Accepted Manuscript

Systematic review of metformin monotherapy and dual therapy with sodium

glucose co-transporter 2 inhibitor (SGLT-2) in treatment of type 2 diabetes
mellitus

Nagashekhara Molugulu, Lai Shu Yee, Yew Tze Ye, Tan Chew Khee, Lee Zhen
Nie, Neoh Jia Yee, Tian Kar Yee, Tan Chee Liang, Prashant Kesharwani

PII: S0168-8227(17)30827-6
DOI: http://dx.doi.org/10.1016/j.diabres.2017.07.025
Reference: DIAB 7035

To appear in: Diabetes Research and Clinical Practice

Received Date: 22 May 2017

Revised Date: 4 July 2017
Accepted Date: 13 July 2017

Please cite this article as: N. Molugulu, L. Shu Yee, Y. Tze Ye, T. Chew Khee, L. Zhen Nie, N. Jia Yee, T. Kar
Yee, T. Chee Liang, P. Kesharwani, Systematic review of metformin monotherapy and dual therapy with sodium
glucose co-transporter 2 inhibitor (SGLT-2) in treatment of type 2 diabetes mellitus, Diabetes Research and Clinical
Practice (2017), doi: http://dx.doi.org/10.1016/j.diabres.2017.07.025

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 Systematic review of metformin monotherapy and dual therapy with sodium

glucose co-transporter 2 inhibitor (SGLT-2) in treatment of type 2 diabetes

mellitus

Nagashekhara Molugulu1, Lai Shu Yee1, Yew Tze Ye1, Tan Chew Khee1, Lee Zhen Nie1,
Neoh Jia Yee1, Tian Kar Yee1, Tan Chee Liang1, Prashant Kesharwani2*

1
Department of Pharmaceutical Technology, International Medical University, Bukit Jalil Kuala
Lumpur, Malaysia
2
Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031 India

*Address for correspondence:

Dr. Prashant Kesharwani (M. Pharm., PhD)
Pharmaceutics Division
CSIR-Central Drug Research Institute
Sector-10, Jankipuram Extension
Lucknow, 226031, U.P., India
E-mail: prashantdops@gmail.com; prashant_pharmacy04@rediffmail.com
Tel / Fax: +91-7999710141

Disclosures: There is no conflict of interest and disclosures associated with the manuscript.
1
ABSTRACT

Background:
Type 2 Diabetes Mellitus (T2DM) is a chronic disorder and its treatment with only metformin often
does not provide optimum glycemic control. Addition of sodium glucose cotransporter 2 inhibitor
(SGLT2) will improve the glycemic control in patients on metformin alone. In this study, an attempt is
made to investigate the combined therapy of SGLT-2 with metformin in managing T2DM in terms of
lowering HbA1c and body weight and monotherapy using metformin alone in HbA1c and body weight
reduction.
Objectives:
To compare the clinical effectiveness of combined therapy using SGLT2 inhibitor and metformin with
monotherapy using metformin alone in HbA1c and body weight reduction.
Method:
A systematic review of the randomized controlled trials has been carried out and Cochrane risk of bias
tool was used for the quality assessment. Patient, Intervention, Comparison and Outcomes (PICO)
technique is used to select the relevant articles to meet the objective.
Results:
The studies used in this article are multicenter, double-blinded randomized controlled trials on SGLT2
inhibitors with methformin, there were a total of 3897 participants, with a range of 182 to 1186
individual study size were included. Studies showed that combined therapy were more effective in
HbA1c and body weight reduction as compared to monotherapy.
Conclusion: The combined therapy of SGLT2 inhibitor along with metformin is more effective in
HbA1c reduction and weight reduction as compared to monotherapy using metformin alone. Among
the three SGLT2 inhibitors such as dapagliflozin canagliflozin and empagliflozin do not differ much
in the efficiency of weight reduction. However, Empagliflozin 25mg is effective in HbA1c reduction.

Keywords: SGLT2 inhibitors; Dapagliflozin; Canagliflozin; Empagliflozin; Metformin; Type 2

diabetes mellitus; HbA1c.

2
1. Introduction

Type 2 diabetes mellitus (T2DM) refers to a chronic condition in which there is a deficiency in insulin
production or in which body is unable to utilize insulin effectively (1). According to the National
Health and Morbidity Survey (NHMS) 2015, the prevalence of diabetes in Malaysia has increased
from 15.2% (2011) to the current 17.5%. 15.2% and 20.8% (2). Knowing that T2DM is a current
global threat that may decrease one’s quality of life by causing blindness, end-stage renal disease and
non-traumatic limb amputation, various clinical trials have been carried out to look for new regimens
for better management of T2DM condition (3).

Common treatment of T2DM often begins with metformin, the first-line therapy for T2DM
patients with overweight and obesity problems(4). Metformin lowers the glucose levels by suppressing
hepatic glucose production. In addition, it can reduce the absorption of glucose from the
gastrointestinal tract (GIT), enhance peripheral glucose uptake as well as increase insulin
sensitivity(5). However, as T2DM progresses, β- cell function declines in presence of insulin
resistance, making the maintenance of glycemic control challenging and usually necessitates add on
therapies (4).

