Effect of Extra Virgin Olive Oil on Postprandial Blood Glucose in Type 2 Diabetes Mellitus: A Randomized Controlled Trial
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Sponsor: Makati Medical Center

TITLE	  PAGE	  
	  
	  
Effect	  of	  Extra	  Virgin	  Olive	  Oil	  on	  
Postprandial	  Blood	  Glucose	  in	  Type	  2	  
Diabetes	  Mellitus	  patients	  
	  
	  
	  
	  
	  
Daphne	  Gayle	  P.	  Galang,	  MD,	  FPCP	  
Makati	  Medical	  Center	  
	  
Maria	  Jocelyn	  Isidro,	  MD,	  FPCP,	  FPSEDM	  	  
Makati	  Medical	  Center	  
	  
Ma	  Cecilia	  Gonzales,	  MD,	  FPCP,	  FPSEDM	  
Makati	  Medical	  Center	  
	  
Andrea	  Macabuag-­‐Oliva,	  MD,	  FPCP,	  FPSEDM	  
Makati	  Medical	  Center	  
	  
	  
 
 
 
 
 
	  
February	  22,	  2019	  
	  
	  
	  
 

Effect of EVOO on postprandial blood glucose in patients with T2DM 3 
 
 
INTRODUCTION 
Diabetes mellitus is a devastating global pandemic that poses an enormous public 
health challenge. Despite the numerous efforts of the public, and the current available 
drugs in the market, the burden of diabetes mellitus remains at large.  Epidemiologic 
studies show that about 3.7 million Filipinos have the disease, and the Philippines ranks 
15 in the world when it comes to diabetes prevalence.1, 2 Just like people with diabetes, 
individuals with chronic medical conditions are turning to complementary and alternative 
medicines, to serve as adjuncts in the treatment of their diseases. Hence, efforts are made 
to find the most effective and safe options for these patients.   
Olive oil, believed to be the most powerful factor in the Mediterranean diet, has 
long been known for its health benefits. However, the fascination with olive oil came 
only in the last decade, when epidemiological research confirmed its protective role 
against several chronic diseases.3 A large randomized controlled trial4 provided evidence, 
a higher baseline total olive oil consumption was associated with improved lipid profile, 
decreased blood pressure and reduced the risk of major cardiovascular events.4 Extra 
virgin olive oil intake was also associated with a decreased risk to develop Type 2 
Diabetes Mellitus in healthy individuals, as found by a systematic review involving 29 
randomized controlled trials.5 
Indeed, the olive oil market has been growing steadily over the decade, especially 
catering to the health conscious, and patients with Type 2 Diabetes Mellitus are no 
exempt. Questioning what has been dubbed “a good fat”, this study explored the effect of 

Effect of EVOO on postprandial blood glucose in patients with T2DM 4 
 
extra virgin olive oil on the glucose control of patients with Type 2 Diabetes Mellitus, 
specifically on their postprandial blood glucose. Specifically, this study determined if 
there is a significant difference in the trans-meal blood glucose 2 hours after a test meal 
with EVOO versus without EVOO. 
 
RESEARCH QUESTION 
Is there a significant difference in the postprandial blood sugar between meals 
with extra virgin olive oil (EVOO) and without EVOO among Type 2 Diabetes Mellitus 
patients?  
 
METHODOLOGY 
Study design and population 
 
This study was a randomized controlled crossover trial conducted from September 
to November 2018. All adult patients aged 30-65 years old, diagnosed with Type 2 
Diabetes Mellitus were recruited to participate in this study, with body mass index under 
the overweight or obese class I category (by Asia Pacific guidelines). All prescription 
medications for their diabetes, including insulin and other oral hypoglycemic medications 
were kept stable throughout the duration of the study.  
Excluded in the study were: 1) pregnant patients, 2) patients with history of 
frequent hypoglycemic episodes, 3) those at high risk of developing ketoacidosis and 
hyperglycemic hyperosmolar syndrome, 4) those with identified acute stress during the 

Effect of EVOO on postprandial blood glucose in patients with T2DM 5 
 
study (illness, fever, trauma leading to hospitalization), 5) current intake of steroids, 6) 
olive oil allergy or intolerance and 7) digestive disorders.  
 
Study design 
The participants were selected from a pool of patients with Type 2 Diabetes in the 
outpatient Diabetes Clinic of Makati Medical Center, Philippines.  
During their first visit, the participants were oriented on the conduct of the study. 
They were advised to be compliant with their medications throughout the duration of the 
trial.  
On their second visit, participants were asked to do a six to eight-hour overnight 
fast, and their fasting blood sugar was drawn. Serum samples were analyzed through the 
hexokinase method. The participants were then randomly allocated (first allocation) 
through a coin toss to receive a standard breakfast without EVOO or a meal admixed 
with one tablespoon of EVOO. The standard meals were labeled with serial numbers, and 
both the participants and the investigator were blinded to the intervention. The meals 
were consumed steadily in 15 to 20 minutes, after which, the food containers were 
collected to ensure its full consumption. Breakfast was chosen in order to avoid a second 
meal bias. The participants were asked to sit in the waiting area of the laboratory until the 
2-hour postprandial blood sugar was due to be drawn.   
 
