40
Journal of The Association of Physicians of India ■ Vol. 64 ■ September 2016
Original Article
A Prospective Analysis of the Efficacy and Safety
of Sodium Glucose Cotransporter 2 Inhibitors:
Real World Evidence from Clinical Practice in
India
Bhavana Sosale1, Aravind R Sosale 2, Prassanna M Kumar3, Shashank R Joshi4
Abstract
Editorial Viewpoint
Background and Aim: The number of patients with type 2 diabetes
(T2DM) is increasing. Most patients with T2DM are uncontrolled and fail
to achieve their target Hba1c. In recent years, newer agents such as SGLT2
inhibitors (SGLT2i) have been approved for clinical use. Though data from
clinical trials and sub set analysis of Indian patients in global studies are
promising, real world evidence from standard clinical practice in India is
lacking. The aim of this study was to analyze the metabolic parameters
in patients with T2DM on SGLT2i in real world clinical practice.
• S G LT 2 i n h i b i t o r i s t h e
latest introduction into
the armamentarium of
antidiabetic drugs.
Materials and Methods: This was a prospective, longitudinal study
of 100 patients with uncontrolled T2DM attending the outpatient of a
specialized diabetes hospital. Their metabolic parameters were evaluated
at baseline and after 3 months of follow up. They were categorized based
on their baseline anti diabetic medications into four groups (25 in each).
The groups were as follows: metformin plus sulfonylurea, metformin plus
DPP4 inhibitor, triple drug regimen with metformin plus DPP4 inhibitor
plus sulfonylurea, and patients on insulin and on triple drug therapy with
metformin plus sulfonylurea plus DPP4 inhibitor. Patients in each group
were initiated with an SGLT2i. Descriptive statistical analysis was carried
out using Microsoft excel. T test was used to calculate the p value at 5
% level of significance
Results: The mean age of the subjects in the study population was
53.20±12.1 years and the duration of diabetes was 13.1±7.26 years. The
mean Hba1c reduction and weight reduction observed was 1.02±0.24%
and 2.64±1.27 kg respectively. Genital pruritis was reported in 4% of the
patients. There was a 16.6% reduction in the daily insulin requirement
at follow up when compared to baseline. No other side effects were
observed. The reductions in Hba1c and weight were statistically
significant (p<0.05) across all groups.
Conclusion: This study demonstrates that when SGLT2i are added at any
stage of the disease spectrum with any of the preexisting therapeutic
agents for patients with uncontrolled T2DM, there is an improvement in
glycemic control and body weight, with minimal side effects. The real
world study data on Indian patients appears to be promising.
• The study demonstrates
an improvement in
glycaemic control and
body weight in previously
uncontrolled type 2
diabetes mellitus.
Introduction
I
nternational Diabetes Federation
estimates show that India is
home to 69.2 million people with
diabetes. 1 An increase in diabetes
prevalence has not only resulted
in an increase in the complications
associated with diabetes but has
also exponentially added to heath
care costs while decreasing the
quality of life. 2
Even though we have several
agents for the treatment of
T2DM one or two are rarely
sufficient to maintain normal
or near normal glycemia and
continuous reevaluation and up
titration is often necessary. This
1
Consultant Diabetologist, 2 Director and
Consultant Diabetologist, Diacon Hospital,
Bangalore, Karnataka; 3Professor Emeritus, MS
Ramaiah Medical College, CDEC, Bangalore,
Karnataka; 4Department of Endocrinology,
Lilavati Hospital, Mumbai, Maharashtra
Received: 05.02.2016; Accepted: 03.03.2016
Journal of The Association of Physicians of India ■ Vol. 64 ■ September 2016
may be attributed to the beta cell
decline that occurs as a part of the
natural history of T2DM. 3Cost of
health care, lack of education, side
effects of existing medications like
weight gain and hypoglycemia,
lack of lifestyle modification, fear
of injections and even physician
inertia to up titrate medications are
other factors amongst many that
contribute to hyperglycemia.
Sodium glucose transporter
receptor 2 inhibitors (SGLT2 i) are
now recognized as a novel therapy
for T2DM management. They act
by blocking the sodium glucose co
transporter located at the proximal
convoluted tubule of the nephron
which is responsible for about 90%
of glucose reabsorption. These
agents decrease the renal threshold
for glucose and cause glycosuria.
