Power Point - New Mexico Pharmacists Association
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Transcript Power Point - New Mexico Pharmacists Association
The Diabetes
Download: Diabetes
Update 2017
KIM NEFF, PHARMD, PHC
CLINICAL PHARMACY SPECIALIST, AMBULATORY CARE
NEW MEXICO VA HEALTHCARE SYSTEM
Objectives
Pharmacist Objectives:
Explain the 2016 FDA safety alerts and labeling changes for diabetes
medications
Counsel patients on diabetic medications incorporating the information
from the FDA safety alerts
Describe the 2017 updates to the American Diabetes Association standards
of care in diabetes
Technician Objectives
Identify medications affected by recent FDA safety alerts
Describe the 2016 safety alerts and labeling changes for diabetes
medications
Describe the 2017 updates to the American Diabetes Association standards
of care in diabetes
https://www.pinterest.com/kascott29/rx/
Safety Studies for Diabetes
Medications
FDA change in 2008 regarding expectation of drug studies for new
diabetic medications to ensure there is no unacceptable
cardiovascular risk1
Prompted by1-2
Recommendations of the 2008 Endocrinologic and Metabolic Drugs
Advisory Committee
High cardiovascular risk in patients with diabetes
Safety issues with
Rosiglitazone
Muraglitizar
Intense glucose lowering in the ACCORD trial
Safety Studies for Diabetes
Medications
FDA expectations1
Independent cardiovascular endpoints committee
Evaluation of
Cardiovascular mortality
Stroke
Myocardial infarction
Design studies so can be easily and clearly analyzed via a meta-analysis at study
completion
Should include patients with high cardiovascular risk
Elderly
Renal impairment
Advanced cardiovascular disease
Pre and post-marketing trials may be required for new drugs depending upon
estimated risk of pre-marketing studies
DPP4 Inhibitors
FDA 1st
safety
communic
ation about
saxagliptin
and heart
failure
Sitagliptin
2006
2005
Saxagliptin
2009
Linagliptin
2011
2011
And then
this year…
Alogliptin
2013
2017
DPP4 Inhibitors and Heart failure
4/5/2016
“FDA Drug Safety communication: FDA adds warnings about heart
failure risk to labels of type 2 diabetes medicines containing saxagliptin
and alogliptin”3
Safety trials for DPP4 Inhibitors
Study
Name
SAVOR-TIMI
534
EXAMINE5-6
TECOS7
# of
patients
16, 492
5,380
14,671
Study drug
vs placebo
Saxagliptin
Alogliptin
Sitagliptin
A1C
Range
(%)
6.5 - 12
6.5 - 11
6.5 - 8
Primary
Outcome
(DPP4 vs
placebo)
Noninferior
Noninferior
Noninferior
Hospitalization P value
due to heart
failure (DPP4 vs
placebo)
289 (3.5%) vs
223 (2.8%)
106 (3.9%) vs
89 (3.3%)
228 (3.1%) vs
229 (3.1%)
Comments/other
results
0.007
Higher risk HF in
history of HF, renal
impairment
0.22
Significant higher
risk of hospitalization
due to heart failure
in patients without
previous history of
HF (P = 0.026)
0.98
Excluded patients
with eGFR <3 0
ml/min per 1.73m2
DPP4 Inhibitors and Heart failure:
Retrospective Study8
Evaluated new users of
Saxagliptin
Sitagliptin
Second generation sulfonylureas
Pioglitazone
Long acting insulin
Follow up time <1 year
No overall increase in incidence of hospitalization due to HF in new
users of saxagliptin and sitagliptin compared to pioglitazone,
sulfonylureas, or long acting insulin
DPP4 Inhibitors and Heart failure:
Retrospective Study8
DPP4 Inhibitors and Heart failure:
Retrospective Study8
Recommend cautious interpretation
Retrospective study design
Short follow up time
Re-enforces lack of association of sitagliptin with heart failure
BUT, 2/3 cohort studies found a positive association of sitagliptin with
heart failure9-11
And…
Results from the FDA Adverse Event
Reporting System (FAERS)12
Results from the FDA Adverse Event
Reporting System (FAERS)12
What About Linagliptin?
