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Sponsored Symposium Highlights
Dapagliflozin: The first-in-class SGLT2 inhibitor for
the management of type 2 diabetes
At the 20th ASEAN Federation of Cardiology Congress 2014, Professor Roger Chen gave an update on dapagliflozin, the first
SGLT2 inhibitor, and how this fits in type 2 diabetes armamentarium.
Clinical Associate Professor, University of Sydney
Director of Diabetes Services, Senior Staff Endocrinologist
Concord Repatriation General Hospital
Worldwide, the prevalence of type 2 diabetes (T2D) is on the rise,
and Malaysia is not spared. According to the National Health and
Morbidity Survey (NHMS), the prevalence of T2D in adults aged
≥30 years has increased from 8.3% (NHMS II, 1996) to 20.8% (NHMS
2011).1 The diabetic state poses a great threat to cardiovascular
health – the risk of cardiovascular disease (CVD) is 2–4 times higher
in a diabetic person compared to people without diabetes, and CVD
is the leading cause of death for people with diabetes.2
Dapagliflozin clinical development
programme
0.0
As part of its clinical development programme, dapagliflozin has
been studied extensively in a broad range of T2D patients, in both
placebo-controlled and active comparator studies.11
In 2009, DeFronzo highlighted the ominous octet that results in
hyperglycaemia in T2D; and the need for multiple drugs used in
combination to target the various pathological defects in order to
manage T2D effectively (Figure 1).3
Figure 1: "The ominous octet" and site of action of oral
antidiabetic agents3
Figure 2: Dapagliflozin versus sulphonylurea as add-on to
metformin: Change in HbA1c over 208 weeks13
GLP-1 RA; AGIs
GLP-1 RA; TZDs,
DPP4i, SU
Increased glucagon
secretion
0.4
HYPERGLYCAEMIA
Increased glucose
reabsorption
Increased hepatic
glucose production
Neurotransmitter
dysfunction
Metformin, TZDs,
GLP-1 RA
SGLT2
inhibitors
Decreased glucose
uptake
TZDs, metformin
GLP-1 RA
AGI, alpha-glucosidase inhibitor; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like
peptide-1 receptor agonist; SU, sulfonylurea; TZD, thiazolidinedione.
The American Diabetes Association in its recent position statement,
reiterated the need for individualised treatment goals and plans
in managing T2D. Metformin, if not contraindicated , is the
preferred initial choice of pharmacotherapy. The following agents
– sulphonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1
receptor agonists, and insulin, are considered as suitable choices
for combination therapy should glycaemic targets not be met with
metformin monotherapy.4
SGLT2 inhibition in T2D
The kidneys have been implicated in the pathogenesis of
hyperglycaemia in T2D. Glucose, filtered by the kidneys, is
reabsorbed in the proximal renal tubule. Approximately 90% of
renal glucose reabsorption occurs through the sodium-glucose cotransporter-2 (SGLT2), a protein transporter that is almost exclusively
found in the proximal renal tubule.5,6 The result is that minimal or no
glucose appears in the urine under normal physiological conditions.