This in turn results in improvement
in glycemia and provides extra
glycemic benefits like weight loss
attributed to osmotic diuresis,
calorie loss and decrease in visceral
fat. Extra glycemic benefits also
include decrease in uric acid levels
and improvements in systolic and
diastolic blood pressure. 4-8
The risk of hypoglycemia with
these agents is low, but it has been
reported in patients on insulin and
insulin secretagogues. An increase
in mild genital mycotic infections
and urinary tract infections has
been reported. Most of these have
subsided with antifungal therapy,
have been isolated cases and have
rarely warranted discontinuation
o f t r e a t m e n t . 4,8-10 E u g l y c e m i c
ketoacidosis when used off label
in patients with type 1 diabetes
and in post operative type 2
diabetes patients with reduced
oral intake or in those who have
been taken off of insulin therapy is
a known side effect. 11 An increase
in fracture risk when used in
elderly patients with moderate
renal impairment and additional
comorbidities like osteoporosis
and renal osteodystrophy is also
reported. 4,12
While the results of the CV
safety trials for dapagliflozin and
c a n a g l i f l o z i n a r e a wa i t e d , t h e
results of the EMPA REG OUTCOME
TRIAL, the cardiovascular safety
randomized control trial with
empagliflozin 13 is noteworthy. The
results of this trial demonstrated
a relative risk reduction of 38%,
35% and 32% with respect to
death from a cardiovascular
event, hospitalization due to heart
failure and all cause mortality
respectively. 13
S G LT 2 i n h i b i t o r s h a ve b e e n
a p p r o ve d f o r t h e t r e a t m e n t o f
T2DM as mono therapy, as an add
on second or third line agent in
combination with any other known
therapeutic options for diabetes,
both oral and injectable by the
ADA, EASD and the AACE. These
class of agents may be used at any
stage of T2DM owing to their novel
insulin independent mechanism of
action, provided the renal function
is above a certain threshold. 4,13-18
Though data from randomized
control trials (RCTs) are promising,
real world evidence from standard
clinical practice needs to be
analyzed. 4-8,13 RCTs which are the
gold standard method of assessing
the efficacy and safety of new
d r u g s u s u a l l y i n v o l ve a s m a l l
group of patients, for a short
p eriod of t ime in a cont rolled
environment. However, clinical
practice constitutes treating a
heterogeneous population in a
realistic uncontrolled environment.
The aim of this real world study
wa s t o a n a l y z e t h e m e t a b o l i c
parameters, tolerability and side
effects of SGLT2i s on patients with
T2DM in standard clinical practice.
Materials
This was a prospective
longitudinal study of 100 patients
with uncontrolled T2DM attending
the outpatient of a specialized
diabetes hospital from May 2015
to August 2015. Each patient gave
a written informed consent to
participate in the study and the
institutions’ ethics and review
board approved the study protocol.
41
Inclusion Criteria: Patients with
T2DM and a Hba1c > 8 % meeting
one of the criteria below
1. P a t i e n t s o n d u a l t h e r a p y
(metformin + sulfonylurea/
DPP4i)
2. Patients on triple oral therapy
with metformin + sulfonylurea
+ DPP4i
3. Patients on insulin and triple
oral therapy with metformin +
sulfonylurea + DPP4i
E x c l u s i o n C r i t e r i a : Pa t i e n t s
with history of genital mycotic
infections, recurrent urinary tract
infections, pyelonephritis, acute
illness, type 1 diabetes, pregnant
or lactating women and those with
an eGFR below 45.
A l l p a t i e n t s we r e e va l u a t e d
and screened for complications
of diabetes as per standard of
care. All patients were subjected
to the following investigations:
Fasting plasma glucose (FPG)
postprandial plasma glucose (PPG)
hemoglobinA1c (Hba1c), lipid
profile, renal function tests and
urine analysis.
Patients who were only on oral
a n t i d i a b e t i c m e d i c a t i o n we r e
advised insulin initiation. Only
those who refused insulin initiation
were included in the study and
categorized into group 1, 2 or 3 as
given below based on their baseline
medications. Group 4 included
patients on insulin. Patients in each
group were initiated with a SGLT2i
and the preexisting medications
were continued. SGLT2i was added
to even those on insulin to assess the
weight reduction and improvement
in glycemic control. All patients
we r e c o u n s e l e d r e g a r d i n g t h e
possible side effects of SGLT2i.
