Journal of Diabetes Mellitus, 2022, 12, 271-283

https://www.scirp.org/journal/jdm
ISSN Online: 2160-5858
ISSN Print: 2160-5831

The Safety and Efficacy of Combination Therapy

of Dapagliflozin and Metformin in Patient with
Type 2 Diabetes Mellitus: A Review Study

Saif K. Alkhanferi1,2,3, Khadeejah H. Alhuraiz1,2,3, Hussein S. Alyami1,2,3, Sultan L. Alenazi1,2,4,

Mohammed F. Aldhaban1,2,4, Naif Alrowedann1,2,4, Yazeed Y. Albedaiwi1,2,3, Nawal Alnazawi1,2,3,
Abrar Bokhamseen1,2,3, Fatimah A. Talaqof1,2,3
1
King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia
2
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
3
Imam Abdurrahman Bin Faisal Hospital, National Guard Health Affairs, Dammam, Saudi Arabia
4
Qassim Primary Health Care Center, National Guard Health Affairs, Qassim, Saudi Arabia

How to cite this paper: Alkhanferi, S.K., Abstract

Alhuraiz, K.H., Alyami, H.S., Alenazi, S.L.,
Aldhaban, M.F., Alrowedann, N., Albedai- Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new
wi, Y.Y., Alnazawi, N., Bokhamseen, A. and class that approved by FDA for patient with type 2 DM. Dapagliflozin alone
Talaqof, F.A. (2022) The Safety and Effica-
or in combination therapy with metformin provided effective glycemic con-
cy of Combination Therapy of Dapagliflo-
zin and Metformin in Patient with Type 2
trol and HbA1c reduction, with minimal hypoglycemia and hypotension ad-
Diabetes Mellitus: A Review Study. Journal verse effects. Objective: To evaluate the safety and efficacy of the combina-
of Diabetes Mellitus, 12, 271-283. tion therapy of dapagliflozin and metformin in type 2 diabetes mellitus pa-
https://doi.org/10.4236/jdm.2022.124022
tients. Methods: Research was conducted through MEDLINE and Embase
Received: November 1, 2022
databases in search of randomized controlled studies including dapagliflozin,
Accepted: November 22, 2022 sodium glucose co-transporter 2, metformin, and efficacy. Results: Forty seven
Published: November 25, 2022 articles were spotted, 3 randomized controlled studies were involved in this
review. Dapagliflozin and metformin combination was found beneficial in
Copyright © 2022 by author(s) and
Scientific Research Publishing Inc.
HbA1c reduction equal to 20.7% - 31.5% from the baseline compared to pa-
This work is licensed under the Creative tients on metformin alone. 40.6% of patients on combination therapy achieved
Commons Attribution International the ADA recommended reduction in HbA1c to less than 7%. Moreover fasting
License (CC BY 4.0).
plasma glucose level was reduced by 23.4 mg/dl from the baseline in the com-
http://creativecommons.org/licenses/by/4.0/
bination therapy compared to 5.9 mg/dl in metformin group. Body weight
Open Access
reduction was statistically significant (P < 0.0001) in the combination group.
Moreover reduction in patient’s waist circumference was observed to be
greater in all combination groups compared to MET group. Mild intensity of
adverse effects such as major hypoglycemia, hypotension, or incidence of
electrolyte changes was perceived. Therapy discontinuation was less likely
with combination group. While UTI and genital infection were observed at

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S. K. Alkhanferi et al.

higher extent in combination group than MET group. Conclusion: The com-
bination therapy of dapagliflozin and metformin found to be safe and effec-
tive in type 2 diabetes mellitus management with minimal adverse effects.

