canagliflozin in diabetes mellitus

1. Dr Saurabh Gupta
PG Medicine

2. Journal- The Lancet (sep 2013)
Study name – CANTATA-SU

3.  Type two daibetes managed initially by lifestyle
modification and monotherapy of Metformin.
 After metformin failure various other options are
available like sulfonylureas, insullin,
thiazolidinediones, and incretins.
 Many of these drugs use is being limited by their
effect on weight gain and tendency to cause
hypoglycemia
 In this regard pharmacological inhibition of
Sodium- glucose co-transporter 2(SGLT 2) is
an appealing alternative.
 These drugs have a tendency to lower the renal
glucose threshold and cause increased urinary
glucose excretion and mild osmotic diuresis, and a
net loss of calories.

4.  Thus they have an insulin independent
mechanism of correction of hypoglycemia
through decreased renal glucose reabsorption.
 In patients with type 2 diabetes inadequately
controlled with metformin , canagliflozin has
been associated with significant reductons in
HbA1c , fasting plasma glucose and bodyweight
at 12 weeks with a low frequency of
hypoglycemia(compared with placebo).
 So, in this study efficacy and safety of this drug
is compared with glimepiride as add on
therapy in patients with type 2 DM.

5.  The study was an double blind, randomized,
active- controlled, phase -3 non- inferiority trial
at 157 centres in 19 countries
 Eligible participnats were aged between 18-80
years , had type 2 diabetes and HbA1c of 7-
9.5% and were recieving stable metformin
therapy(> 1500mg per day) for at least 10
weeks.
 Participants recieving metfromin in combination
with other oral non thiozoledinedione
ahtihyperglycemic drug at screenig discontinued
the second drug and if needed increased their
metformin doses .

7.  Key exclusion criteria included
 a history of more than one severe hypoglycemia
episode (within 6 months )
 Estimated GFR of of less than 60 ml/ min/ 1.73
m2.
 Patients who Were given thiozolidinediones within
16 weeks before screening
 Patients were randomize in three groups in a 1:1:1
ratio recieving canagliflozin 100 mg or 300 mg or
glimiperide .
 After randomization HbA1c and fasting plasma
glucose values weere masked to staff at study
centre unless values met glycemic rescue criteria.

8.  Doses of canagliflozin were used according to
previous studies as 100 mg and 300 mg .
 Titration of glimiperide ranged from a starting dose of
1 mg to a maximum of 6 mg or 8 mg after 2 or more
weeks at the current dose if patients met protocol
specific glycemic criteria ( i.e >50% of glycemic
reading more than 6 mmol/L or 110 mg/dl) .
 Primary Efficacy end point was change in HbA1c
from baseline to 52 week
 Secondary efficacy endpoints were percentage
change from baseline in bodyweigth, and proportion
of patients with documented hypoglycemic episodes,
including boichemically documented episodes and
severe episodes needing assistance or causing
seizures or loss of consciousness.

9.  Additional endpoints include patients
achieving HbA1c less than 7 or 6.5 %, change
in fasting plasma glucose or systolic and
diastolic bp, and percentage change in fasting
plasma lipids.
 The body composition endpoints like total fat
measurements were assesed and percentage
changes in subcutaneous fat visceral fat by CT
scans.
 The adverse event profile like genital mycotic
infection and urinary tract infection were
assesed clinically and culture results.

10.  1450 of 1452 patients recieved at least one dose
of glimiperide or canagliflozin.
 1161 patients completed the 52 weeks of
treatment , wit almost similar rates of
discontinuation beetween the groups.
 For patients recieving glimiperide the mean
maximum dosse achieved was 5.6mg per day .
 Patients in glimiperide group were given more
glycemic rescue (11%) than in cnagliflozin
100mg(7%) and 300mg (5%) groups.
 All the treatments were successful in reducing
the baseline HbA1c from baseline to 52 weeks .

12.  In the primary analysis both canagliflozin doses were
noninferior to glimiperide in lowering the HbA1c and
canagliflozin 300mg was superior to glimiperide for
hbA1c reduction.
 Patients recieving canagliflozin 100mg and 300mg had
numerically greater reduction in fasting plasma
glucose than with glimiperide.
 Both canagliflozin doses provided sustained reduction
in fasting plasma glucose over 52 weeks which was
seen after 18 weeks in increasing trend with
glimiperide.
 The proportion of patients with documented
hypoglycemia episodes was significantly lower with
canagliflozin 100 mg and 300mg than with
glimiperide.
 Decrease in fasting plasma insulin were noted in
both canagliflozin group as compared to other group.

13.  Both canagliflozin doses significantly reduced body
weight at week 52 whereas a slight increase was
noted with glimiperide.
 In canagliflozin group roughly two thirds of the
reduction in body weight was from fat mass and a
third from lean body mass.
 Increase in body weight with glimiperide included
both fat and lean body mass.
 Analysis of abdominal fat with ct imaging in
canagliflozin group showed slight greater reduction
in visceral adipose tissue than subcutaneous
tissue.
 Canagliflozin modestly reduced systolic and diastolic
blood pressure compared with glimiperide.
 It was also noted that an increase in dose related
increase in LDL cholesterol and ratio of LDL to HDL
cholesterol with canagliflozin.

15.  Overall frequency of study discontinuation and
andverse events was almost similar in both groups.
 Canagliflozin grp was associated with higher rates of
genital tract mycotic infection and urinary tract
infection in both males and females.
 Adverse events more common with Canagliflozin
group were-
 Osmotic diuresis{ polyuria and pollakiuria}
 Postural hypotension
 Almost all lab parammeters were within normal
limits except small increse in bilirubin, haemoglobin
and blood urea nitrogen in Canagliflozin group.
 After an initial decrease in GFR it was stable from 12
to 52 weeks but with glimiperide a progressive
decrease was noted from baseline to 44 weeks.

18. The favourable outcomes
Noninferior as
compared to
glimiperide with
100mg and
statistically superior
wih 300 mg dose for
reductiion of HbA1c
Reduction in
fasting plasma
glucose were
sustained over 52
weeks but were
seen gradually
increasing after 18
weeks with
glimiperide.
Weight reductoion
seen associated
with glycosuria
which was static
after 26 weeks
with no further
gain in weigth.

21.  The low incidence of hypoglycemia noted with
canagliflozin was due to the usual threshold of
hypoglycemia is 3.9mmol/L which was below
mean renal threshold for glucose with
canagliflozin i.e. 4.5-5mmol/L.
 Since obesity is a common comorbidity in patients
with DM, canagliflozin, by reducing weight
contributes to improvement in glycemic
control.
 Overall canagliflozin treatment showed favourable
effects on cardiovascular risk by improvement in
systolic blood pressure with no increase in heart
rate.
 The increase in serum bilirubin , haemoglobin and
BUN might be related to the water loss .

23.  The patient population included a range of
HbA1c from 7-9.5% so no conclusions can be
made for patients with severe hyperglycemia.
 A furthur longer duration of treatment is
required to know whether the cardiovascula
effects can become the benefits of drugs.
 A change in post prandial glucose was not being
estimated .

24.  Trade Name:
International- Invokana
 Contraindications- Contraindicated in patients with
severe kidney impairment, ESRD, or on dialysis and
known hypersensitivity.
 Pregnancy Category : C
 Dosage: The recommended initial dose is 100 mg
once daily andshould be taken before the first meal
of the day.
 Side Effects : Postural Hypotension , Genital
vulvovagintis, - Female genital mycotic infections,
urinary tract infection and increased urination.