Two large trials ongoing, results not out
yet
CARMELINA– cardiovascular
CAROLINA—cardiovascular and renal
outcomes
Pooled study of 19 study results and
ADEs13
Increased heart failure incidence but not
clear if significant
Must interpret w/caution since pooled
data
DPP4 Inhibitors and Heart Failure:
Clinical Considerations
Conflicting evidence regarding HF risk
Avoid DPP4I if has HF and other treatment options available
If to use DPP4I, sitagliptin likely safest option
Careful w/renal impairment
Still may have some HF risk
May consider alternate option even if any risk factors for HF
Do not recommend with very poor blood sugar control
Low level of A1C lowering
Possibility that poorer control may be more associated with higher HF risk
Counseling on DPP4 Inhibitors
Possibility of heart failure
Patients need to contact their provider right away if:
Difficulty breathing w/laying down
Edema/swelling in ankles, feet, legs, stomach
Unusual SOB
Dyspnea on exertion
If on a renally adjusted dose, HF education may be more important
Other possible ADEs to educate on
Arthralgias
Pancreatitis
hypoglycemia
The New Kids on the Block
http://images4.fanpop.com/image/photos/22100000/nkotb-new-kids-on-the-block-22146585-1152-1156.jpg
http://www.mims.co.uk/sglt2-inhibitors-risk-diabetic-ketoacidosis/diabetes/article/1353980
Empagliflozin and CV Protection
12/2/2016
Jardiance® (Empagliflozin) gains new FDA approval14
To reduce cardiac death in patients with type 2 DM
Approval based on EMPA-REG study15
Significant improvement in various cardiovascular endpoints
Composite cardiovascular outcome
Death from cardiovascular causes
Non-fatal MI*
Non-fatal stroke*
Death from any cause
Hospitalization from heart failure
* defines not independently significant difference
EMPA-REG Study
15
Results
EMPA-REG Study
15
Results
Empagliflozin and CV
15
Protection
CV benefit thought to be due to mechanisms other than just A1C
lowering
Changes in arterial stiffness, cardiac function and cardiac oxygen
demand
Cardiorenal effects
Reduction in
Albuminuria
uric acid
Weight
visceral adiposity
Blood pressure
Improved blood sugar
Empagliflozin and CV
15
Protection
Significant safety outcomes
Less than placebo
UTI in women than placebo
Acute renal failure
Acute kidney injury
ADEs leading to study discontinuation
More than placebo
Genital infections in both men and women
Non-significant but more urosepsis
Empagliflozin For Everyone?
https://koshersamurai.files.wordpress.com/2012/12/monopoly-man-rich-guy.jpg
http://www.multivu.com/players/English/7617351-bi-lilly-empa-reg-cv-results/
Moving Forward with Empagliflozin
CV benefit impressive
Prevents death in 1 in 45 patients over 3 years16
Prevents overall mortality in 1 in 39 patients16
Points to keep in mind
Benefit was shown in patients
with cardiovascular disease
In addition to optimal treatment
Patients without cardiovascular disease were not a part of the study
No significant reduction in stroke or heart attack
Empagliflozin isn’t cheap
Although less than other SGLT2s, empagliflozin has side effects
Canagliflozin and Amputations
5/18/2016
FDA warns of increase risk of leg and foot amputations, mostly
affecting the toes, with the diabetes medicine canaglfilozin17
Canagliflozin Cardiovascular Assessment Study (CANVAS)
Investigating cardiovascular safety
Interim analysis showed higher risk of amputation (particularly toe) in
canagliflozin than placebo17
7/1000 with canagliflozin 100mg daily
5/1000 with canagliflozin 300mg daily
3/1000 with placebo daily
Study was permitted to continue
Canagliflozin and Amputations
European Medicine’s Agency (EMA) has also started to review
canagliflozin after this interim result from CANVAS18
CANVAS R trial (A study of the effects of canagliflozin on renal
endpoints in adult participants with type 2 diabetes mellitus)
Hasn’t shown same results17
Non-statistically significant difference between canagliflozin and
placebo for amputations19
16 amputations in canagliflozin group, 12 in placebo
Estimated incidence 7/1000 compared to 5/1000
Inagaki et al20
Didn’t show increased amputation risk
Canagliflozin and Amputations
Mechanism– not clear
Dehydration?
Volume depletion?