 
 

Effect of EVOO on postprandial blood glucose in patients with T2DM 7 
 
After a one-week washout period, the participants were asked to come back for a 
cross over to the other treatment arm (second allocation). The participants were given the 
same test meal to ensure that that the glycemic index of the food remained constant.  
 
Standard meal 
The standard meal was prepared by a registered dietician. Calories were 
calculated based on the ideal body weight of each participant multiplied by a factor of 25 
for obese or overweight individuals divided by 3. The meal was composed of 50% 
carbohydrates, 20% protein and 30% fat. Water (250 ml) was served with each meal. 
 
Extra Virgin Olive Oil (EVOO)  
According to the International Olive Oil Council16, virgin olive oils are obtained 
from the fruit of the olive tree (Olea eurpaea) exclusively by cold-press technique under 
conditions that do not alter the oil. Extra virgin olive oil (EVOO) differs from ordinary 
olive oil in its free acidity, which is not allowed to exceed 0.8 g per 100 grams.  
This study used the FDA approved Doña Elena Extra virgin olive oil, which is 
readily available in local supermarkets. Its free acidity expressed as oleic acid was found 
to be 0.26%, comparable with the International food standards.15 
 
 
 

Effect of EVOO on postprandial blood glucose in patients with T2DM 8 
 
Outcomes 
The main outcome measured in the study was the trans-meal blood glucose, 
which is expressed as percent change in 2-hour postprandial blood glucose. This was 
calculated as the fasting blood sugar subtracted from the 2-hour postprandial glucose 
divided by the fasting blood sugar multiplied by 100.  
 
Sample size calculation 
A minimum total of 12 patients were needed for this RCT study with cross-over design, 
setting a two-sided significance level of 0.05, power of 90% to detect a significant 
difference between the two interventions, and population variance taken from the study 
of Violi et al.8  
 
Formula: 
 
Legend: 
n=sample size per arm 
zα = critical value for 2-sided alpha of 0.05 
zβ = critical value for power of 90% 
µ-µ0 = true difference between the two mean values at which the power is calculated 
δ = superiority margin or non-inferiority margin 
σ = population variance 
 
Calculation: 
 
 
(
)
(
)
2
0
2
2
2
δ
µ
µ
σ
β
α
−
−
+
=
z
z
n
(
)
(
)
5
5
0
2
33
.
23
282
.1
96
.1
2
2
2
=
−
+
=
n
n

Effect of EVOO on postprandial blood glucose in patients with T2DM 9 
 
The minimum number of participants needed per arm is 5, or a study population of 10. To 
compensate for a possible dropout rate of 20%, the sample size is recalculated as follows: 
 
Adj. N = 10 (120%) = 12 
 
Analysis of Data 
Univariate analysis 
Descriptive statistics was used to summarize the general and clinical 
characteristics of the participants. Frequency and proportion was used for nominal data, 
median and range for nonparametric data, and mean and standard deviation for 
parametric data.  
Crossover data analysis 
ANOVA for crossover studies was used to determine relative effect of EVOO or 
no intervention, magnitude of treatment effect, period effect, and treatment or period 
interaction. 
 
 
Ethical Considerations 
 
Data gathered from this study were treated in conformance with the principles of 
confidentiality, codes were used in data collection forms and documents accessible only 
by the primary investigator. 
The technical aspect of this study was reviewed and approved by the Institutional 
Review Board (IRB) of Makati Medical Center. The ethical principles based on the 
Declaration of Helsinki and the National Guidelines for Biomedical Research of the 

Effect of EVOO on postprandial blood glucose in patients with T2DM 10 
 
National Ethics Committee (NEC) of the Philippines were considered in the conduct of 
this study. 
No monetary compensation was given to participants for recruitment. However, a 
reasonable transportation allowance of Php 200.00 each, to cover for their every visit was 
provided. Assurance was made that exclusion or withdrawal from this study will not 
result in any form of denial to any future medical service or assistance. 
 
 
RESULTS 
 
 
Table 1.  
Baseline characteristics of participants with type 2 DM (n = 13)  
 
Mean ± SD; Frequency 
(%) 
Age (years) 
57.92 ± 5.01 
Sex 
 
Male 
6 (46.15) 
Female 
7 (53.85)  
Weight (kg)  
61.75 ± 5.04 
Height (cm)  
155.72 ± 8.79 
BMI (kg/m2) 
24.56 (23.51 – 31.07)  
Normal 
0  
Overweight  
7 (53.85)    
Obese  
6 (46.15)   
Comorbidities 
 
Hypertension 
9 (69.23)  
CAD 
4 (30.77)  
Liver disease  
0 
Renal disease 
0 
COPD 
0 
Others 
0 
Smoking history (pack-years) 
2 
Never smoker  
10 
Current smoker  
0 
Quit smoking  
1 (7.69)  
Alcohol drinking  
0 
CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease. 