The patients were categorized
into 4 groups of 25 each as follows:
Group 1 or G 1 - metformin +
sulfonylurea + SGLT2i
Group 2 or G 2 - metformin +
DPP4 inhibitor + SGLT2i
Group 3 or G 3 - metformin +
DPP4 inhibitor + sulfonylurea+
SGLT2i
42
Journal of The Association of Physicians of India ■ Vol. 64 ■ September 2016
medication was well tolerated.
Table 1: Changes in weight and Hba1c
G1
Baseline Weight at Δ Weight P value
weight kg 3 months
Kg
kg
83.02±27.42 78.95±24.53 4.07±2.89
<0.05
9.51±1.17 8.71±1.07
G2
74.67±9.68 71.81±9.6 2.86±0.08
<0.05
8.86±0.97 7.71±0.95 1.15±0.02
<0.05
G3
74.36±6.15 72.06±5.01 2.3±1.14
<0.05
9.54±1.16 8.88±1.13 0.66±0.03
<0.05
<0.05
10.14±1.65 8.66±0.82 1.48±0.83
<0.05
<0.05
9.51±1.23 8.49±0.99 1.02±0.24
<0.05
G4
Mean ±
SD
74.35±11
73±10
1.35±1
76.6±13.56 73.95±12.28 2.64±1.27
Group 4 or G 4 - insulin +
metformin + DPP4 inhibitor +
sulfonylurea + SGLT2i
The preexisting medications
included sulfonylurea’s
(glimiperide 4 mg/day and
gliclazide XR 120mg/day), DPP4
inhibitors (sitagliptin 100mg/day,
saxagliptin 5 mg/day, vildagliptin
100mg/day, linagliptin 5mg/day,
tenelagliptin 20mg/day) along with
metformin 2 gm/day. The patients
on insulin were continued with
the preexisting dose of insulin
and dose titration was taught to
them based on the insulin regimen
they were on (basal/basal bolus/
premixed). Diet and lifestyle was
intensified.
T h e c o m m e r c i a l l y a va i l a b l e
SGLT2i at that point of time in
India, i.e. dapagliflozin 10 mg
and canagliflozin 100 mg were
prescribed once a day alternately
in a 1:1 ratio to all patients. The
patients on insulin were educated
on the importance of self monitoring
of blood glucose (SMBG) and were
asked to perform SMBG and insulin
dosage adjustments based on
their individualized targets twice
a week. All patients on insulin
and insulin secretagogues were
e d u c a t e d o n t h e p os s ibility of
hypoglycemia and were asked to
contact the hospital for adjustment
of insulin/ sulfonylurea dosages.
The duration of follow up was
three months. The tolerability,
side effects, the efficacy and safety
parameters like Hba1c, weight,
renal function tests, urine analysis,
fasting lipid profile and complete
blood count were evaluated at the
follow up clinic visit.
Baseline Hba1c at Δ Hba1c p value
Hba1c 3 months
%
0.8±0.1
<0.05
Statistical Analysis
T h e s t a t i s t i c a l a n a l y s i s wa s
carried out using Microsoft
excel and results on continuous
measurements have been presented
as mean ± standard deviation
(SD) and results on categorical
measurements have been presented
in percentages (%). P value at 5%
level of significance was calculated
using the T test.
Results
The mean age, duration of
diabetes, weight and Hba1c in the
study population was 53.20±12.1
years, 13.1±7.26 years, 76.6±13.56 kg
and 9.51 ± 1.23 % respectively. The
duration of diabetes in Group 1,
Group 2, Group 3 and Group 4 was
16.75 ± 9.43, 8.87 ± 7.18, 14.4 ± 6.7
and 12.4 ± 5.76 years respectively.
The mean weight and Hba1c
reduction at follow up was 2.64±1.27
kg (p<0.05) and 1.02±0.24 %
(p<0.05) respectively. The changes
in weight and Hemoglobin A1c
were statistically significant across
all groups and are represented in
Table 1.