On the contrary, sodium-glucose co-transporter 2 inhibitor (SGLT-2), a new approach for T2DM
management has been reported to increase urinary glucose excretion by reducing renal glucose
reabsorption, leading to a reduction in plasma glucose with a low risk of hypoglycemia in T2DM (6,7).
As the action of SGLT-2 inhibitor is independent of insulin, its inhibition should not be affected by
pancreatic β- cell function or the degree of insulin resistance. Additionally, the non–insulin-dependent
mechanism of action of SGLT2 inhibitors gives them the potential to be used in combination with any
of the existing classes of glucose-lowering agents, including metformin (7).

A systematic review also reported that with the progressive nature of T2DM, significant
proportions of patients who receive anti-diabetic drug monotherapy usually fail to achieve glycemic
control and, thus, inevitably require multiple anti-diabetic agents to achieve glycemic control(5).
Therefore, we undertook a systematic review on whether combined therapy of SGLT-2 with
metformin is better than monotherapy of metformin in managing T2DM patients, in terms of lowering
HbA1c and body weight.
3
2. Materials and methods:

2.1. Data sources and literature search

A literature search using PubMed database was conducted in January 2017: (2012-2017). The
following MeSH search terms were used: “Type 2 Diabetes”, “SGLT-2”, and “Metformin”. The gist of
each research paper used for the literature review is tabulated in Appendix 1.
Based on Patient, Intervention, Comparison and Outcomes (PICO), a table was constructed to
identify the clinical outcomes of the studies included in the review (Table 1).
After obtaining the relevant articles, some of the articles are excluded, such as articles related
to animal studies, more than past 5 years, without full-text and foreign language other than English.
Further screening was done by all reviewers to exclude the articles which do not meet the requirements
of PICO technique. From the finalized areticles, data was extracted with respect to:

● Characteristic of the included studies: titles, author, country, study design, participants,
intervention and control.
● Clinical outcomes: HbA1c, weight reduction.
● Bias assessment: As there would be a variation of qualities among the studies included, there
may be studies of poor quality. We therefore considered that the assessment of methodological
quality was especially important. Hence, we used Cochrane risk of bias tool (modified) for
quality assessment of randomized controlled trials.
2.2. Eligibility criteria

Among the seven Randomized controlled trials, the selection criteria for the patients who were on
metformin at a stable dose of 1500mg/day. Furthermore, the patients data with a baseline HbA1c levels
ranging between 6.5% and 12%, mean age between 18 and 77 years, and BMI of less than 45kg/m2 is
used in the study.

2.3. Intervention

Any use of SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) in combination therapy
with metformin.
3. Results

4
3.1. Study selection
A huge number of studies are screened, assessed for eligibility and the reasons for exclusion are shown
in Figure 1. Of the 555 records, 397 studies was identified for full-test review. Subsequently, 368
studies was reported after excluding the foreign language. Around 41 studies are excluded due to non
–human studies and 29 studies excluded because the articles were found in foreign laungage. Majority
of the studies excluded because of irrevalent patient populations. Lastly, only seven studies were used
based on the PICO requirements.
3.1. Bias assessment
Cochrane risk of bias tool (modified) was used for the quality assessment of the mixed quality of the
studies. There are total 7 study validity domains to be answered, including sequence generation,
allocation concealment, blinding of participants and personnel, blinding of outcome assessors,
incomplete outcome data, selective outcome reporting, and other sources of bias. Based on the results
of Appendix 2, the overall result was 6 studies with unclear risk of bias and 1 study with high risk of
bias.
3.2. Study characteristics
Seven articles were selected and a there was a total of 3897 subjects. The sample size in the articles
varied from 182 to 1186. Six articles mentioned the countries where the studies were conducted. The
countries mentioned were Argentina, Brazil, Canada, Mexico, USA, South Africa, Bulgaria, Czech
Republic, Hungary, Poland and Sweden. There was only one article which did not mention about the
country where the study was conducted. All seven studies were multicenter, double-blinded randomized
controlled trials.
3.2.1. Synthesis of main findings
The results of each study is shown in Table 2.
3.2.2. Quantitative synthesis
The summary of RCT assessing monotherapy (MET) versus combined therapy (SGLT 2 + MET) for
diabetes included in the review is presented in Table 1.
3.2.2.1. Combined therapy versus monotherapy in HbA1C
Out of the seven studies, all the results showed statistically significant outcome in HbA1C reduction,
in which combined therapy (SGLT 2 + MET) was more effective than monotherapy (MET).

