than 3 units of alcohol per day.

16. Use of weight loss drugs (e.g., lorcaserin [Belviq]; phentermine/topiramate [Qsymia],
liraglutide [Saxenda], Xenical [orlistat], Meridia [sibutramine], Acutrim
[phenylpropanol-amine], or similar over-the-counter medications) within 3 months of
the screening visit.

17. Intentional weight loss of ≥ 10 lbs in the previous 6 months.

18. Use of dietary supplements that may have glucose-lowering effects (e.g. Sesame,
Polygonatum odoratum, Chromium, Vanadium).

19. Concurrent enrollment in a weight loss program, such as Weight Watchers.

20. Other endocrine disorders affecting glucose metabolism including Cushing' syndrome,
acromegaly, hyperthyroidism, hypothyroidism or adrenal insufficiency.

21. Fasting plasma triglyceride >500 mg/dl.

22. Oral corticosteroids within 3 months.

23. Pregnancy and/ or Lactation: Women of childbearing potential will be required to have
a negative urine pregnancy test and to use contraception measures during the study and
for at least 1 month after participating in the study. Acceptable contraception
includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD,
the double barrier method (the woman uses a diaphragm and spermicide and the man uses
a condom), or abstinence.

24. Moderate anemia, defined as hemoglobin <10.9 in both men and women based on WHO
criteria