Genital pruritis was reported as
a side effect in 4% of the patients.
None of them had mycotic genital
infection on examination and
all four chose to discontinue the
S G LT 2 i n h i b i t o r a s a r e s u l t o f
pruritis at follow up. Side effects
reported in literature like urinary
tract infections, polyuria, thirst,
giddiness, postural hypotension,
hypovolemia, dehydration,
hemoconcentration, euglycemic
ketoacidosis, worsening of eGFR,
electrolyte imbalance, increase in
LDL were not observed and the
Hypoglycemia was reported only
in the group on insulin. The exact
number of episodes of hypoglycemia
was not documented but none of the
patients had severe hypoglycemia/
loss of consciousness requiring
hospitalization or intravenous
dextrose administration. The
patients themselves had gradually
reduced their insulin dose based on
SMBG. The baseline daily insulin
dose was 42 ± 29 units and at three
months was 35 ± 24 units. Thus a
16.6% reduction in the daily insulin
requirement at follow up when
compared to baseline was noted.
Discussion
There is substantial evidence to
show that SGLT2 inhibitors help in
reducing Hba1c, FPG and PPG in
patients with T2DM. SGLT2i also
have non-glycemic benefits such as
weight loss, reduction in abdominal
circumference, visceral fat, blood
pressure reduction, and reduction
of albuminuria. 4-8,19 If the CV safety
data seen with empagliflozin is also
observed 13as a class effect with the
other drugs in this group, these
medications might even have the
potential to occupy a higher place
in the treatment algorithm as the
first class of antidiabetic agents to
have reduced cardiovascular and
all cause death. 13,20-22
While evidence from RCTs is
the highest level of evidence while
analyzing the efficacy of a drug, the
performance of an agent outside
of a controlled environment may
be variable. Real world evidence
(RWE) is necessary to ascertain if
the efficacy and safety profiles seen
in RCTs can be extrapolated from
efficacy to clinical effectiveness in
practice.
This real world study
demonstrates that when SGLT2i
are added at any stage of the
disease spectrum with any of the
preexisting therapeutic agents
for patients with uncontrolled
type 2 diabetes, there is a clinical
and statistically significant
Journal of The Association of Physicians of India ■ Vol. 64 ■ September 2016
improvement in glycemic control
and body weight, with minimal
side effects.
A significant Hba1c reduction
(p<0.05) was seen across all groups
of patients studied, irrespective
of duration of diabetes and the
baseline therapy. The maximum
Hba1c reduction was seen in Group
4 patients (insulin + metformin +
DPP4 inhibitor + sulfonylurea +
SGLT2i). This reduction may not
be solely attributed to the drug, as
intensification of lifestyle changes
and frequent dosage adjustment
of insulin based on SMBG also
contributes to improved glycemic
control. As the highest baseline
Hba1c was seen in this group, this
could also have resulted in greater
Hba1c reduction at follow up.
The patients in group 2
(metformin + DPP4 inhibitor +
SGLT2i) showed a greater Hba1c
reduction than those in group
1 ( m e t f o r m i n + s ulfonylu rea +
SGLT2i) and Group 3 (metformin
+ DPP4 inhibitor + sulfonylurea
+ SGLT2i). Patients in group 2
had a lesser duration of diabetes
compared to those in group 1 and 3.
Changes in FPG and PPG were
not analyzed, as clinic based
estimation was done only at
baseline and patients used their
own glucose monitors for SMBG.
The patients on insulin showed
a reduction in their daily insulin
dose by 16.6% (42 ± 29 to 35 ± 24
units). This is in concordance with
other studies that have reported a
reduction in insulin requirements
with the addition of SGLT2 i 19,23-25
All groups demonstrated a
significant decrease in body weight
(p<0.05) and those on metformin
plus sulfonylurea with the highest
baseline weight had the highest
we i g h t l o s s o f 4 k g . T h i s wa s
followed by those in group 2 and
group 3 respectively. Patients in
group 4 on insulin demonstrated
the least weight loss. However it
is important to note that those on
insulin had the highest baseline
Hba1c, demonstrated the maximum
Hba1c reduction and even with
improvement in glycemic control,
there was no additional weight
gain. They further demonstrated
a weight loss of 1.3 kg compared
t o b a s e l i n e . We i g h t l o s s w i t h
improved glycemia is pivotal to
diabetes care as meta analysis
of cardiovascular outcome trials
with glucose lowering therapies
have demonstrated that with each
kilogram of increase in weight the
risk of heart failure increase by
7%. 26
This study has several
limitations. The study sample was
small and the while the patients
continue to be on follow up at the
hospital, the findings presented
here only include data of the initial
3 months of follow up.Changes in
blood pressure were not analyzed
as patients in clinical practice as
per routine care had an office blood
pressure measurement at baseline
and follow up and several variables
are known to contribute to single
office blood pressure readings.