Keywords
Dapagliflozin, Sodium Glucose Co-Transporter 2, SGLT2, Metformin,
Efficacy

1. Introduction
Diabetes mellitus (DM) is a chronic metabolic disease characterized by high
fasting plasma glucose level (FPG ≥ 126 mg/dl) due to insufficient production
(Type 1 DM, accounting for 5 - 10%) or poor effectiveness of insulin (Type 2
DM, accounting for 90% - 95%). Diagnostic tests for diabetes include the FPG
test, glycosylated hemoglobin (HbA1c) which gives a better estimation of plasma
glucose in previous 3 months and good indicator of complication due to di-
abetes, and 2 hours after 75-g oral glucose tolerance (OGTT) test (Table 1). Ob-
esity and sedentary lifestyle are risk factors for type 2 DM [1]. Uncontrolled
hyperglycemia leads to microvascular complications such as retinopathy, neph-
ropathy, and neuropathy and macrovascular complications such as cardiovascu-
lar, cerebrovascular, and peripheral arterial disease. Other complications include
nervous system damage, dental disease, limb amputation, and ketoacidosis [2]. It
is not surprising, therefore, that diabetes is a leading cause of morbidity and

Table 1. Summary ADA criteria for diagnosis and target goals of DM.

TEST Pre-diabetes Diagnosed Target COMMENTS

Glycosylated 5.7% - 6.4% ≥6.5 ≤7% • Shows the average level of glucose over the previous 3
hemoglobin A1c months.
(HbA1c) • The A1C test should be performed using a method
that is certified by the NGSP and standardized or
traceable to the DCCT reference assay.
• A1C levels may vary with patients’ race/ethnicity
Fasting plasma 100 - 125 mg/dl ≥126 mg/dl 70 - 130 mg/dl • Patient should be fast for at least 8 hours before the
glucose (FPG) (5.6mmol/L - 6.9 (7 mmol/L) (3.9 - 7.2 mmol/L) test.
mmol/L)
Oral glucose 140 - 199 mg/dl ≥200 mg/dl 180 mg/dl • Use to measure patient’s ability to utilize glucose at
tolerance test (7.8 mmol/L (11.1 mmol/L) (10.0 mmol/L) certain time.
(OGTT) - 11.0 mmol/L) • Patient should be fast to perform 2-hours after 75
gram of glucose drink. For pregnant women use 100
gram of glucose test.
• Recommended in gestational diabetes patient.
Random plasma - ≥200 mg/dl - • Perform at any time of the day.
glucose (11.1 mmol/L)

NGSP: National Glycohemoglobin Standardization Program. DCCT: Diabetes Control and Complications Trial.

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 S. K. Alkhanferi et al.

mortality [3]. In 2010, about 25 million people in the US were affected by DM

and almost 80 million were diagnosed as pre-diabetic (Table 1) [3]. Motivation
for controlling DM and discover new effective medication will help prospective
patients (366 million) in 2030 [4].
The American Diabetes Association (ADA) recommends for lowering FPG
and postprandial (OGTT) glucose levels (Table 1) for all diabetic patients. In
addition, lower HbA1c ≤ 7% has been shown to reduce microvascular and ma-
crovascular complications. Targeting HbA1c to ≤6.5% in younger patients with-
out a cardiovascular disease and therefore expected live longer may be treated
more aggressively since they are less likely to have hypoglycemia, other adverse
effects of treatment, and slower progression of the disease [2].
Type 2 DM is treated with lifestyle modifications (reduced intake of calories
and fat, 7% of the body weight loss, and 150 minutes of physical activity per
week) alone or in combination with oral antidiabetic medications (OADs).
When OADs are indicated, metformin is the recommended by ADA because of
its high efficacy in reducing HbA1c, less risk of hypoglycemia, and its low cost
compared to other OADs. If ADA goals are not achieved over 3 months by met-
formin, adding another class of OAD such as sulfonylurea, thiazolidinedione,
Glucagon like peptide 1 receptor agonist, dipeptidyl peptidase-4 inhibitor, or
even insulin injection is recommended by ADA. Combination therapy with dif-
ferent mechanisms of action is crucial to control patient hyperglycemia and re-
duce long term complications. Mechanism of action, effectiveness, safety, ad-
verse reactions, tolerability, cost, and reduction of long term complications are
strategies used for selection of add-on OADs. However, common limiting ad-
verse effects of some OAD medications are weight gain and hypoglycemia with
sulfonylurea and insulin, fluid retention and progression of heart failure with
thiazolidinedione, and gastrointestinal side effects with alpha-glucosidase inhi-
bitors [2] [5]. Thus, newer drugs are needed that may be effective in combina-
tion with metformin to achieve treatment goals with minimal adverse effects.
Sodium glucose co-transporter 2 (SGLT2) inhibitors are a novel class that ap-
proved for use in patient with type 2 DM. SGLT2 is a membrane transporter lo-
cated in the proximal renal tubules responsible for 90% of the glucose reabsorp-
tion. Inhibition of SGLT2 will inhibit the reabsorption of glucose and thus in-
creases glucose and sodium excretion in urine. As a result, plasma glucose levels
decrease [6] [7]. Canagliflozin (Invokana®) was the first SGLT2 inhibitor drug
approved (March 2013) to treat adults with type 2 DM. Although Canagliflozin
is efficacious, high risk of urogenital tract infections and hyperkalemia are the
most common limitations for wide spread use [8]. Dapagliflozin (Farxiga®) is
also SGLT2 inhibitor approved in the US (January 2014). SGLT2 medications
are independent of insulin hormone and can be used as a monotherapy or in
combination with other OADs [9] [10]. The use of Dapagliflozin as a treatment
for type 2 DM as monotherapy has been already reviewed [11] [12]. The purpose
of this review was to investigate the safety and efficacy of Dapagliflozin in com-
bination with metformin in type 2 DM patients.