5
Generally, the reduction in HbA1c increases as the dose of SGLT-2 increases. However, three studies
(P.-M. Schumm-Draeger et al, 2014; J. Rosenstock et al, 2012 and 2013) showed decline in HbA1c
reduction when higher dose of SGLT-2 was used.(8–10) Based on the study conducted by P.-M.
Schumm-Draeger et al, reduction of HbA1c by dapagliflozin 10mg was supposed to be more than that
of dapagliflozin 5mg.(8) However, the reduction by dapagliflozin 10mg was lower than dapagliflozin
5mg which is -0.59% and -0.65% respectively. Besides, a study showed decline in the reduction of
HbA1c from -0.56%, -0.55% to -0.49% for empagliflozin 10mg, 25mg and 50mg(10). Another study
showed inconsistent trend in the reduction of HbA1c by canagliflozin 50mg OD, 100mg OD, 200mg
OD, 300mg BD and 300mg QID, which were -0.79%, -0.76%, -0.70%, -0% and -0.92%
respectively.(9)
3.2.2.2. Combined therapy versus monotherapy in weight reduction
Based on the seven studies, all the results proposed statistically significant outcome in body weight
reduction. Hence, all the seven studies showed that combined therapy (SGLT 2 + MET) was more
effective than monotherapy (MET) in body weight reduction. Generally, the reduction of weight
increases as the dose of SGLT 2 increases. However, there are 3 studies showing an inconsistent trend
in weight reduction as the dose of SGLT increases.(6,8,11) In a study reported by Bailey et al
(UK-2013), the extent of weight reduction in dapagliflozin 2.5mg is less than that of placebo.(6) In a
study reported by J. Rosenstock et al. (USA - 2013), the weight reduction in Empagliflozin 25mg is
lesser than that of Empagliflozin 10mg.(10,12). Additionally, in the studies done by J. Rosenstock et
al. (USA - 2012), the amount of weight reduction similar in canagliflozin 300mg although the
frequency of dose increases.(9) The detailed studies including the duration of trials, baseline HbA1c
levels and the number of patients are recorded in Appendix 1.
4. Discussion
SGLT2 inhibitors, when used in combination therapies for patients with type 2 diabetes mellitus with
poorly controlled blood glucose were shown to be more effective in reducing HbaA1c and body weight
as compared to monotherapy by using metformin alone. The recent clinical studies on SGLT2
inhibitorrs like dapagliflozin and empagliflozin have now been approved for clinical use in patients with
T2DM in US, Europe and other countries. These drugs also exert indirect renoprotection through
spressing renal glucose reabsorption to reduce blood glucose and body weight. In addition, many studies

6
concluded that SGLT2 inhibitors with their novel mechanism and associated benefits on
glucose-lowering, body weight, renoprotection, cardiovascular safety etc., have proved to be promising
choices when used in combination therapy(14,15).
4.1. SGLT2 inhibitor in HbA1c reduction
The present evidence suggested that the optimal dose for canagliflozin is 300mg as it shown a
significant reduction in HbA1c level as compared to canagliflozin 100mg.(9,13) The optimal dose of
dapagliflozin was ambiguous as one study suggested 10mg and another study suggested 5mg based on
the reduction value in HbA1c.(6,8,11) As for the optimal dose for empagliflozin, it was uncertain as
well since one study proposed 10mg while another study proposed 25mg. For the study which suggested
10mg, it was comparatively insignificant than another study as it showed a slight difference of only
0.01% between the reductions of HbA1c level for 10mg and 25mg. Hence, it can be concluded that the
ideal dose of empagliflozin should be 25mg.(10,12)
4.2. SGLT2 Inhibitor in weight reduction
From the result of Bailey et al., P.-M. Schumm-Draeger et al. and J. Bolinder et al., the optimal dose
of dapagliflozin for weight reduction is 10mg when used as add-on medication to metformin.(6,8,11)
Both the studies from J. Rosenstock et al. for canagliflozin showed that 300mg of canagliflozin
provides the best result in weight reduction.(9,13) On the other hand, the best dose for the
empagliflozin in reducing weight is uncertain, L. Merker et al. showed that 25mg is the best while J.
Rosenstock et al. showed that 50mg is the best.(10,12).
Among the 3 drugs in the class of SGLT2 inhibitor, the study that has been done on dapagliflozin
is more as compared to canagliflozin and empagliflozin when used in combination with metformin.
In the overall, the efficiency of the 3 drugs in weight reduction do not differ much, the efficiency of
the various SGLT2 inhibitors in weight reduction are almost similar.
4.3. Limitation of studies review

One of the major downside of Bailey et al study is the number of patient needing rescue medication
(primarily pioglitazone, or acarbose) in the placebo group. Thus, patients whose HbA1c exceeded 8.0%
at week 24, 7.5% at 50 weeks or 7.0% at 76 weeks received rescue therapy and were not included in the
final efficacy analysis. Although this might limit the statistical interpretation of durability of the
glucose-lowering effect of dapagliflozin, it also emphasizes the clinical utility of dapagliflozin.

7
 The shortcoming of J. Rosenstock et al (2013) has been reported that the washout period may not
be sufficient due to the short duration of studies of 12 weeks and sample size of ~500 participants.
Another pitfall that has been found is that a slightly greater placebo-adjusted changes in the active
treatment groups may have been resulted from the slight increase in HbA1c in the placebo group.
Furthermore, J. Rosenstock et al (2012) contented that the response of using a second oral agent for
those on metformin monotherapy who did not undergo washout was better than those who were
already on combination therapy.

J. Bolinder et al studies claimed that their approach is not well suited to patients with body weight
over 120 kg.(11) Moreover, one issue that needs to be raised is that the baseline HbA1c was low in this
study, and therefore, changes in HbA1c with dapagliflozin were not significant. Another downside of
this study is there is an uncertainty with regard to the precise mechanism of dapagliflozin-induced
weight loss in the absence of control for food and fluid intake, and 24-h quantification of urinary
glucose excretion. An additional weakness that has been clearly recognized is the effect of
dapagliflozin on food intake and satiety is not conclusive. Therefore, it was suggested that full
calorimetric and fluid-balance studies are required to resolve these issues. In terms of body weight,
weight loss observed in the current study is unlikely to have been caused by concomitant medication
use. On the other hand, a related previous study has failed to demonstrate the pharmacokinetic
interaction between dapagliflozin and metformin.

According to the studies that we reviewed, the cost effectiveness cannot be assessed due to not
known costs of SGLT2 inhibitor. The sulphonylureas are now very low cost, so the SGLT2 receptor
inhibitors are very unlikely to be cost-effective compared to them.
The studies in this review recruited patients with type 2 diabetes mellitus with inadequately
controlled HbA1c level and body weight that are on metformin. The aim of this review is to examine
the evidence as to whether with an addition of SGLT-2 inhibitors to metformin, the HbA1c level and
patient’s body weight will be reduced.