Effect of EVOO on postprandial blood glucose in patients with T2DM 11 
 
A total of 14 patients were randomized to the first allocation in the study, 
however, one patient withdrew from the study due to watery diarrhea experienced one 
hour after eating the meal with extra virgin olive oil.  
 
 
Table 2.   
Clinical and laboratory profile of participants with  
 
 
Type 2 Diabetes Mellitus (n = 13) 
 
Mean ±SD; Median 
(Range); Frequency (%) 
Vital signs 
 
Heart rate (/min) 
76.77 ± 7.00 
Respiratory rate (/min) 
20 (16 – 20)  
Systolic blood pressure (mmHg) 
115.38 ± 11.98  
Diastolic blood pressure (mmHg) 
74.62 ± 7.76  
Medications used 
 
Metformin  
11 (84.62)  
DPP4 inhibitor  
8 (61.54)  
Insulin  
5 (38.46)  
SUR 
5 (38.46)  
Pioglitazone 
1 (7.69)  
SLGT2 inhibitors 
1 (7.69)  
Lipid profile (mg/dL)  
 
Total cholesterol  
183.35 ± 37.40 
LDL-C  
97.77 ± 33.37  
HDL-C 
56.07 ± 15.63   
Triglyceride 
102 (54.91 – 708.85)   
Blood glucose control 
HbA1c (%) 
 
7.7 (6.77 – 11.12)  
Serum creatinine (mg/dl) 
0.89 ± 0.25 
Liver profile (U/L) 
 
Alanine transaminase 
26 (13 – 117)  
Aspartate transaminase 
30 (17 – 88)  
HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein 
cholesterol 
 
Of the 13 patients included in the final analysis, four were assigned to Group A 
(with EVOO to without EVOO) and nine were assigned to Group B (without EVOO to 

Effect of EVOO on postprandial blood glucose in patients with T2DM 12 
 
with EVOO). The mean age of these patients was 57.92 (±5.01) years, seven (53.85%) 
were female, all were either overweight (53.85%) or obese (46.15%), and nine (69.23%) 
have hypertension, while four (30.77%) have CAD (Table 1). 
The average vital signs values were within normal (Table 2). The most common 
medications used were metformin (84.62%), DPP4 inhibitor (61.54%), insulin (38.46%), 
and SUR (38.46%). The median HbA1c (%) was at 7.7 (range 6.77 – 11.12). 
 
A significant difference was found between groups, with treatment effect at p = 
0.044. For both groups and both periods, whenever EVOO was used, the percent increase 
was significantly higher with the use of EVOO. See Table 3.  
 
Table 3.   
Serum glucose before and after interventions (n = 13) 
 
 
Period 1  
 
Period 2  
 
Fasting 
2 hours 
post-
prandial  
% 
Change 
Fasting 
2 hours 
post-
prandial 
% 
Change 
 
Mean ± SD 
 
With-
Without 
EVOO 
144.57 ± 
17.48  
 275.80 ± 
71.22 
88.55 ± 
26.92 
138.87 ± 
27.35 
241.28 ± 
68.15 
72.11 ± 
20.34 
Without-
With EVOO 
148 ± 
71.17  
208.79 ± 
65.02 
49.22 ± 
36.08 
125.87 ± 
13.80 
214.38 ± 
43.50 
71.08 ± 
34.88 
p-value 
0.928 
0.123 
0.079 
0.267 
0.403 
0.958 
Sequence effect  (p-value): 
0.280 
Period effect (p-value): 
0.754 
Treatment effect (p-value): 
0.044 
Interaction of sequence and treatment  
(p-value): 
0.754 
Interaction of period and treatment  (p-
value): 
0.161 
Normality: 
With-Without: 0.986 
Without-With: 0.552 
 
 
 

Effect of EVOO on postprandial blood glucose in patients with T2DM 13 
 
The sequence by which EVOO was given had no statistical effect on the blood 
glucose levels (p = 0.280) and no interaction with treatment effect (p = 0.754). The 
period effect, or the carryover effect, likewise had no statistical effect on the blood 
glucose levels (period effect, p = 0.754) and no interaction with treatment effect (p = 
0.161). We verified normality of the data for both EVOO-first (p = 0.986) and EVOO-
second groups (p = 0.552). See Table 3. 
 