In T2D, uncontrolled hyperglycaemia leads to excretion of moderate
levels of glucose in the urine, and the maladaptive function of
the kidneys results in an absolute increase in renal absorption of
glucose.3 Therefore, agents that exhibit an ability to inhibit renal
glucose reabsorption (i.e. SGLT2) and increase glucose elimination,
present a novel way to treat T2D.7–9
Dapagliflozin is the first-in-class SGLT2 inhibitor approved
for improvement of glycaemic control in T2D. Early studies of
Change in HbA1c(%)*
Impaired insulin
secretion
GLP-1 RA;
DPP4i
• HbA1c durability was better with dapagliflozin than glipizide
-The rise from 52–208 weeks was less compared with glipizide, giving a significant
diﬀerence between treatments at 208 weeks
TZDs
Increased
lipolysis
Decreased incretin
effect
Dapagliflozin + Metformin
(DAPA+MET)
Glipizide + Metformin
(GLIP+MET)
Week 208 values
0.20% (95% CI: 0.05, 0.36)
0.2
Diﬀ. -0.30% (95% CI: -0.51, -0.09)
0.0
-0.2
-0.6
-1.0
PLA+INS
n=193
DAPA 2.5mg+INS
n=202
DAPA 5/10mg+INS
n=211
DAPA 10mg+INS
n=194
Week 104 adjusted mean change,
(95% CI)
-0.1
-0.2
-0.3
-0.43 (-0.58, -0.28) [placebo]
-0.4
-0.5
-0.6
-0.64 (-0.78, -0.50) [DAPA 2.5 mg]
-0.78 (-0.92, -0.65) [DAPA 10 mg]
-0.82 (-0.96, -0.68) [DAPA 5/10 mg]
-0.7
-0.8
-0.9
-1.0
-1.1
-1.2
ST period
LT period 1
LT period 2
-1.3
65
78
91
0 4 8 12 16 20 24 32 40 48 52
Study Week
Sample size per time point
PLA+INS
193 183 173 169 167 164 166 163 159 157 122
116
DAPA 2.5 mg + INS 202 198 190 187 185 181 179 175 176 172 147
142
DAPA 5/10 mg + INS 211 201 195 191 187 187 185 184 180 173 150
143
DAPA 10 mg + INS 193 188 184 183 179 176 173 175 173 164 148
145
*Including data after insulin uptitration
Legend: DAPA=Dapagliflozin; PLA=Placebo; INS=Insulin; ST=Short-term; LT=Long-term
114
140
133
144
109
136
131
140
104
107
132
128
139
Dapagliflozin in renal impairment
Based on its mode of action, the efficacy of dapagliflozin is
dependent on renal function. In the long-term study by Kohan et al
to evaluate the safety and efficacy of dapagliflozin in T2D patients
with moderate renal impairment, the mean change in HbA1c level
with dapagliflozin was not statistically different from placebo at 24
weeks (-0.41% and -0.44% for 5 mg and 10 mg doses, respectively,
and -0.32% for placebo). Dapagliflozin-treated patients did however,
experience reductions in body weight and improvements in blood
pressure control.16
-0.10% (95% CI: -0.25, 0.05)
-0.4
-0.8
Figure 3: Dapagliflozin as add-on insulin: Change in HbA1c over
104 weeks15
• Dapagliflozin added to insulin for 104 weeks enabled sustained reductions in HbA1c*
As add-on to background metformin vs. sulphonylurea
This was a 52-week, double-blind, multicentre, active-controlled,
non-inferiority trial comparing dapagliflozin with glipizide in T2D
patients who were receiving metformin monotherapy. Dapagliflozin
produced similar reductions in HbA1c levels as glipizide (-0.52%
for both treatment), statistically noninferior at 52 weeks.12 When
glycaemic efficacy was assessed over an extended period of up
to 208 weeks, dapagliflozin demonstrated better HbA1c durability,
which resulted in a significant treatment difference at 208 weeks
compared to glipizide (Figure 2).13
Pathogenesis and management of T2D
MY_Forxiga_127,710.022_24/07/2014
dapagliflozin showed that it exhibited dose-dependent urinary
glucose excretion,10 that was maintained over an extended period
(2 years).11
Change in Mean HbA1c(%)
Professor Roger Chen
MBBS (Hons), PhD, FRACP
Rescue therapy NOT available
0 6 12 18 26 34 42 52
Sample size
(excluding data after rescue), n
DAPA+MET 400
GLIP+MET 401
321
315
65
78
Rescue therapy available
91 104 117 130 143 156 169 182 195 208
Study week
233
208
79
71
*Data are adjusted mean change from baseline ±95% CI derived from a longitudinal repeated-measures mixed model.