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S. K. Alkhanferi et al.

2. Data Sources and Selection

A literature search was performed through MEDLINE and Embase. Keywords
included Dapagliflozin, Sodium glucose co-transporter 2, SGLT2, Metformin,
and Efficacy. The search was limited to English language, human, Randomized
controlled trial, and clinical trials (phase 3 and phase 4). This yielded 9 articles in
MEDLINE and 38 articles in Embase. Studies were excluded if they discussed
SGLT2 drugs other than Dapagliflozin, were duplicated, or were published as
systemic review articles or as conference abstract articles. Three studies that
compared the efficacy of combination therapy of Dapagliflozin and metformin
in patient with Type 2 Diabetes mellitus met our inclusion criteria and were
therefore selected for this review (Figure 1).

3. Results
The efficacy and safety of Dapagliflozin (Farxiga®) and metformin (MET) com-
bination in patients with type 2 DM who have inadequate glycemic control with
metformin and have high baseline HbA1c were evaluated in three different stu-
dies (Table 2). Bailey et al. published the results of the trial at the end of 24
weeks and 102 weeks of one study research [5] [13]. Two separate studies inves-
tigating two separate doses (5 mg and 10 mg) of Dapagliflozin were reported to-
gether in one article [14].
All these studies [5] [13] [14], had similar inclusion and exclusion criteria. Pa-
tients were included if they were aged ≥ 18 years, had type 2 diabetes, C-peptide
concentration was ≥1 ng/ml, body-mass index (BMI) was ≤45 kg/m2, and were
administering metformin (≥1500 mg per day). Patients were excluded from the
study if the serum creatinine was ≥1.5 mg/dl (for men) or ≥1.4 mg/dl (for
women), urine albumin/creatinine ratio was >1800 mg/g, aspartate aminotrans-
ferase, alanine aminotransferase, or creatine kinase was greater than three times
the upper limit of normal, or had symptoms of poorly controlled diabetes (po-
lyuria and polydipsia with >10% weight loss during the 3 months before enroll-
ment). Patients were also excluded if they suffered from clinically significant dis-
ease (renal, hepatic, hematological, oncology, endocrine, psychiatric, or rheumatic
diseases), BP was ≥180/110mm Hg, had a recent (within 6 months) cardiovascular

Figure 1. Summary of data sources and article selection.

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 S. K. Alkhanferi et al.

Table 2. Summary of Dapagliflozin trials as a combination therapy with metformin.