Application to Clinical Practice
Noteworthy possible risk but shouldn’t significantly affect prescribing
Avoid and/or discontinue in patient with lower limb complications
Closely monitor patients with risk factors for amputation
Peripheral vascular disease
Neuropathy
Previous amputations
Education on preventative foot care and good hydration important
SGLT2 and Renal Impairment
6/14/2016
“FDA strengthens kidney warnings for diabetes medicines canagliflozin
(Invokana®, Invokamet®) and dapagliflozin (Farxiga®, Xigduo XR®)”21
Prompted by case reports after drug approval
Canagliflozin/Dapagliflozin and
Renal Impairment21
Oct 2014-sept 2015, ~1.5 million got prescription for dapagliflozin or
canagliflozin
In 2.5 years (March 2013-Oct 2015), 101 confirmed cases of acute
kidney injury (AKI) with dapagliflozin or canagliflozin use
96 required hospitalization
22 admitted to intensive care units
4 deaths (2 cardiac-related)
15 patients received dialysis
3 had underlying CKD
6 were also on ACEI and diuretic
~50% happened within 1 month of drug start
Canagliflozin/Dapagliflozin and
Renal Impairment21
Patient characteristics
28-79 yo, median age 57
Over 50% <60 yo
51 on ACEI
26 diuretic
6 NSAID
10 previous CKD
Canagliflozin/Dapagliflozin and
Renal Impairment21
Change in renal function
Median reported increase of SCr = 1.5mg/dL
Median decrease in eGFR 46 ml/in/1.73m2
Most cases reversible but not all (76 reported discontinuation)
56 reported improvement
11 didn’t improve (including 4 deaths)
3 recovered with sequela
Canagliflozin and Renal
22
Effects
Generally a drop in GFR in the first 3-6 weeks of canagliflozin
initiation ~2-6mL/min/1.73m2 across studies
Trends of eGFR similar across most subsets
Degree of eGFR slightly higher in elderly and worsened renal function
but clinical significance questionable
Most eGFR drops stabilize or are attenuated by 26-104 weeks
>30% reductions in eGFR more common in CKD patients with
canagliflozin vs placebo
Canagliflozin 100mg - 31/332 (9.3%)
Canagliflozin 300mg - 43/352 (12.2%)
Placebo - 18/367 (4.9%)
Canagliflozin and Renal
>50% reduction not significantly different across groups with normal
renal function and moderate renal impairment (all less than 1%)
22
Effects
Normal renal impairment
Canagliflozin 100mg - none
Canagliflozin 300mg - 1/805 (0.1%)
Placebo- 1/624 (0.2%)
Stage 3 CKD pts: canagliflozin1.5% w/>50% drop in SCr, 0.9% of 300, none for
placebo
Canagliflozin 100mg – 5/332 (1.5%)
Canagliflozin 300mg – 3/352 (0.9%)
Placebo- none
In all cases, fewer patients had significant reductions at last postbaseline assessment
Canagliflozin and
22
eGFR
Dapagliflozin and
23
eGFR
Decrease in eGFR Generally
Reversible22
Intern tells you he learned in class
SGLT2s may be renal protective…
BAD?
OR
GOOD?
http://www.ebay.com/itm/DARTH-VADER-STAR-WARS-LIFESIZE-CARDBOARD-STANDUP-STANDEE-CUTOUT-POSTER-FIGURE-/271239202903
https://en.wikipedia.org/wiki/Yoda Accessed 12/3/2016
SGLT2 effect on the
22
Kidney
Empagliflozin and Renal Protection
EMPA-REG OUTCOME trial24
Empagliflozin showed renal protection
Less incident nephropathy (12.7 % vs 18.8%, P < 0.001)
Most independent components significantly less in empagliflozin group as
well (shown as empagliflozin vs placebo)
Progression to macroalbuminuria (11.2% vs 16.2%), RRR 38%
Doubling of serum creatinine (1.5 vs 2.6%) RRR 44%
Progression to renal replacement therapy (0.3% vs 0.6%) rrr 55%
Benefits seen across pre-specified subgroups and both doses
Less acute renal failure in empagliflozin than placebo
EMPAREG and Renal
24
Outcomes
EMPAREG and Renal
24
Outcomes
EMPAREG and Renal
24
Outcomes
Good or Bad?