Weight gain and risk of hypoglycaemia are important considerations
when choosing a suitable T2D treatment. Dapagliflozin produced
significant weight loss (-3.2 kg) versus weight gain in glipizide
(+1.2 kg, p=0.0001), and significantly decreased the proportion of
patients who experienced hypoglycaemia (3.5%) versus glipizide
(40.8%, p=0.0001).12 The weight reduction seen with dapagliflozin
also persisted up to 208 weeks.13 In the study by Bolinder et al,
weight loss seen with dapagliflozin was largely due to a reduction
in total body fat mass.14
Additionally, Del Prato et al noticed a consistently lower systolic
blood pressure in dapagliflozin-treated patients compared to
glipizide.13
As add-on to insulin
Dapagliflozin improved glycaemic control, stabilised insulin dosing,
and mitigated insulin-associated weight gain over 48 weeks in
inadequately controlled T2D patients despite high doses of insulin.
After long-term follow-up of up to 104 weeks (2 years), HbA1c
changes from baseline at 104 weeks were -0.43% in the placebo
group, and -0.64% to -0.82% in the dapagliflozin groups (Figure 3).
Placebo-treated patients saw their mean insulin dose increased by
18.3 IU/day and experienced weight increase by 1.8 kg at 104 weeks,
whereas the insulin dose remained stable and was accompanied
by weight loss of between 0.9–1.4 kg in the dapagliflozin-treated
patients.15
Dapagliflozin safety summary11
• Dapagliflozin has a low potential of causing hypoglycaemia
when used as monotherapy. The risk of hypoglycaemia is
increased when it is used with agents with known side effects of
hypoglycaemia (e.g. insulin, sulphonylureas)
• Estimated glomerular filtration rate (eGFR) remained stable over
long-term follow-up.
• A small increase of urinary tract infection (UTI) and genital tract
infection (GTI) events were reported in patients on dapagliflozin
versus placebo.
• Dapagliflozin has no clinically relevant impact on serum
electrolytes, and no increased risk of hyperkalaemia.
Conclusion
Treatment limitations of currently available antidiabetic
drugs present an opportunity for the advent of newer
pharmacotherapeutic agents with novel modes of action.
Dapagliflozin, the first-in-class SGLT2 inhibitor, promotes
renal excretion of glucose, which was maintained over an
extended period. Clinically, dapagliflozin has demonstrated
HbA1c lowering efficacy and durability, is associated with
low incidence of hypoglycaemia, and presents an attractive
treatment option to current T2D armamentarium.
References:
1. Tahir A, Noor Ani A. National Health and Morbidity Survey 2011. Presented at: Conference on
Non-Communicable Diseases (NCDs), 26-27 March 2013, Kuala Lumpur. 2. World Heart Federation. Cardiovascular
disease risk factors - diabetes. Available at: http://www.world-heart-federation.org/cardiovascular-health/
cardiovascular-disease-risk-factors/diabetes/. Accessed on: 1 July 2014. 3. DeFronzo RA. Diabetes 2009;58(4):773795. 4. American Diabetes Association. Diabetes Care 2014;37(suppl 1):S14-S80. 5. Abdul-Ghani MA, et al. Endocr
Pract 2008;14(6):782-790. 6. Bays H. Curr Med Res Opin 2009;25(3):671-681. 7. Wright EM. Am J Physiol Renal Physiol
2001;280(1):F10-F18. 8. Lee YJ, et al. Kidney Int Suppl 2007;(106):S27-S35. 9. Han S, et al. Diabetes 2008;57(6):17231729. 10. Komoroski B, et al. Clin Pharmacol Ther 2009;85(5):520-526. 11. US FDA EMDAC Background Document
– Dapagliflozin. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/
drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. 12. Nauck MA, et al. Diabetes Care
2011;34:2015-2022. 13. Del Prato S, et al. Presented at the 73rd Scientific Sessions of the American Diabetes
Association. 21-25 June 2013. Chicago, Illinois. 14. Bolinder J, et al. Diabetes Obes Metab 2013. doi: 10.1111/
dom.12189. 15. Wilding JP, et al. Diabetes Obes Metab 2013. doi: 10.1111/dom.12187. 16. Kohan DE, et al. Kidney
Int 2014;85(4):962-971.
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