Reference Design (n) Duration Primary Interventions Results Safety outcome)

(week) outcome (s)

Bailey MC, R, PC, 102 HbA1c changes MET only 0.02% • Three deaths reported, 2 in DAP 2.5 mg group
(2013) DB, PGT from baseline MET + DAP (cardiac arrest and MI) and 1 in placebo group
(476) at 78 weeks. • 2.5 mg −0.48%* (lung cancer)
• 5 mg −0.58%* • UTI incidence was higher in DAP 10 mg.
• 10 mg −0.78%* • In general, renal impairment was observed to a
great extent in DAP groups than placebo.
• A significant beneficial reduction of blood
pressure was observed in patients with
hypertension with DAP groups.

Henry MC, R, DB, 24 HbA1c changes • MET only −1.35 • No major hypoglycemia was observed in any
(2012) ACS (598) from baseline • DAP 5 mg −1.19 groups.
at 24 weeks. • DAP + MET −2.05* • Mild to moderate ADR among groups.
• Diarrhea was more common in MET groups
Henry MC, R, DB, 24 HbA1c changes • MET only −1.44
than DAP groups.
(2012) ACS (638) from baseline • DAP 10 mg −1.45
• UTI was reported more frequently in DAP +
at 24 weeks. • DAP + MET −1.98*
MET groups.
• Significant changes in the renal function were
not detected.
• A significant reduction of blood pressure was
observed in patients with hypertension with
DAP + MET groups.

Bailey MC, R, PC, 24 HbA1c changes MET only −0.30% • No major hypoglycemia was observed in any
(2010) DB, PGT from baseline MET + DAP groups.
(546) at 24 weeks. • 2.5 mg −0.67%* • Discontinuation of therapy was less frequent in
• 5 mg −0.70%* the DAP groups.
• 10 mg −0.84%* • UTI was observed in all groups, but was higher
in DAP groups.
• No major differences were observed in serum
electrolytes, renal function, and lipid profiles.
• A significant reduction of blood pressure was
observed in patients with hypertension with
DAP groups.

MC = Multicenter; R= randomized; PR = placebo-controlled; DB = double bind; PGT = Parallel-group trial; ACS = active-
controlled studies, DAP = Dapagliflozin, MET = Metformin, ADR = adverse reaction, UT I = urinary tract infection. *P value <
0.001 as compared to either baseline or placebo (MET).

event or diagnosed with congestive heart failure class III or IV, based on New
York Heart Association.
All primary and secondary endpoints were same in all trials. The primary
endpoint was to observe the reduction of HbA1c from the baseline at the end of
the study whereas secondary endpoints included changes in FPG, total body
weight, and adverse effects such as hypoglycemia, hypotension, UTI and genital
infections, and abnormalities in electrolytes and kidney function.
Bailey et al. conducted a phase 3 randomized, multicenter, double-blind, and
placebo-controlled trial, and published their finding at two different time points

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S. K. Alkhanferi et al.