Empagliflozin
http://www.ebay.com/itm/DARTH-VADER-STAR-WARS-LIFESIZE-CARDBOARD-STANDUP-STANDEE-CUTOUT-POSTER-FIGURE-/271239202903
https://en.wikipedia.org/wiki/Yoda Accessed 12/3/2016
Other SGLT2s and Albuminuria
Some studies have shown reductions in albumin to creatinine ratios
with canagliflozin25-28
Most favored improvement in albuminuria but not statistically significant
Kohan et al23 showed dapagliflozin more likely to regress to a lower
albumin excretion category
SGLT2 and Renal Impairment
Concern for risk of acute renal impairment
Canagliflozin
Dapagliflozin
Important time for monitoring is in the first 4-6 weeks
Use caution in:
HF
Poor hydration status
Fluid loss
Acute GI illness
ACE, ARB, NSAIDs, and diuretics
Other meds which can potentially cause renal impairment
Normotensive patients
SGLT2 and Renal Impairment
Renal impairment is often reversible
Empagliflozin provides long term renal protection
May be some new data when CANVAS R study is completed
SGLT2 not recommended in patients with impaired renal function
Dapagliflozin:
Do not initiate therapy with eGFR less than 60 mL/min/1.73 m2
Not recommended if eGFR is persistently between 30 and 60 mL/min/1.73 m2
Empagliflozin
Do not initiate therapy with eGFR less than 45 mL/min/1.73 m2
Discontinue if eGFR is persists below 45 mL/min/1.73 m2
Canagliflozin
Do not exceed 100mg orally once daily if eGFR is 45 to 60 mL/min/1.73 m2
Do not initiate therapy with eGFR less than 45 mL/min/1.73 m 2
Discontinue if eGFR is persists below 45 mL/min/1.73 m2
SGLT2 Counseling
Preventative foot care
monitoring for cuts/scrapes
Seek attention right away if any open wounds, discoloration, or new
onset pain or tenderness
Importance of good hydration
Seek attention if s/sx of water or salt loss
Use caution w/diuretics, HF
Signs of renal impairment
Decreased urine production
Swelling in legs or feet
Importance of lab follow up
SGLT2 Counseling
Risk of genital infection/UTI, corresponding symptoms
Risk of hypotension
Seek attention if develops dizziness
Recommend blood pressure monitoring while on tx
DKA
Counsel on symptoms and risk
Highly importance of seeking IMMEDIATE attention if has symptoms
Highlight for empagliflozin only
CV benefit in patients with CV disease
Renal protection
Metformin and Renal Dosing
Previous labeling:
Contraindicated
Men with SCr >1.5mg/dL
Women with SCr >1.4mg/dL
Intended to prevent use in patients with any type of renal impairment
for safety
Main concern was lactic acidosis risk
Metformin and Renal Dosing
4/8/2016
FDA determined after evaluating the current evidence29
eGFR should be used for determination of renal function
Safe use of metformin in mild renal impairment
Labeling modified
New guidance has been used prior to FDA label change30
FDA Changes to Metformin
Labeling29
Before starting, check creatinine/determine eGFR
Check eGFR
At least annually
More often in high risk populations
Iodinated contrast imaging
Stop prior in below patients
eGFR 30-60 mL/minute/1.73 m2
Liver disease
Alcoholism
Heart failure
Re-check eGFR 48 hours after
Resume when renal function stable
FDA Changes to Metformin
Labeling29
eGFR level
Recommendation
Less than 30 ml/min per 1.73m2
-Contraindicated. Do NOT use.
-Discontinue if currently taking
<45 and > 30 ml/min per 1.73m2
-Assess the benefits and risks of
continuing treatment
-Do not start new patients on
metformin
Metformin and Renal Dosing:
Clinical Application
Possible implications
Decrease in medical costs
Delayed need for insulin
May decrease weight in some patients from net decrease in insulin
requirements
Other factors beyond renal impairment must be considered prior to
metformin initiation/continuation
TZDs and Bladder Cancer
12/12/2016
“Updated FDA review concludes that use of type 2 diabetes
medicine pioglitazone may be linked to an increased risk of bladder
cancer”31
Risk already included in current labeling
FDA approved label updates to include new data that has been
reviewed
Animal models have shown bladder tumors with pioglitazone
exposure32
Higher reporting of bladder cancer to FDA Adverse Event Reporting
System for pioglitazone than other diabetes treatment33
Human studies produced conflicting evidence
Is Pioglitazone Associated with a
Higher Risk of Bladder cancer?