Factors to be considered whether SGLT-2 is efficacy and safe to be used in type 2 diabetes
mellitus patients are:

● Glycemic control in type 2 diabetes mellitus patients as reflected in HbA1c reductions

8
 ● Effect on weight, when combined with metformin compared to metformin alone
(placebo)
● Adverse effects, especially on urinary tract and genital tract infection
● Duration of effectiveness
● Drugs interaction in patients receiving treatment for comorbidities
● Ease of use (oral intake instead of injection)
● Cost
Further studies, which take efficacy and safety of monotherapy (metformin) and combined
therapy (metformin and SGLT-2) into account, will need to be performed in diabetes patients.

5. Conclusions

The combined therapy of SGLT2 inhibitor and metformin is more effective in HbA1c reduction
and weight reduction as compared to monotherapy using metformin alone. The recent clinical studies
on SGLT2 inhibitorrs like dapagliflozin and empagliflozin have now been approved for clinical use in
patients with T2DM in US, Europe and other countries. These drugs also exert indirect renoprotection
through spressing renal glucose reabsorption to reduce blood glucose and body weight. In addition,
many studies concluded that SGLT2 inhibitors with their novel mechanism and associated benefits on
glucose-lowering, body weight, renoprotection, cardiovascular safety etc., have proved to be
promising choices when used in combination therapy(14,15). In addition, SGLT2 inhibitors along with
metformin as dual therapy are recommended by the National Institute for Health and Care Excellence
(NICE) for the management of T2DM if a sulphonylurea is contraindicated/not tolerated or if a patient
is at significant risk of hypoglycaemia (16). However, there is a need to study its cost effectiveness
when used in combination therapy.

Conflict of interest:

The authors declare that they have no conflict of interest.

Note: This is CSIR-CDRI communication 115/2017/PK.

9
References
1. Diabetes mellitus (Internet). WHO. (cited 2017 Mar 1). Available from:
http://www.who.int/mediacentre/factsheets/fs138/en/
2. Non-communicable disease, risk factors and other health problems. National Health and
Morbidity Survey 2015. Ministry of Health Malaysia. 2015; 2: 14-6.
3. Mortality among Type 2 Diabetic In-Patient in a Nigerian Tertiary Hospital. AJDM. November
2016; 24(2): 14-20.
4. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors and
cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis
Res. 2015 Mar; 12(2): 90–100.
5. Tan X, Hu J. Combination therapy for type 2 diabetes: dapagliflozin plus metformin. Expert
Opin Pharmacother. 2016; 17(1): 117–26.
6. Bailey CJ, Morales Villegas EC, Woo V, Tang W, Ptaszynska A, List JF. Efficacy and safety of
dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double-blind
placebo-controlled 102-week trial. Diabet Med J Br Diabet Assoc. 2015 Apr; 32(4): 531–41.
7. Cuypers J, Mathieu C, Benhalima K. Sglt2-Inhibitors: A Novel Class for the Treatment of Type 2
Diabetes Introduction of Sglt2-Inhibitors in Clinical Practice. Acta Clinica Belgica. 2013 Aug 1;
68(4): 287–93.
8. Schumm-Draeger P-M, Burgess L, Korányi L, Hruba V, Hamer-Maansson JE, de Bruin TWA.
Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week
randomized, placebo-controlled clinical trial. Diabetes Obes Metab. 2015 Jan; 17(1): 42–51.
9. Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, et al. Dose-ranging effects
of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects
with type 2 diabetes. Diabetes Care. 2012 Jun; 35(6): 1232–8.
10. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, et al. Efficacy and safety of
empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in
type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013 Dec; 15(12): 1154–60.
11. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al.
Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2
years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes
Obes Metab. 2014 Feb; 16(2): 159–69.
12. Merker L, Häring H-U, Christiansen AV, Roux F, Salsali A, Kim G, et al. Empagliflozin as
add-on to metformin in people with Type 2 diabetes. Diabet Med J Br Diabet Assoc. 2015 Dec;
32(12): 1555–67.
13. Rosenstock J, Chuck L, González-Ortiz M, Merton K, Craig J, Capuano G, et al. Initial
Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as
Monotherapy for Drug-Naïve Type 2 Diabetes. Diabetes Care. 2016 Mar;39(3):353–62.
14. Honghong Zou, Baoqin Zhou, Gaosi Xu SGLT2 inhibitors:a novel choice for the combination
therapy in diabetic kidney disease. Cardiovasc Diabetrol, 2017 16:65
15. Elisaf M, Tzavela E, Karanatsis N, Tsimichodimos V. Antidiabetic drugs and the kidney. Curr
Pharm Des. 2017. doi:10.2174/138161282366617030710 3222

10
 Table 1: Patient, Intervention, Comparison and Outcomes

Patient Intervention Comparison Outcome

Diabetic Sodium Glucose Placebo in Patient outcomes:

patients Co-transporter 2 addition to ● Reduction in
(SGLT-2) metformin HbA1c
(dapagliflozin, /metformin ● Reduction in
empagliflozin, only. mean body
canagliflozin…) weight
inhibitor in addition to
metformin