(24 weeks and 102 weeks (78 weeks extension of the first trial)). Of the 546 pa-
tients who were included at the end of 24 weeks, only 476 patients continued the
study up to 102 weeks. [5] [13]. HbA1c level of those patients were between 7% -
10%. Each patient received 2-weeks of placebo single blind to assess patient
compliance by Interactive voice response system (IVRS). Medication compliant
patients were randomly assigned to one of the four groups of the study, metfor-
min alone (MET) group or combination of metformin + Dapagliflozin (MET +
DAP), 2.5 mg, 5 mg, and 10 mg groups (Table 2).
FPG was assessed from week 4 to the end of the study to determine if patients
needed a rescue medication (Pioglitazone or Acarbose). Rescue medication was
administered if FPG higher than the predetermined levels. Patients also received
diet and exercise counseling throughout the study.
The reduction in the HbA1c was significantly higher compared to baseline in
the combination (MET + DAP) groups than metformin alone (MET) group at
the end of 24 weeks and 102 weeks (Table 2). Moreover, at the end of 24 weeks,
33% - 40.6% of patients in the MET + DAP groups achieved the ADA recom-
mended reduction in HbA1c to less than 7% compared to 25.9% of patients in
MET group. However, at the end of 102 weeks, these percentages dropped to
20.7% - 31.5% of patients in the MET + DAP groups compared to 15.4% of pa-
tients in MET group.
A significant reduction in number of patients with HbA1c ≥ 9% at baseline was
observed in MET + DAP 5 mg and 10 mg groups (P < 0.03) but not in MET +
DAP 2.5 mg group at week 24. Moreover, patients with MET + DAP 10 mg
group showed a greater reduction in patients’ HbA1c to ≤ 6.5% (P < 0.02). These
end points were not reported in 102 weeks because the patients HbA1c baseline at
the beginning of the extension period (78 weeks) was less than 9%. However, it
was surprising to note that at 102 weeks study, reduction of HbA1c ≤ 6.5% was
not reported.
A reduction in patients’ FPG was observed from the baseline at the end of first
week and this reduction was statistically significant only in MET + DAP 5 mg
and 10 mg groups (P < 0.001). At week 24, FPG was reduced by 17.8 - 23.4 mg/dl
from the baseline in all MET + DAP groups and by 5.9 mg/dl in MET alone
group. FPG also was observed to reduce by 19.3 to 26.5 mg/dl from the baseline
in all MET + DAP groups at the end of week 102 while the reduction in FPG was
10.5 mg/dl in MET alone group. Moreover, all study groups except MET +DAP
2.5 mg group showed a significant reduction in patients FPG at the end of the
study (P < 0.002).
A continuous reduction in patient body weight (−2.2 kg to −3.0 kg) was ob-
served from week 1 up to week 24 in MET + DAP groups. This reduction of pa-
tient body weight from the baseline was statistically significant in MET + DAP
groups as compared to MET alone group (P < 0.0001) at week 24 and week 102.
However, a small increase in body weight from week 24 to week 102 was ob-
served. At the end of the 24 weeks, the reduction of body weight ≥ 5% was sig-

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 S. K. Alkhanferi et al.

nificantly higher in MET + DAP groups (18.1%, 19.5%, 22.1% in 2.5 mg, 5 mg,
10 mg, respectively) as compared to MET group. Moreover, the reduction in pa-
tient’s waist circumference was observed to a greater extent in all MET + DAP
groups (−1.7 cm, −2.7 cm, and −2.5 cm in 2.5 mg, 5 mg, 10 mg, respectively)
compared to −1.3 cm in the MET group. However, it was surprising to note that
the authors did not report the change in waist circumference at the week 102 as
they did at the end of week 24.
Adverse effects leading to therapy discontinuation were less likely with pa-
tients in MET + DAP groups as compared to MET alone group. Moreover, the
incidence of high urinary glucose/creatinine ratio was observed to a greater ex-
tent in patients in MET + DAP groups. This elevation was dose dependent. Mi-
nimal differences existed between all groups of the study regarding major hy-
poglycemia, hypotension, or incidence of electrolyte changes. Changes in the so-
dium and potassium levels were transient but not clinical relevant in any study
group at any point.
UTI was observed to a greater extent in MET + DAP 10 mg group. Genital in-
fections occurred more frequently in all MET + DAP groups (8% to 14.6%) than
MET group (5%). UTI and genital infections were observed at similar extent in
both sexes at week 24 while women showed more frequent UTI and genital in-
fections at the end of the 102 weeks. The tests for renal, hepatic and lipid func-
tions did not show any significant differences between any groups at week 24.
However, patients in MET + DAP groups at week 102 showed a higher incidence
of renal failure. But the incidence in patients in MET + DAP 10 mg group and
MET alone group was similar. Moreover, MET + DAP groups showed a robust
reduction in the serum uric acid at week 24 and 102 than MET alone group. The
reduction of blood pressure (systolic and diastolic) from the baseline was ob-
served more frequently in MET + DAP groups at week 24, but minimal changes
were observed at week 102. Reduction of blood pressure was not associated with
orthostatic hypotension. A robust, reduction in blood pressure of patients with
hypertension (>130/80) at baseline was observed at the end of 24 weeks in all
MET + DAP groups (29.5% - 37.5%). Three deaths were reported during the ex-
tension study (78 weeks). Two deaths occurred in MET + DAP 2.5 mg group
(cardiopulmonary arrest and myocardial infarction) and one death occurred in
MET alone group (malignant lung neoplasm). Fractures also were reported in all
groups but noticed to be at higher extent in patients in DAP + MET 10 mg
group.
Henry et al. [14] performed two randomized, multicenter, double-blind, three
arms, active controlled, 24 weeks studies (study 1 and study 2). Study 1 included
598 patients, distributed as 201, 203, and 194 patients in METXR group, METXR +
DAP 5 mg group, and DAP 5 mg group respectively. Study 2 included 638 pa-
tients, distributed as 208, 219, and 211 patients in METXR group, METXR + DAP
10 mg group, and DAP 10 mg group respectively. In addition to inclusion and
exclusion criteria mentioned above, patients who had HbA1c 7.5% - 12% were