Studies with significant risk
Lewis et al 5 year interim analysis34
Only in patients on pio >2 years
Hazard ratio 1.4 (CI 1.03-2.0)
Higher risk overall (HR1.63, 1.222.19)
Higher risk >2 years use (HR1.78,
1.21-2.64)
Dose response relation (p =0.01 for
trend)
Ferwana meta-analysis36
Overall risk (HR 1.23, CI 1.09-1.39)
Lewis et al 10 Year follow up
study37**
Tuccori et al35
Studies with no significant risk
No significant difference overall,
based on duration OR dose
PROactive trial38**
14/2605 in pio vs 6/2633 in placebo
P = 0.069
P = 0.309 when cases in first year
were removed
PROactive 10 year follow up39**
21 (1.2%) in pio vs 14 (0.8%) in
placebo, (RR 0.65, CI 0.33-1.28)
**denotes no significant risk but trend suggested higher risk in pio group
What Do We Make of All This?
Incidence of bladder cancer in pio and placebo is low
Causality cannot be confirmed
RCT study suggests no significant risk38
Risk in observational studies may be in part related to unequal
distribution of risk factors in pioglitazone vs placebo
Bladder cancer risk cannot be excluded
Until more definitive conclusions, must use caution and take heed of this
possible risk
Not recommended in patients with bladder cancer or a history of
bladder cancer
Recommend caution in family history of bladder cancer or other risk
factors for bladder cancer
Risk/benefit must be weighed on a patient specific basis
Counseling
Advise patients to seek attention if:
Blood in urine
New or worsening urge to urinate
Pain when urinating
Other counseling points
Edema
SOB
Weight gain
Reminders from 2016 FDA Alerts
With new medication benefits come new risks
Diabetes treatment selection is highly patient specific
Education is very important for patient safety
American Diabetes Association
2017 Updates40
Recommend periodic B12 monitoring in patients on metformin
Figure 8.1 updated to acknowledge high insulin costs
American Diabetes Association
2017 Updates40
Update to
Figure 8.2
American Diabetes Association
2017 Updates40
New Table 8.2
American Diabetes Association
2017 Updates40
New Table 8.3
American Diabetes Association
2017 Updates40
Recommendation to consider empagliflozin or liraglitide in patients with
history of cardiovascular disease to reduce risk of mortality
Section on new biosimilar insulins
Any of following recommended for hypertension treatment if no
albuminuria
ACEI/ARB
Thiazide diuretics
Dihydropyridine calcium channel blockers
American Diabetes Association
2017 Updates40
Specific recommendations added for treatment of neuropathic
pain
Pregabalin
Duloxetine
Inpatient diabetes management
Basal + correctional scale ok in non-critically ill patients but not
correctional scale alone
American Diabetes Association
2017 Updates40
American Diabetes Association
2017 Updates40
Non pharmacologic updates (included but not limited to)
Advise interruption of sitting every 30 minutes
Possibly discuss unifying DM classification scheme based on beta cell
function
Blood pressure targets for pregnant women changed:
120-160/80-105
optimize maternal health without inducing fetal harm
Recommendations added surrounding incorporating social considerations
into treatment decisions
Pharmacists’ Roles in Diabetes
COACH
https://timemanagementninja.com/2014/03/how-many-hats-are-you-trying-to-wear/
Potential Areas of Pharmacist
Impact in Diabetes
Medication-related
Proper
Timing
Administration
Storage
Hypoglycemia
Lifestyle/Other
Risks of poor DM control
Eating behaviors
Exercise
Lab monitoring
Signs and symptoms
Blood sugar testing
Treatment
Glucose/A1c targets
Lancets
Social support
Optimizing drug treatment
Safety
Efficacy
Cost
Questions?
References
1.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research.
Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular risk in new antidiabetic therapies to treat type 2
diabetes. December 2008. Pages 1-5
2.
Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for Type 2 diabetes: time to
reassess? Diabetes Care 2016;39:738-42.
3.
FDA Drug Safety Communication. FDA adds warning about heart failure risk to labels of type 2 diabetes medicines
containing saxagliptin and alogliptin. http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm Issued 4/5/16, Accessed
12/2/16.
4.