Specific Type 2 Sodium Glucose Placebo Reduction of HbA1c

term diabetes Co-transporter 2 (metformin and mean body
mellitus (SGLT-2) inhibitor only/ placebo weight in diabetic
patients combined with + metformin) patients
metformin

Similar Diabetes, SGLT- 2, Metformin HbA1c reduction,

terms diabetes empagliflozin, hemoglobin A1c
patients, 2-(3-(4-ethoxybenzyl) reduction, HbA1c
diabetic -4-chlorophenyl)-6-hy test, glycated
patients, droxymethyltetrahydr hemoglobin,
diabetes o-2H-pyran-3,4,5-triol glycosylated
mellitus , Canagliflozin, hemoglobin, weight
patients, remogliflozin loss, weight
diabetes etabonate, sergliflozin reduction, body
mellitus type etabonate, weight loss, body

11
 2, type 2 6-((4-ethylphenyl)met weight reduction
diabetes hyl)-3',4',5',6'-tetrahyd
mellitus, ro-6'-(hydroxymethyl)
diabetes type 2 spiro(isobenzofuran-1
(3H),2'-(2H)pyran)-3',
4',5'-triol, ipragliflozin

Combining Search for phrases using quotation marks, e.g.: “SGLT2 metformin” and can
terms combine terms using AND, OR and NOT, e.g.: “SGLT 2 AND metformin” (this
will give us documents containing both terms) “SGLT 2 OR metformin” (this will
give us documents containing either term), “SGLT 2 NOT metformin” (this will
give us documents which do not mention metformin).

12
 Table 2: Summary of main findings

Authors Age (years) Reduction in HbA1c level (%) Reduction in body weight (kg) Ref.
(country-years)

J. Rosenstock et al 18-75 MET = –1.30 MET = –1.9 (13)

(USA-2016) Canagliflozin 100mg/MET = -1.77 Canagliflozin 100mg/MET = -3.2
Canagliflozin 300mg/MET = -1.78 Canagliflozin 300mg/MET = -3.9

Bailey et al Placebo/ MET = 0.02 Placebo/ MET= 1.36 (6)

-
(UK-2013) Dapagliflozin 2.5mg/ MET = -0.48 Dapagliflozin 2.5mg/ MET = -1.10
Dapagliflozin 5mg/ MET = -0.58 Dapagliflozin 5mg/ MET = -1.70
Dapagliflozin 10mg/MET= -0.78 Dapagliflozin 10mg/ MET = -1.74

L. Merker et al, 45-65 Placebo / MET = + 0.1 Placebo/ MET = -0.6 (12)
(UK-2015) Empagliflozin 10mg/MET = -0.6 Empagliflozin 10mg/MET = -2.9
Empagliflozin 25 mg/MET = -0.8 Empagliflozin 25 mg/MET = -3.1

P.-M. 18–77 Placebo/MET = −0.30 Placebo/MET = −0.86 (8)

Schumm-Draeger et dapagliflozin 2.5mg/ MET = −0.52 dapagliflozin 2.5mg/ MET=
al dapagliflozin 5mg/ MET = −0.65 −2.34
(Germany -2014) dapagliflozin 10mg/ MET = −0.59 dapagliflozin 5mg/ MET =
−2.48
dapagliflozin 10mg/ MET =
−2.74

J. Rosenstock et 18-79 Placebo / MET = 0.15 Placebo / MET = -1.2 (10)

al. Empagliflozin 1mg / MET = -0.09
(USA - 2013) Empagliflozin 5mg / MET = -0.23
Empagliflozin 10mg / MET = -0.56
Empagliflozin 25mg / MET = -0.55
Empagliflozin 50mg / MET = -0.49
Empagliflozin 1mg / MET = -1.6
Empagliflozin 5mg / MET = -2.3
Empagliflozin 10mg / MET = -2.7
Empagliflozin 25mg / MET = -2.6
Empagliflozin 50mg / MET = -2.9

30-75 Placebo/MET = 0.12 Placebo/MET = −2.12 (11)

J. Bolinder et al. Dapagliflozin 10mg/ MET = −0.30 Dapagliflozin 10mg/ MET =
(Sweden - 2014) −4.54

13
J. Rosenstock et al. 18–65
(USA - 2012)
*The detailed studies including the duration of trials, baseline HbA1c levels and the number of patients
are recorded in Appendix 1.
Placebo / MET = -0.22
Canagliflozin 50mg / MET = -0.79
Canagliflozin 100mg / MET = -0.76
Canagliflozin 200mg / MET = -0.70
Canagliflozin 300 mg BD / MET = -0
Canagliflozin 300 mg QID / MET =
-0.92
Placebo / MET = -0.8 (9)
Canagliflozin 50mg / MET = -2.0
Canagliflozin 100mg / MET = -2.2
Canagliflozin 200mg / MET = -2.3
Canagliflozin 300 mg BD / MET =
-2.9
Canagliflozin 300 mg QID / MET =
-2.9
14
Appendix 1: The gist of research papers used in this study as part of literature review
Title Author Country Study design Participants Intervention Compare Outcome Result
(inclusion
criteria)