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S. K. Alkhanferi et al.

included while patients who had a history of diabetes insipidus were excluded
from studies. Study 2 tested non inferiority of DAP 10 mg to METXR for changes
in HbA1c (0.35% margin) and FPG (14.96 mg/dl margin).
All patients received one week of placebo single blind to assess patient com-
pliance. Patients who were determined to be medication complaint by IVRS
were randomly assigned into one of the three groups of the studies. In addition
to the treatment options, all patients received diet and exercise counseling. Pa-
tients were also assessed for uncontrolled FPG level from week 6 to determine if
patient needed a rescue medication (Pioglitazone, Sitagliptin, or Acarbose).
Both studies (study 1 and study 2) showed a statistically significant reduction
of HbA1c in the combination therapy (METXR + DAP 5 mg and 10 mg) com-
pared to either METXR alone or DAP alone groups (P < 0.0001). Moreover, re-
duction of HbA1c less than 7% as ADA recommended was significant in combi-
nation therapy groups compared to either of the monotherapy groups (P < 0.02).
The reduction in the number of patients with baseline HbA1c ≥ 9% also was sig-
nificant to a greater extent in the combination therapy groups compared to the
monotherapy groups (P < 0.02). However, METXR + DAP 5 mg group showed a
greater reduction in patients HbA1c ≥ 9% at baseline than METXR + DAP 10 mg
group when compared to either of the monotherapy groups. Additionally, both
studies showed a significant reduction in FPG in combination therapy compared
to either of the monotherapy (P < 0.0001). Reduction of patients body weight
also was statistically significant in both combination therapy compared only to
MET alone group (P < 0.0001).
At the end of the study 2, data showed a non-inferiority of DAP 10 mg group
alone in HbA1c reduction, superiority for reduction of FPG, and significant re-
duction in patient body weight when compared to METXR alone group.
Mild to moderate intensity of adverse effects were observed throughout the
studies. DAP 5 mg and 10 mg as monotherapy or in combination showed less
discontinuation from treatment groups and lesser need to add rescue medication
to control high FPG compared to METXR alone group. However, patients who
received METXR (combination or alone) showed more frequent diarrhea and
nausea (7%- 9.6%) than patients in DAP 5 mg or 10 mg groups (2.7% - 3.9%).
UTI and genital infections were observed more frequently with patients in DAP
5 mg and 10 mg groups (combination or monotherapy) than METXR groups.
Moreover, UTI and genital infections were observed more commonly in women
than men. This was in agreement with the finding of previous studies [5] [13].
All study groups except METXR group showed a robust reduction in patient se-
rum uric acid level. Reduction of blood pressure was observed in patients in
DAP 5 mg and 10 mg (monotherapy or in combination therapy) to a greater ex-
tent than METXR groups.
The strengths of all studies include a randomized, multicenter, and double-blind
design, and the fact that they were sufficiently powered studies. Since metformin
is contraindicated in patients who have high serum creatinine (1.5 mg/dl for
men and 1.4 mg/dl for women), excluding these patients is important to avoid

