effects of canagliflozin on cvs and rs in t2dm

1. EFFECTS OF CANAGLIFLOZIN ON
CARDIOVASCULAR AND RENAL
EVENTS IN TYPE 2 DIABETES
MELLITUS
presented by :Dr Shaz Pamangadan

3. MECHANISM OF ACTION
• SGLT2 (90%) IN PCT is responsible for majority of
the reabsorption of filtered glucose from the tubular
lumen. SGLT1 being responsible for the remaining
10%
• Patients with diabetes have elevated renal glucose
reabsorption which contributes to persistent
elevated blood glucose concentrations.

4. CANAGLIFLOZIN
 is an inhibitor of subtype 2 sodium-glucose
transport proteins (SGLT2), which is responsible
for at least 90% of renal glucose reabsorption
(SGLT1 being responsible for the remaining 10%).
 Blocking this transporter causes up to 119 grams
of blood glucose per day to be eliminated through
the urine. It was developed by Mitsubishi Tanabe
Pharma and is marketed under license by Janssen, a
division of Johnson & Johnson.

5. Medicines in the SGLT2 inhibitor class include
1)canagliflozin,
2)dapagliflozin, and
3)empagliflozin.
They are available as single-ingredient products
and also in combination with other diabetes
medicines such as metformin.
• Canagliflozin is taken once a day , effect starting
immediately with peak efficacy coming within 6 to 8
weeks.

6. The landmark CANVAS Program, consisting of 10,142
participants, is a combination of data from two studies
, 4330 in CANVAS and 5812 in CANVAS-R. A total of 9734
participants (96.0%) completed the trial (i.e., were alive
and were assessed for safety and efficacy outcomes during
the final fol- low-up window or died before the final
follow- up).
1)The Canagliflozin Cardiovascular Assessment Study
(CANVAS) and
2)The CANVAS on Renal Endpoints Trial (CANVAS-R).

7. The purpose of the CANVAS Program was
to evaluate the cardiovascular safety and
efficacy with the use of canagliflozin in
type 2 diabetics with a high risk or history
of cardiovascular disease.
667 centres in 30 countries involved in
the clinical trial

8. Researchers were primarily interested in the
composite of three components;
a)) death from cardiovascular causes,
b) nonfatal myocardial infarction and
c) nonfatal stroke.
Other outcomes of interest included death from
any cause, progression of albuminuria,
hospitalization of heart failure and a composite of
renal outcomes.

9. CANVAS
In 2009, CANVAS enrolled 4,330 participants. These
participants were randomized and given either
placebo, 100 mg of canagliflozin or 300 mg of
canagliflozin in a 1:1:1 ratio.
The CANVAS Program, comprising two sister trials,
was designed to assess the cardiovascular safety and
efficacy of canagliflozin and to evaluate the balance
between any potential benefits of the drug and the
risks associated with it, such as genito urinary
infection, diabetic ketoacidosis, and fracture.

10. CANVAS-R
The study was initiated in 2014 , enrolled 5,812
participants was also designed to assess effects on
albuminuria .
These participants were randomized in a 1:1 ratio and
received placebo or 100 mg of canagliflozin. In
CANVAS-R, participants in the canagliflozin study
group had the opportunity to titrate up to 300 mg of
canagliflozin at week 13, if additional glycemic control
was needed.
Serum creatinine with GFR and urinary albumin-to-
creatinine ratio was measured every 26 weeks in
CANVAS-R .

11.  Progression of albuminuria was
defined as more than a 30% increase in
albuminuria and a change from either
normoalbuminuria to microalbuminuria
or macroalbuminuria or from
microalbuminuria to macroalbuminuria.

12. The integrated analysis of CANVAS and CANVAS-R
as the CANVAS Program
was undertaken to maximize statistical power to
detect plausible effects of canaglilozin on
cardiovascular, kidney, and safety outcomes as
suggested from evolving evidence about SGLT2
inhibitors.