Changes in albuminuria, uric acid
levels and visceral fat were not
studied.
While longer follow up and
further study into this new class of
drugs is needed on several areas,
the evidence on Indian patients
appears to be promising. 27 In spite
of showing Hba1c reduction, none
of the groups in this study reached
their target Hba1c. Will patients
reach a target Hba1c over the next
three to six months? If patients
reach their target Hba1c, can this
justify a delay in insulin initiation
in patients who can afford SGLT2i?
If the Hba1c target is not met, how
many of our patients will go on
to require insulin initiation? How
many of our patients on insulin,
will need insulin intensification?
What will be the durability of
weight loss in our patients? Time
may give us a clear answer.
References
1.
IDF Atlas, 7th edition revision 2015.
2.
Standards of Medical Care in Diabetes-
43
2014: A position statement of the American
Diabetes Association. Diabetes Care 2014;
37:S14-S80.
3.
U.K. prospective diabetes study 16.
Overview of 6 years’ therapy of type
II diabetes: a progressive disease. U.K.
Prospective Diabetes Study Group.
Diabetes 1995; 44:1249.
4.
Inzucchi SE, Bergenstal RM, Buse JB,
et al. Management of hyperglycemia
in type 2 diabetes: a patient-centered
approach: position statement of the
American Diabetes Association (ADA) and
the European Association for the Study
of Diabetes (EASD). Diabetes Care 2015;
38:140-149.
5.
Vasilakou D, Karagiannis T, Athanasiadou
E, et al. Sodium-glucose cotransporter 2
inhibitors for type 2 diabetes: a systematic
review and metaanalysis. Ann Intern Med
2013; 159:262–274.
6.
Nauck MA, Del Prato S, Meier JJ, et
al. Dapagliflozin versus glipizide as
add-on therapy in patients with type 2
diabetes who have inadequate glycemic
controlwithmetformin: a randomized,
52-week, double-blind, active-controlled
noninferiority trial. Diabetes Care 2011;
34:2015–2022.
7.
Rosenstock J, Seman LJ, Jelaska A, 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; 15:1154–1160.
8.
Monami M, Nardini C, Mannucci E.
Efficacy and safety of sodium glucose cotransport-2 inhibitors in type 2 diabetes: a
meta-analysis of randomized clinical trials.
Diabetes Obes Metab 2014; 16:457–466.
9.
Nyirjesy P, Sobel JD, Fung A, et al. Genital
mycotic infections with canagliflozin, a
sodium glucose co-transporter 2 inhibitor,
in patients with type 2 diabetes mellitus: a
pooled analysis of clinical studies. Curr Med
Res Opin 2014; 30:1109–1119.
10. Johnsson KM, Ptaszynska A, Schmitz B,
Sugg J, Parikh SJ, List JF. Vulvovaginitis and
balanitis in patients with diabetes treated
with dapagliflozin. J Diabetes Complications
2013; 27:479–484.
11. Taylor, Blau, Rother. SGLT2 inhibitors may
predispose to ketoacidosis. J Clin Endocrinol
Metab 2015; 100:2849-52.
12. Taylor, Blau, Rother. Possible adverse effects
on SGLT2 inhibitors on bone. The Lancet
Diabetes and Endocrinology 2015; 3:8-10.
13. Zinman B, Wanner C, Lachin J, et al for
the EMPA REG OUTCOME investigators.
Empagliflozin, Cardiovascular Outcomes,
and Mortality in Type 2 Diabetes. NEJM
2015; 373:2117-28.