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 S. K. Alkhanferi et al.

accumulation of metformin. This accumulation of the drug may lead to serious

adverse effects such as lactic acidosis which is disturbed plasma electrolytes and
lead to tissue hypoxia. Some of the limitations of these studies are using interac-
tive voice response system (IVRS) for determining patient compliance, which
may introduce patient bias in different ways. Some patient may be pretend me-
dication compliance or miss understanding the meaning of compliance when
they response to the IVRS. Patients with clinically significant diseases such as
hepatic or renal impairment, HbA1c more than 10%, or C-peptide concentration
less than 1 ng/ml also were excluded, which may limit the extrapolation of safety
and efficacy finding of these studies to those populations. Those patients who
are excluded because of the previous criteria may be form the majority of elderly
patients with multi diseases. Moreover, all these studies were funded by the
companies making Dapagliflozin (Farxiga®) which may introduce bias. In addi-
tion to the above limitations, discontinuing the follow up patients with HbA1c ≤
6.5% in the 102 weeks study was surprising and limiting the future adverse effect
such hypoglycemia predication.

4. Discussion
Dapagliflozin pharmacological mechanism of action is inhibition of sodium-
glucose cotransporter 2 (SGLT2), found in the proximal renal tubules, which is
responsible for the majority of the reabsorption of filtered glucose from the tu-
bular lumen. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered
glucose and thereby promotes urinary glucose excretion [9]. Metformin acts
through decreasing hepatic glucose production, decreases intestinal absorption
of glucose, and improves insulin sensitivity by increasing peripheral glucose up-
take and utilization [15].
Results from all 3 studies reviewed, indicate that combination of metformin
plus Dapagliflozin is effective in reducing of HbA1c, increasing the proportion of
patients achieving target HbA1c levels, and reducing FPG when compared to either
metformin or Dapagliflozin alone. A significant reduction in HbA1c (−0.48% to
−0.78%) was achieved in all patients who had HbA1c more than 7% at the begin-
ning of the studies. This reduction in HbA1c is dose related and can be as much
as 0.9% with 50 mg dose of Dapagliflozin [12]. The reduction in HbA1c (>9% at
baseline) observed at higher extent with all metformin plus Dapagliflozin groups,
however, metformin plus Dapagliflozin 5 mg showed more reduction than mo-
notherapy and metformin plus Dapagliflozin 10 mg [13] [14]. Reduction of
HbA1c showed beneficial effects more than reducing cardiovascular risks in
many patients [2]. FPG was significantly reduced in all 3 studies (−17.8 to −61
mg/dl) and this reduction was dose related as observed in other study [12].
Dapagliflozin (Farxiga©) is a selective SGLT2 inhibitor approved to manage
patients with type 2 DM. Blocking SGLT2 in the proximal renal tubules increase
glucose and sodium excretion in the urine and reduce hyperglycemia [9]. Da-
pagliflozin has several advantages over current available OADs. For example,
unlike other OADs, the action of Dapagliflozin is insulin independent. Some

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S. K. Alkhanferi et al.