Julio Phase 3 study double-blind, A total of 1,186 CANA 100mg CANA100 a) Glycemic Efficacy Initial therapy with CANA
Initial Rosenstock, was conducted five-arm, patients were CANA100/ (n=237), At week 26, reductions from baseline in plus MET was more effective
Combination Leonard at 158 centers parallel group randomized MET CANA300 HbA1c were seen with CANA100/MET, and generally well tolerated
Therapy with Chuck, in 12 countries a) >18 and <75 (n=237), CANA (n=238), or CANA300/MET, CANA100, versus each monotherapy in
Canagliflozin Manuel years of age with 300mg MET(n=237). CANA300, and MET (–1.77%, -1.78%, drug-naıve type 2 diabetes.
Plus Metformin Gonzalez-Or drug-naıve type 2 (CANA300)/ME –1.37%, –1.42%, and –1.30% (–19.3, CANA monotherapy
Versus Each tiz, Kate diabetes T –19.5, –15.0, –15.5, and –14.2 demonstrated noninferior
Component as Merton, (not on AHA (n=237) mmol/mol), respectively), resulting in HbA1c lowering versus
Monotherapy for Jagriti Craig, therapy or off final mean HbA1c values of 7.0%, MET.
Drug-Naıve Type George for >12 weeks 7.0%, 7.4%, 7.3%, and 7.4% (53, 53, 57,
2 Diabetes Capuano, before screening) 56, and 57 mmol/mol), respectively.
and Rong b) HbA1c >7.5%
Qiu and <12.0% (>58 b) At week 26, reductions in body

and <108 weight from baseline were observed

mmol/mol) at across groups (–3.2, –3.9, –2.8, –3.7,

screening and –1.9 kg (-3.5%, –4.2%, –3.0%,

–3.9%, and –2.1%) with
CANA100/MET, CANA300/MET,
CANA100, CANA300, and MET,
respectively

Dapagliflozin Clifford Patient a 24-week A total of 546 Dapagliflozi Open-label - At week 102, mean changes from Dapagliflozin added to
add-on to J Bailey, recruited phase 3, patients from n 2.5mg, metformin baseline HbA1c (8.06%) were metformin over 102
metformin in Jorge L from 80 multicenter, 80 5mg, 10mg (> +0.02% for placebo compared with weeks showed sustained

16
type 2 Gross, sites in randomized sites in once daily. 1500mg/day) -0.48% improved glycemic
diabetes Delphine Argentina, , Argentina, (P = 0.0008), -0.58% (P <0.0001), control, modest weight
inadequately Hennick Brazil, placebo-co Brazil, Canada, and -0.78% (P <0.0001) for reduction, and no
controlled en, Canada, ntrolled, Mexico, and dapagliflozin 2.5 to 5, and 10 mg, increased risk of
with Nayyar Mexico and double-blin USA. respectively. hypoglycemia in type 2
metformin: Iqbal, USA. d, diabetes inadequately
a randomized, Traci A parallel-gro - In addition, all dapagliflozin controlled with
double-blind, Mansfiel up trial. groups had sustained reductions metformin alone.
placebo-contr d and from baseline in FPG (-1.07 to -1.47
olled James F mmol/l) and body
102-week List weight (-1.10 to -1.74 kg) at 102
trial weeks.

Empagliflozin L. - Randomize 637 Empagliflozi Placebo Compared with placebo, adjusted In people with Type 2
as add-on to Merker, d, participants n 10 mg (207 patient) mean reductions in HbA1c at week 76 diabetes, empagliflozin
metformin in H-U. placebo-co Adults with (217 were significantly greater with both 10 mg and 25 mg given
people with Hearing, ntrolled, Type 2 diabetes patients), AND doses of empagliflozin: as add-on to metformin
Type 2 A. V. double-blin and insufficient Empagliflozi 1) 7 mmol/mol (0.6%) with for 76 weeks were well
diabetes Christian d study glycaemic n 25 mg Receiving a empagliflozin 10 mg (95% CI 8, 5 tolerated and led to
sen, F. control (HbA1c (214 stable mmol/mol (0.8, 0.5%); P < 0.001) sustained reductions in
Roux, A. ≥ 53 mmol/mol patients) regimen of 2) 8 mmol/mol (0.7%) with HbA1c, weight and
Salsali, (≥ 7%) and immediate empagliflozin 25 mg (95% CI 10, 6 systolic blood pressure.
G. Kim, ≤ 86 mmol/mol AND release mmol/mol (0.9, 0.6%); P < 0.001
T. (≤ 10%)), metformin
Meinicke despite being Receiving a (≥ 1500 Empagliflozin significantly reduced
, on a diet and stable mg/day or body weight at week 76 compared
H. J. exercise regimen of maximum with placebo (adjusted mean 1.9 kg
Woerle programme and immediaterel dose (95% CI 2.5, 1.3); P < 0.001 for
and U. receiving a ease according to empagliflozin 10 mg and 2.2 kg (95%
C. stable regimen metformin the local CI 2.8, 1.6); P < 0.001 for

17
 Broedl of immediate (≥ 1500 label empagliflozin 25 mg.
release mg/day or
metformin (≥ maximum Compared with placebo, adjusted
1500 mg/day or dose mean changes in systolic blood
maximum dose according to pressure at week 76 were 4.4 mmHg
according the local (95% CI 6.6, 2.3) with empagliflozin
to the local label 10 mg (P < 0.001) and 3.7 mmHg
label; (95% CI 5.9, 1.5) with empagliflozin
unchanged for 25 mg (P < 0.001)
≥ 12 weeks
before
randomization)
,who had a
bodymass
index (BMI) ≤
45 kg/m2
were enrolled