14. Garber AJ, Abrahamson MJ, Barzilay JI,
et al. AACE/ACE comprehensive diabetes
44
Journal of The Association of Physicians of India ■ Vol. 64 ■ September 2016
management algorithm. Endocr Pract 2015;
21:438-447.
15. Lavalle-Gonzalez FJ, Januszewicz A,
Davidson J, et al. Efficacy and safety of
canagli- flozin compared with placebo and
sitagliptin in patients with type 2 diabetes
on background metformin monotherapy:
a randomised trial. Diabetologia 2013;
56:2582–2592.
16. Wilding JP, Charpentier G, Hollander P,
et al. Efficacy and safety of canagliflozin
in patients with type 2 diabetes mellitus
inadequately controlled with metformin
and sulphonylurea: a randomised trial. Int
J Clin Pract 2013; 67: 1267–1282.
17. Devineni D, Morrow L, Hompesch M,
et al. Canagliflozin improves glycaemic
control over 28 days in subjects with
type 2 diabetes not optimally controlled
on insulin. Diabetes Obes Metab 2012;
14:539–545.
18. Janssen Research and Development, LLC;
Endocrinologic and Metabolic Drugs
Advisory Committee. Canagliflozin as
an adjunctive treatment to diet and
exercise alone or coadministered with
other antihyperglycemic agents to
improve glycemic control in adults with
type 2 diabetes mellitus. JNJ-28431754
(Canagliflozin). NDA 204042 [Internet],
2013. Available from http://www.fda.
gov/downloads/advisorycommittees/
committeesmeetingmaterials/
drugsendocrinologicand
metabolicdrugsadvisorycommittee/
ucm334551.pdf. Accessed 15 January 2014.
Efficacy and safety of Canagliflozin, an
inhibitor of sodium-glucose cotransporter
2, when used in conjuction with insulin
therapy in patients with type 2 diabetes
mellitus. Diabetes Care 2015; 38:403-411.
19. Abdul-Ghani MA, Norton L, Defronzo RA.
Role of sodium-glucose cotransporter 2
(SGLT 2) inhibitors in the treatment of type
2 diabetes. Endocr Rev 2011; 32:515–531.
24. Rosenstock J, Jelaska A, Frappin G, et al.
Improved glucose control with weight
loss, lower insulin doses, and no increased
hypoglycemia with empagliflozin added to
titrated multiple daily injections of insulin
in obese inadequately controlled type 2
diabetes. Diabetes Care 2014; 37:1815-2.
20. Inzucchi S, Zinman B, Wanner C et al.
SGLT-2 inhibitors and cardiovascular risk:
Proposed pathways and review of ongoing
outcome trials. Diabetes and Vascular
Disease Research 2015; 12:90-100.
21. Cefalu W, Leiter W, Bruin T et al.
Dapagliflozin’s Effects on Glycemia and
Cardiovascular Risk Factors in High-Risk
Patients With Type 2 Diabetes: A 24-Week,
Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study With a 28-Week
Extension. Diabetes Care 2015; 38:12181227
22. N e a l B, Pe r k ov i c V, d e Ze e u w D,
et al. Rationale, design, and baseline
characteristics of the Canagliflozin
Ca rd i ova s c u l a r As s e s s m e nt St u d y
(CANVAS) randomized placebo-controlled
trial. Am Heart J 2013; 166:217–223, e11.
23. Neal B, Perkovic V, Zeeuw D. et al on behalf
of the CANVAS trial collaborative group.
25. Wilding J, Woo V, Norman G et al. Long-Term
Efficacy of Dapagliflozin in Patients With
Type 2 Diabetes Mellitus Receiving High
Doses of Insulin: A Randomized Trial. Ann
Intern Med 2012; 156:405-415.
26. Udell Jacob A, et al. Glucose lowering
drugs or strategies and cardiovascular
outcomes in patients with or at risk of type
2 diabetes: a meta analysis of randomized
controlled trials. The Lancet Diabetes and
Endocrinology 2015; 3:356–366.
27. Kumar KMP, Mohan V, Sethi B, et al. et al
Efficacy and Safety of Canagliflozin in
Patients With Type 2 Diabetes Mellitus
From India, Poster presented at the 10th
International Diabetes Federation –
Western pacific region (IDF-WPR) congress,
21-24 November 2014, Suntec, Singapore.