other OADs such as sulfonylurea and Glucagon like peptide 1 agonists need
enough insulin concentration to present in patient’s blood to be effective. How-
ever, the present studies included patients who had C-peptide concentration ≥ 1
ng/ml. Dapagliflozin efficacy should be assessed in patients with very low insulin
production, C-peptide concentration less than 1 ng/ml. Since, serum sodium
and potassium levels were normally distributed even when Dapagliflozin facili-
tated the excretion of sodium in the urine. Unlike canagliflozin, Dapagliflozin
does not show any clinical changes in serum potassium level. Adding Dapaglif-
lozin to metformin considered as safe and effective [5] [12] [13] [14].
After few weeks of significant body weight reduction were observed in the be-
ginning of all studies, the body weight reduction was less extent at the end of all
studies. One study measured the amount of glucose (calories) excreted by pa-
tients who used Dapagliflozin and it found to be arranged from 50 - 85 gram per
day and that may explained the slowdown in the weight reduction throughout
and at the end of the studies [12]. Moreover, the reduction in patients’ body
weight may be related to lose fluid due to the osmotic diuretic effect of Dapag-
liflozin [12] [16]. Losing both glucose and fluid in patients’ urine are the best ex-
planation for weight reduction at these studies. Further investigation should be
done to get a full understanding for patient’s weight changes with Dapagliflozin.
Reduction of patients’ body weight ≥ 7% is recommended by ADA to prevent or
delay type 2 DM [2]. Dapagliflozin as monotherapy or in combination with
metformin achieved > 5% reduction in body weight [5] [12]. Moreover, metfor-
min plus Dapagliflozin in Bailey et al. showed a reduction in waist circumference
of patients at 24 weeks which is a good indication of losing fat from abdominal
area. However, the authors did not report the reduction in the waist circumfe-
rence at end of 102 weeks. This is needed to fully understand patient body
weight changes and long term efficacy [5] [14] [17].
Fewer adverse effects with Dapagliflozin were noticed and it was well tole-
rated. Major hypoglycemia does not appear to be a serious adverse effect with
Dapagliflozin as monotherapy [12], or in combination [5] [13] [14]. One trial
compared combination of Dapagliflozin with Pioglitazone to Pioglitazone alone,
found no major incidence of hypoglycemia for almost one year with Dapagliflo-
zin [18]. Moreover, Comparing Dapagliflozin to Glipizide in a study with patient
who were already on metformin, found Dapagliflozin had 10 fold lesser inci-
dences of hypoglycemia and less treatment discontinuation compared to Glipi-
zide group [16]. All these studies showed neither major incidences nor treatment
discontinuation because of hypoglycemia with Dapagliflozin and that may be
related to the Dapagliflozin mechanism and less aggressive of losing glucose in
the urine.
The reduction in the blood pressure in patients who already had high blood
pressure (>130/80mm Hg) was observed in the first 24 weeks of both studies and
that does not increased chance of hypotension or orthostatic hypotension with
patients. This reduction was observed in either Dapagliflozin alone or in combi-
nation at short period of the study with no clear relation to dose [5] [12] [13]

DOI: 10.4236/jdm.2022.124022 280 Journal of Diabetes Mellitus

 S. K. Alkhanferi et al.

[14] [16]. This reduction in blood pressure is suggested to be related to osmotic

diuretic effect of Dapagliflozin as well as body weight loss. On the other hand, a
recent meta-analysis study stated that bias in the studies which showed a great
reduction in the blood pressure with patients on Dapagliflozin compared to pla-
cebo or other OADs was high [10]. Blood pressure reduction may be beneficial
in patients who are at high risk of stroke and heart failure with type 2 DM. Other
adverse effects must be also considered with patients who are using Dapagliflo-
zin alone or in combination are UTI and genital infections which were always
higher and especially with women than men. Usually, infections were treated
and resolved with standard treatment of antibiotics and rarely lead to discontin-
uation from studies. Results from different studies manifested that UTI and ge-
nital infections were higher than placebo or other OADs and seen greater in high
doses of Dapagliflozin, dose related [12] [18] [19].
Serum uric acid was also significantly reduce with any Dapagliflozin dose or
in combination and that appeared not dose related [12] [13] [14]. A reason of
this effect is unclear but the level of serum uric acid returned toward baseline af-
ter Dapagliflozin discontinued [12]. Thus, this reduction in serum uric acid may
be beneficial in patient with type 2 DM who has gout or hyperuricemia.

5. Conclusion
Dapagliflozin is SGLT2 inhibitor indicated to be used for type 2 diabetes mellitus
in adult patients. This review study establishes that combination therapy of da-
pagliflozin and metformin is safe and effective in type 2 diabetes mellitus with
minimal adverse effects.

Acknowledgments
The authors listed in the byline are the only investigators responsible for this re-
view article. This review was performed through electronic medical search en-
gines. This review article has been not presented at any conference or meeting.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.

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