 
 
DISCUSSION 
 
Although olive oil has long been part of the Mediterranean diet, its popularity 
soared only over the last decade, as studies4 have linked it to benefits on cardiovascular 
health. Recent studies8, 10 further explored its effect on glucose metabolism. A study8 on 
healthy subjects found that 10 grams of EVOO compared to placebo lowered the 
postprandial blood glucose after a standard meal. Another study10 was done among 
among Type 1 Diabetes Mellitus patients, and found that 37 grams of EVOO added to 
meals significantly lowered the postprandial glucose. This effect was attributed to the 
high content of monosaturated fats (MUFAs) in EVOO, which improves postprandial 
insulin sensitivity by prolonging the effect of incretins. This effect was mainly achieved 
through the inhibition of the enzyme dipeptidyl peptidase- 4 (DPP-4), which degrades 
incretins.  Incretins are substances that heighten glucose-induced insulin release, causing 
70% of the postprandial insulin increase.18 Insulin-independent glucose-lowering actions 
of incretin include the inhibition of hepatic glucose production, suppression of glucagon 

Effect of EVOO on postprandial blood glucose in patients with T2DM 14 
 
release and the prolongation of gastric emptying19, explaining its benefits even in Type I 
Diabetes Mellitus patients, where the defect is insulin deficiency. 
However, in contrast to these studies, our study found a significantly higher 
percent change in the 2-hour postprandial blood sugar of patients taking EVOO with 
meals compared to those taking meals without EVOO (p = 0.044). These results can be 
explained by the effect of an elevated free fatty acid on glucose metabolism. A 
tablespoon (15 ml) of EVOO contains 120 calories and 13.5 g of fat, which is an added 
15.75% to the recommended daily allowance compared to meals without EVOO. 
Elevated free fatty acids can impair the glucose metabolism.19 Free fatty acids compete 
with glucose for substrate oxidation, causing a 50% reduction in glucose oxidation. Aside 
from this, they also affect insulin signaling at the level of Protein Kinase C, with resultant 
reduction in insulin-mediated glucose uptake. 
The difference in our findings may be explained by the difference in ethnicity 
between the study populations. These metabolically adverse effects of extra virgin olive 
oil may be more dominant in the Asian Type 2 Diabetes population compared to its 
agonist effects on incretin, as exhibited by Caucasian patients. Compared to Caucasians, 
Asian Type 2 Diabetes Mellitus patients are known have more visceral adiposity, which 
contributes to lipotoxicity and insulin resistance. Hence, it is plausible that the difference 
in ethnicity may account for the nuances of insulin and fat metabolism in these 
populations. Data addressing the role of insulin secretion in meals with and without 
EVOO, however, was not explored in this study and should be investigated. 

Effect of EVOO on postprandial blood glucose in patients with T2DM 15 
 
 
Another limitation of this study is that the effect of EVOO added to meals was 
only measured at one point. Although other studies8 have estimated their outcomes with 
just one dose of EVOO, it is recommended that a long term EVOO consumption be 
employed in future studies, as it remains to establish if changes in the glucose profile will 
be observed if EVOO is to be taken longer. This study design will also enable the 
measurement of HbA1c. 
Another limitation of this study is in the profiling of the phenolic content of 
EVOO. Some studies have suggested that the anti-oxidant effect of EVOO is mainly 
responsible for lowering the post-prandial blood sugar, and this is mainly accounted for 
by its phenolic acid content. Oxidative stress has been found to lead to insulin resistance 
and the generation of the advanced glycosylated end-products (AGEs) from reactive 
oxygen species (ROS). Apart from the formation of AGEs, the generation of ROS has 
been known to upregulate DPP4 concentrations, the enzyme known to breakdown 
incretins, which eventually inhibits the secretion of insulin. Profiling the phenolic content 
of the EVOO may explain the difference in the results, especially that much of the 
mechanism for the effects of EVOO are attributed to their antioxidant effects, however 
further studies are needed. 
Despite its limitations, however, this study was able to demonstrate a 
disadvantageous increase in postprandial blood sugar when EVOO is added to a standard 
meal among patients with Type 2 Diabetes Mellitus. These findings do not alter the 
current dietary recommendations: to reduce saturated and trans fat intake in general, 

Effect of EVOO on postprandial blood glucose in patients with T2DM 16 
 
however highlights the need for further elucidation of the effects of different dietary fats 
and our carbohydrate metabolism. 
 
CONCLUSION 
The postprandial glycemic response is hugely influenced by the fat content of a 
meal. In this study, the authors have demonstrated a significantly increased postprandial 
glucose levels in Type 2 Diabetes Mellitus patients who added a tablespoon of EVOO on 
top of meals compared to the same meal without EVOO. 
 
Acknowledgements 
The authors would like to thank Ms. Ivy Obispo Desembrana from the Makati Medical 
Center Diabetes Care Center for the provision of the standard meals by the participants.