13. PARTICIPANTS
• Mean age of participant = 63.3 years
• Women =36%
• Mean duration of diabetes =13.5 years
• 65 % with cvd risk

14. • Men and women with T2dm
• HbA1c b/w 7 and 10.5
• >30 yrs with cardiovascular disease
• 50+ with 2 or more risk factors of cardiovascular
disease.
• Duration of diabetes  atleast 10 years
• Systolic BP >140mmHg , receiving 1 or more
antihypertensive.
• Current smoking
• Microalbuminuria or macroalbuminuria
• HDL < 38.7mg/dl
• GFR >30ml/mt/1.73m2 surface area

15. RESULT
• In two trials involving patients with type 2 diabetes and
an elevated risk of cardiovascular disease, patients
treated with canagliflozin had a lower risk of cardio-
vascular events than those who received placebo but a
greater risk of amputation, primarily at the level of the
toe or metatarsal.
• The highest absolute risk of amputation occurred
among patients who had a history of amputation or
peripheral vascular disease, but the relative risk of
amputation with canagliflozin as compared with
placebo was similar across these subgroups.

16. DISCUSSION
• T2DM is associated with increased risk of CVS and
renal disease.
• Canagliflozin results in favourable effects on
biomarkers , including glycemia ,BP, weight ,
intrarenal hemodynamics and albuminuria. It also
reduces risk of cardiovascular complications ,kidney
disease and death.

17. Among the participants,
• 22.6% had microalbuminuria,
• 7.6% had macro- albuminuria, and
• 65.6% had a history of cardio- vascular disease at
baseline.

18. the results also showed that patients treated with
canagliflozin
• had a lower risk of hospitalization for heart failure,
• progression of albuminuria, and
• substantive loss of kidney function than patients who
received placebo

19. • No higher risk of hypoglycemia,
hyperkalemia, acute kidney injury,
pancreatitis, malignancies, or venous
thromboembolism detected with
canagliflozin than with placebo.
The rate of all fractures was
higher with canagliflozin than
with placebo

22. • Patients with type 2 diabetes and established car-
diovascular disease or at high risk for cardiovascular
events who were treated with canagliflozin had
significantly lower rates of the primary car-
diovascular outcome than patients assigned to
placebo.
• All three components of the primary outcome —
death from cardiovascular causes, nonfatal
myocardial infarction, and nonfatal stroke — showed
point estimates of effect that suggested benefit,
although the individual effects did not reach
significance.

23. • several established effects of SGLT2 inhibitors on
intermediate outcomes may contribute to
cardiovascular and renal protection.
• Although pleiotropic effects have been inferred,
improved glycemic control, lowering of blood
pressure, decrease in intraglomerular pressure,
reduction in albuminuria, and amelioration of
volume over load are all plausible protective
mechanisms.

24. • The increased rate of amputation is a new finding for
which the mechanism is unknown, and care is
warranted in the use of canagliflozin in patients at
risk for amputation.

25. Side effects include:
Hypoglycemia –if taken with sulphonylurea medication or
insulin
Hypotension (low blood pressure)
Genital thrush
Increased likelihood of urinary tract infections
polyuria
Constipation
Nausea
Increases in LDL cholesterol

26. • Canaglifozin is contraindicated in:
• Type 1 diabetes
• Diabetic ketoacidosis
• Severe renal impairment (estimated glomerular
filtration rate <30 mL/min/1.73 m2), end-stage renal
disease
• Patients on dialysis

27. The results of this study is clinically important because it
correlates with previous findings of SGLT-2 Inhibitors being
associated with decrease risk of adverse cardiovascular
outcomes and renal disease.
.
Although canagliflozin did not show a reduction in
cardiovascular death, it did reduce the risk of
cardiovascular events by 14%, reduce the risk of heart
failure hospitalization by 33% and reduce the rate of renal
decline by 40%.

28. SGLT2 inhibition may have an important kidney- protective
effect in type 2 diabetes. Since most renal events were based
on changes in GFR, more data are required to confirm the
effects on kidney failure.
Definitive evidence about the effects of canagliflozin on
clinical kidney outcomes are likely to be provided by the
ongoing Canagliflozin and Renal Endpoints in Diabetes with
Established Nephropathy Clinical Evaluation trial (CREDENCE)

29. Thank you