Twice-daily P.-M. 53 sites in randomized 400 adults dapagliflozin placebo 1)At 16 weeks, the adjusted mean Dapagliflozin 2.5 or 5
dapagliflozin Schumm Europe and , placebo (2.5 mg co-administe change in HbA1c from baseline was mg twice daily added to
co-administer -Draeger, South double-blin (n=101), twice daily, red with significantly reduced in the metformin was effective
ed with L. Africa d, dapagliflozin 5 mg twice metformin dapagliflozin 2.5mg twice daily in reducing glycaemic
metformin in Burgess, double-dum 2.5mg twice daily, 10mg twice daily and 5 mg twice daily groups versus levels in patients with
type L. my daily (n=100), once daily) placebo (−0.52 vs. −0.30%, type 2 diabetes
2 diabetes: a Korányi, placebo-co dapagliflozin co-administe p=0.0106 and −0.65% vs. −0.30%, inadequately controlled
16-week V. ntrolled 5mg twice red with p<0.0001). with metformin alone.
randomized, Hruba, J. study daily (n=100) metformin 2)There were also significantly This study supports the
placebo-contr E. or twice daily greater development of a
olled clinical Hamer- dapagliflozin improvements for dapagliflozin fixed-dose combination
trial Maansso 10mg once twice daily groups versus placebo in regimen.

18
n & T. daily (n=99) FPG body weight and achievement
W. A. de of HbA1c level of <7%.
Bruin 1)18–77 years 3)Efficacy outcomes for
old, had type 2 dapagliflozin twice daily were
diabetes numerically similar to those for
dapagliflozin once daily.
2)had been Dapagliflozin twice daily was well
treated with tolerated.
stable
doses of
metformin
≥1500mg/day
monotherapy
for ≥10weeks
before
enrolment

3)showed
inadequate
glycaemic
control,
defined as an
HbA1c level
≥6.7 and
≤10.5% at
screening, or
HbA1c ≥6.5
and ≤10.0%
1week before
randomization

19
Efficacy and J. 104 centres dose-rangin 495 1, 5, 10, 25, placebo Reductions in HbA1c of −0.09 to Reductions in HbA1c of
safety of Rosensto in 16 g, participants or 50 mg −0.56% were observed with −0.09 to −0.56% were
empagliflozin ck, L. J. countries double-blin with type 2 empagliflozi empagliflozin after 12weeks, versus observed with
, a sodium Seman, d, diabetes n once daily an increase of 0.15% with empagliflozin after 12
glucose A. placebo-co inadequately (QD) and placebo (baseline: 7.8–8.1%). weeks, versus an increase
cotransporter Jelaska, ntrolled controlled open-label of 0.15% withplacebo
2 (SGLT2) S. trial on sitagliptin (baseline: 7.8–8.1%).
inhibitor, as Hantel, metformin(hae (100 mg
add-on to S. moglobin A1c QD), added At week 12, the
metformin Pinnetti, (HbA1c) >7 to to metformin reductions in adjusted
in type 2 T. Hach ≤10%) mean body weight
diabetes with & H. J. ranged from −1.6 to −2.9
mild Woerle 1)body mass kg in the empagliflozin
hyperglycaem index (BMI) groups. These reductions
ia ≤40 kg/m2; were significant versus
previous placebo for all dose
treatment with groups except 1 mg
metformin (figure 3).
alone or with
metformin and Empagliflozin doses
one from 5 to 50 mg resulted
other oral in reductions in fasting
antidiabetic plasma glucose (−2 to
agent (OAD) −28 mg/dl vs. 5 mg/dl
with placebo; p <
2)unchanged 0.0001) and body weight
antidiabetic (−2.3 to −2.9 kg vs. −1.2
therapy for ≥10 kg; p < 0.01).
weeks prior to
screening

20
including
stable
metformin
therapy (≥1500
mg/day or
maximum
tolerated
dose)

3) haemoglobin
A1c (HbA1c)
of ≥6.5 to ≤9%
for
patients on
metformin and
one other
OAD, which
had to be
discontinued at
the start of the
washout period

4) HbA1c >7
to
≤10% for those
on metformin
monotherapy;
and HbA1c>7
to ≤10% for all
participants at

21
 start of placebo
run-in period.

J. Phase 3 study Randomized, A total of 182 DAPA 10 mg/day Placebo added to Dapagliflozin improved
Bolinder, was conducted at Parallel-group, patients were added to open-label A total of 140 patients (76.9%) completed glycaemic control, and reduced
O. Ljunggre, 40 sites in Double-blind, randomized open-label metformin ≥1500 the study. weight and fat mass, without
Dapagliflozin L. Johansson, Bulgaria, Czech Placebo-controll Patients with T2DM: metformin ≥1500 mg/day (n=91) affecting markers of bone
maintains a) Over 102 weeks, dapagliflozin-treated
J. Republic, ed a) women aged mg/day (n=89) turnover or BMD in patients
glycaemic control patients showed reductions in HbA1c by
Wilding, Hungary, Poland 55–75 years who with T2DM inadequately
while reducing −0.3%, weight by −4.54 kg, waist
A. M. and Sweden were controlled on metformin
weight and body fat Langkilde, circumference by −5.0 cm and fat mass
postmenopausal for a
mass over 2 years in C. D. Sjostrom, by −2.80 kg without increase in rate of
period of at least 5
patients with type 2 J. Sugg hypoglycaemia. (n=69)
years
diabetes mellitus & OR
b) For placebo group, no meaningful
inadequately S. Parikh men aged 30–75
changes from baseline in markers of bone
controlled on years; haemoglobin
turnover or BMD were identified over
metformin A1c (HbA1c)
102 weeks. (n=71)
6.5–8.5%; fasting
plasma glucose
(FPG) ≤13.2 mmol/l;
body mass index
(BMI) ≥25 kg/m2;
body weight ≤120 kg

b) treatment with
metformin at a stable
dose of ≥1500
mg/day for ≥12
weeks before
enrolment.