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
NEJM 2013;369:1317-26.
5.
Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking
alogliptin versus placebo in EXAMINE: a multicenter, randomized, double blind trial. Lancet 2015; 285:2067-76.
6.
White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. NEJM
2013;369:1327-35.
7.
Green JB, Bethel MA, Armstorng PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. NEJM
2015;373:232-42. (TECOS)
8.
Toh S, Hamp C, Reichman ME, et al. Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other
antihyperglycemic drugs: a retrospective cohort study. Ann Intern Med 2016;164:705-14.
9.
Weir DL, McAlister FA, Senthilselvan, et al. Sitagliptin use in patients with diabetes and heart failure: a population based
retrospective cohort study. JACC Heart Fail 2014;2:573-82.
10.
Wang KL, Liu CJ, Chao TF, et al. Sitagliptin and the risk of hospitalization for heart failure: a population-based study. Int J
Cardiol 2014;177: 86-70.
References
11.
Chen DY, Wang SH, Mao CT, et al. Sitagliptin and cardiovascular outcomes in diabetic patients with chronic kidney
disease and acute myocardial infarction; a nationwide cohort study. Int J Cardiol 2015;181:200-6.
12.
Raschi E, Poluzzi E, Koci A, et al. Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports
submitted to the FDA Adverse Event Reporting System. Nutrition, Metabolism & Cardiovascular Diseases 2016;26:380-6.
13.
Lehrke M, Leiter LA, Hehnke U, et al. Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary
artery disease: analysis of pooled events from 19 clinical trials. Journal of Diabetes and Its Complications 2016;30:1378-84.
14.
FDA. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. FDA News Release
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm Published 12/2/16, Accessed 12/5/16.
15.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozing, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM
2015;373:2117-28.
16.
PL Detail-Document, Empagliflozin and Cardiovascular Disease. Pharmacist’s Letter/Prescriber’s Letter. November 2015
17.
FDA. Canagliflozin (Invokana®, Invokanamet®): Drug safety communication – clinical trial results find increased risk of leg
and foot amputations. http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm Issued 5/18/16, Accessed 12/2/16.
18.
Canagliflozin and the risk of leg and foot amputations. http://www.diabetesincontrol.com/canaglfilozin-amputation-risk/
Article published 6/4/16, Accessed 12/15/16.
19.
Drug Safety Update vol 9 issue 11, June 2016: 1. (accessed https://www.gov.uk/drug-safety-update/canagliflozininvokana-vokanamet-signal-of-increased-risk-of-lower-extremity-amputations-observed-in-trial-in-high-cardiovascular-riskpatients)
20.
Inagaki N, Harashima S, Maruyama N, et al. Efficacy and safety of canagliflozin in combination with insulin: a double-blind,
randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2016;15:89.
References
21.
FDA. Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana®, Invokanamet®)
and dapagliflozin (Farxiga®, Xigduo XR®). http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm Issued 6/14/16, Accessed 12/2/16.
22.
Perkovic V, Jardine M, Vijapurkar U, et al. Renal effects of canagliflozin in type 2 diabetes mellitus. Current Medical Research and
Opinion 2015;31:2219-31.
23.
Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that
dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney International 2014;85:962-71.
24.
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. NEJM 2016;375:323-34.
25.
Leiter LA, Yoon KH, Arias P, et al. Canagliflozin Provides Durable Glycemic Improvements and Body WeightReductionOver104Weeks
Versus Glimepiride in Patients With Type 2 Diabetes on Metformin: A Randomized, Double-Blind, Phase 3 Study. Diabetes Care
2015;38:355-64.
26.
Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease.
Diabetes, Obesity, and Metabolism 2013;15:463-73.
27.
Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and
chronic kidney disease. Diabetes, Obesity, and Metabolism 2014;16:1016-27.
28.
Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes
inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.
Lancet 2013;382:941-50.
29.
FDA. Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with
reduced kidney function. http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm Issued 4/8/16, Accessed 12/2/16.
30.
Insucchi SE, Lipska KJ, Mayo H, et al. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA
2014;312:2668-75.
References
31.
FDA. Drug Safety Communication: Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may
be linked to an increased risk of bladder cancer. http://www.fda.gov/Drugs/DrugSafety/ucm519616.htm Issued 12/12/16,
Accessed 12/20/16.
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