Transcript New Medications for DM2 - Civic Unit - C. Way

New
Medications for
Diabetes
Cynthia Way, BScPharm,
ACPR
June 9, 2015
Learning objectives
At the end of the presentation the
learner will be able to:
 Compare and contrast the newest
DPP-4 inhibitor, alogliptin, with the older
agents
 Describe the mechanism of action of
the SGLT-2 inhibitors
 Describe usual monitoring of patients
on SGLT-2 inhibitors
 Discuss the place in therapy of the
SGLT-s inhibitors
DPP-4 inhibitors
Four available in Canada, alone and in
combination with metformin.
 Sitagliptin (Januvia®; Janumet®,
Janumet XR®)
 Saxagliptin (Onglyza®; Komboglyze®)
 Linagliptin (Trajenta®; Jentadueto®)
 Alogliptin (Nesina®; Kazano®)
All cost approx $3/day and all except Nesina®
& Kazano® are general benefit under Ontario
Drug Benefit (ODB).
DPP-4 inhibitors
Mechanism of Action
Alogliptin (Nessina®; Kazano®)
 Indication
as monotherapy if cannot
take metformin; in combo w/
metformin, pioglitazone, SU, met+pio,
insulin +/- met. Not with met +SU.
 Usual dose 25mg/day
 Dose reduced to 12.5mg/d if CrCl
<50mL/min and to 6.25mg/d if
<30mL/min
 Use w/ caution if dialysis due to little
experience in this population
Alogliptin (Nessina®; Kazano®)
 Can
be taken with or without food
 No known drug interactions
 Did have slightly higher incidence
of hypoglycemia when combined
with metformin & pioglitazone as
triple therapy
 Manufacturer suggests using with
caution if CHF
DPP-4 Inhibitors
How are they the same?
 All
given once daily (unless
combined with regular-release
metformin; exception Janumet XR®)
 Roughly the same effectiveness at
lowering the A1C (about 0.7%)
 All generally well-tolerated
 All have same low risk of inducing
hypoglycemia
DPP-4 Inhibitors
How do they differ from one another?

Saxagliptin



Linagliptin:



More significant drug interactions (metabolized by
CYP3A4/5)? Would only be significant with longer-term
combinations.
Signal for increased risk of heart failure
Not renally eliminated so dose not adjusted for renal
function (caution in ESRD/HD)
The only one that should not be combined with insulin
Different official indications for combination
therapies. All indicated in combination with
metformin. For all other combinations, check the
product monograph in the CPS.
DPP-4 Inhibitors
Cardiovascular Safety
Both EXAMINE and SAVOR showed
that the DPP-4 inhibitors tested
(alogliptin & saxagliptin) do NOT
increase risk of MI, stroke.
 CAROLINA and CARMELINA (both
linagliptin) due to report in 2018 and
TECOS (sitagliptin) due to report 2015

DPP-4 Inhibitors
CV Safety
SAVOR-TIMI found an increase in
hospitalizations due to heart failure in
patients who received saxagliptin in the first
year of treatment (e.g. NNH 142 for 2 yrs)
Risk factors included chronic kidney disease
and previous heart failure.
DPP-4 Inhibitors
CV Safety
Meta-analyses have varying conclusions. At
least two have found a signal that
hospitalizations for heart failure are increased,
while one (performed by the manufacturer of
saxagliptin) has not.
Bottom line: need more data but for now, avoid
in those with pre-existing heart-failure and
consider stopping if new onset CHF, esp in the
first year of tx.
DPP-4 Inhibitors
Summary
Pros
 Once
daily
administration
(unless in combo
pill w/ metformin)
 Low risk of
hypoglycemia
 Weight neutral
 Well-tolerated
Cons