22
 Julio 12 countries Randomized, 451 subjects canagliflozin at Placebo 1)Canagliflozin was associated with Canagliflozin added onto
Dose-Ranging Rosenstock, double-blind, 1)men and women doses significant reductions in A1C from metformin significantly
Effects of Naresh placebo-control 18–65 years of age of 50, 100, 200, baseline improved glycemic control
Canagliflozin,a Aggarwal, led, parallel who were or 300mg once (7.6–8.0%) to week 12: 20.79, 20.76, in type 2 diabetes and was
Sodium-Glucose David group, diagnosed daily (QD) 20.70, 20.92, and 20.95% for associated with low
Cotransporter 2 Polidori, multicenter, with type 2 or 300 mg twice canagliflozin 50, incidence of hypoglycemia
Inhibitor, as Yue Zhao, dose-ranging diabetes for at least daily (BID); 100, 200, 300 mg QD and 300 mg BID, and significant weight loss.
Add-On to Deborah study. 3 months, sitagliptin respectively, versus 20.22% for placebo The safety/tolerability profile
Metformin in Arbit, had an A1C 100 mg QD (all P < of canagliflozin was
Subjects With Keith level >7% and (Sitagliptin was 0.001) and 20.74% for sitagliptin. favorable except for
Type 2 Diabetes Usiskin, <10.5%, included as an increased frequency of
George 2)On metformin active-reference 2)Body weight genital infections in females.
Capuano, monotherapy at a treatment was reduced by 22.3 to 23.4%, with
William stable (>3months) group to provide significant increases in urinary
Canovatchel dose of clinical glucose-to-creatinine ratio.
≥1,500mg/day, 3) perspective.)
A stable body
weight and BMI
25–45 kg/m2
(24–45 kg/m2 for
those of Asian
descent),
4)serum creatinine
levels,1.5mg/dL
for men and ,1.4
mg/dL for women.

23
Appendix 2: Cochrane Risk of Bias Tool (Modified) For Quality Assessment Of Randomized Controlled Trials

Title Sequence Allocation Blinding of Blinding of Incomplete Selective Other Risk

Generation Concealment Participants and Outcome Outcome Data Outcome Sources of
Personnel Assessors Reporting Bias

Initial Combination Therapy with Canagliflozin Plus Metformin Yes Yes Yes Yes Yes Yes Unclear Unclear
Versus Each Component as Monotherapy for Drug-Naıve Type 2 risk of bias.
Diabetes

Dapagliflozin add-on to metformin in type 2 diabetes inadequately Unclear Yes Yes Yes Yes Yes Unclear Unclear
controlled with metformin: a randomized, double-blind, risk of bias.
placebo-controlled 102-week trial

Empagliflozin as add-on to metformin in people with Type 2 Unclear Yes Yes Yes Yes Yes Yes Unclear
diabetes risk of bias.

Twice-daily dapagliflozin co-administered with metformin in type Yes yes Yes Unclear Yes Yes Unclear Unclear
2 diabetes: a 16-week randomized, placebo-controlled clinical risk of bias.
trial

Efficacy and safety of empagliflozin, a sodium glucose Yes Unclear Yes Yes Yes Yes Unclear Unclear
cotransporter 2 (SGLT-2) inhibitor, as add-on to metformin in risk of bias.
type 2 diabetes with mild hyperglycemia

Dapagliflozin maintains glycaemic control while reducing weight and Unclear Yes Yes Yes Yes Yes Unclear Unclear
body fat mass over 2 years in patients with type 2 diabetes mellitus risk of bias.
inadequately controlled on metformin

Dose-Ranging Effects of Canagliflozin,a Sodium-Glucose Unclear No Yes Yes Yes Yes Unclear High risk

24
Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects of bias
With Type 2 Diabetes

25
Records identified in PubMed database after
searching using the above mentioned keywords,
and Randomized Controlled Studies were
selected as our main references.
(n =555) Records excluded due to non-human
studies (animals).
(n =41)
Records relevant to human studies.
(n=514)
Records excluded for more than 5
years.
(n =83)
Records for the recent 5 years.
(n=431)

Records excluded due to full text

unavailability.
(n =34)
Records with full text.
(n=397)
Records excluded for foreign
language.
(n =29)
Full-text articles retrieved for detailed
evaluation assessment for inclusion
(n=368)
Records excluded due to irrelevant
patient populations (T2DM),
interventions
(dapagliflozin,empagliflozin,can
Full text articles which meet all requirement. agliflozin), comparison
(n=7) (placebo/metformin) and outcomes of
Dapagliflozin (n=3), Empagliflozin (n=2), studies (Reduction in HbA1c level
Canagliflozin( n=2) and body weight).
(n =361)

Figure 1: Flow chart of literature search

15
Highlights:

 Type 2 Diabetes Mellitus (T2DM) is a current global threat.

 Sodium-glucose co-transporter 2 inhibitor (SGLT-2) is a new approach for T2DM management.
 Combined therapy of SGLT2 inhibitor and metformin is more effective in HbA1c reduction and weight reduction as compared to monotherapy using
metformin alone.

26