Maybe less effective
than sulfonylurea at
lowering A1C
Not shown to reduce
complications (yet?)
Expensive
Possible concerns re
pancreatic adverse
effects and heart
failure
DPP-4 Inhibitors
What to watch for
 Arrival
of vildagliptin
 Results of TECOS, CAROLINA,
CARMELINA
 Results of VERIFY, a 5-yr trial
comparing early combination
treatment with vildagliptin +
metformin with metformin
monotherapy and second agent
added based on threshold criteria
SGLT-2 Inhibitors
SGLT-2 Inhibitors
Mechanism of Action
SGLT-2 Inhibitors
 Canagliflozin
(Invokana®)
 Dapagliflozin (Forxiga®)
Both cost approximately $3/day,
similar to DPP-4 inhibitors.
Neither are currently covered by ODB.
SGLT-2 Inhibitors
 Effectiveness:
lower A1C by 0.5-0.7%,
roughly comparable to DPP-4 inhibitors.
 No evidence that they reduce
complications of diabetes (yet?)
 Do not work as well in chronic kidney
disease, including reduced renal function
related to age
 Low risk hypoglycemia unless combined
w/ SU or insulin.
SGLT-2 Inhibitors
 Both
given once daily, canagliflozin
preferably before breakfast
 Canagliflozin: 100mg/day, increase to
300mg if needed
 Dapagliflozin: 5mg/day, increase to
10mg/d if needed
 Don’t use dapagliflozin if
CrCl<60mL/min
 Don’t start canagliflozin if
CrCl<60mL/min and stop if <45mL/min
SGLT-2 Inhibitors
Associated with
weight loss of
2-4kg on
average
SGLT-2 Inhibitors
Lower BP
 SBP ↓ 4-5mmHg
 DBP ↓ 2-3mmHg
SGLT-2 Inhibitors
 Theoretically
could be combined with
any other class of anti-diabetic agent
but only some combinations approved
by Health Canada.
 Can be used with insulin
 Because mechanism is insulinindependent, being studied for use in
DM1
SGLT-2 inhibitors
Combinations
Met
SU
Pio
Met +
SU
Cana
+
+
+
+
Dapa
+
+
Met +
pio
Insulin
+/met
+
+
+
SGLT-2 Inhibitors
Adverse effects
 Few
GI adverse effects
 Risk of orthostasis and dehydration due to
increased u/o; not recommended in
combination with loop diuretics (e.g.
furosemide)
 Dose-dependent ↑ creatinine
 Higher risk of UTI and genital mycotic
infections (i.e. vulvovaginitis, balanitis),
tend to be mild to moderate in severity
and respond to usual treatment. (NNH 3040)
 Large CV safety trials underway for both
SGLT-2 Inhibitors
Seem very similar to each other but…
 Canagliflozin
can increase K+; careful if
combined with ACE inhibitor, ARB or K+sparing diuretic
 Dapagliflozin: signal for slight increase risk
of bladder CA. Do not combine w/
pioglitazone or use if previous hx of
bladder CA.
SGLT-2 Inhibitors
Monitoring
 Orthostasis,
hypotension, dehydration
 Creatinine +/- K+ (timing?)
 SMBG, A1C
 Educate patients re symptoms UTI and
candida infections
SGLT-2 Inhibitors
FDA Warning
 FDA
has received >20 reports of DKA in
DM2 patients treated w/ SGLT-2 inhibitors.
 Presentation atypical since glucose was
<10mmol/L in some pts.
 Only ½ of cases identified a triggering
event
 Onset ranged from 1-175d after beginning
tx w/ SGLT-2 inhibitor
 Watch for symptoms, check for acidosis &
stop SGLT-2 inhibitor if acidotic
SGLT-2 Inhibitors
Pros
 Low
risk
hypoglycemia
unless added to SU
or insulin
 Generally welltolerated in
selected groups of
pts
 Likely low risk of
secondary failure
 Weight loss
Cons




No evidence they ↓
risk DM
complications
Don’t work as well in
those w/ ↓ renal fxn
Expensive
Long-term safety
unknown b/c so new
SGLT-2 Inhibitors
Place in therapy?
 Role



in the elderly population unknown
reduced efficacy with reduced renal
function
risk of orthostasis
low risk hypoglycemia attractive
 Option
for those who want to lose weight
or avoid insulin and can afford the $3/day