1/11/2017

1

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

2005 2017 2011

Sitagliptin 2006

Saxagliptin 2009

Linagliptin 2011

Alogliptin 2013

FDA 1st safety

communication about saxagliptin

and heart failure

And then this year…

1/11/2017

2

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

# of patients

Study drug vs placebo

A1C Range

(%)

Primary Outcome

(DPP4 vs placebo)

Hospitalization due to heart

failure (DPP4 vs placebo)

P value Comments/other results

SAVOR-TIMI 534 16, 492 Saxagliptin 6.5 - 12

Non-inferior

289 (3.5%) vs 223 (2.8%)

0.007 Higher risk HF in history of HF, renal

impairment

EXAMINE5-6 5,380 Alogliptin 6.5 - 11 Non-inferior

106 (3.9%) vs 89 (3.3%)

0.22

Significant higher risk of hospitalization due to heart failure in patients without previous history of HF (P = 0.026)

TECOS7 14,671 Sitagliptin 6.5 - 8 Non-inferior

228 (3.1%) vs 229 (3.1%)

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

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…

DPP4 Inhibitors and Heart failure: Retrospective Study8

Results from the FDA Adverse Event Reporting System (FAERS)12

1/11/2017

3

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

1/11/2017

4

EMPA-REG Study Results15

EMPA-REG Study Results15

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 Protection15 Empagliflozin and CV Protection15

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

1/11/2017

5

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

Mechanism– not clear

Dehydration?

Volume depletion?

Canagliflozin and Amputations 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

1/11/2017

6

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

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/Dapagliflozin and Renal Impairment21

Canagliflozin and Renal Effects22

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%)

>50% reduction not significantly different across groups with normal renal function and moderate renal impairment (all less than 1%)

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 post-baseline assessment

Canagliflozin and Renal Effects22

Canagliflozin and eGFR22 Dapagliflozin and eGFR23

1/11/2017

7

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 Kidney22 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 Outcomes24 EMPAREG and Renal Outcomes24

1/11/2017

8

EMPAREG and Renal Outcomes24

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 m2

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

1/11/2017

9

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

SGLT2 Counseling 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

1/11/2017

10

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)

Tuccori et al35

Higher risk overall (HR1.63, 1.22-2.19)

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)

Studies with no significant risk

Lewis et al 10 Year follow up study37**

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

1/11/2017

11

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

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

1/11/2017

12

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

Signs and symptoms

Treatment

Optimizing drug treatment

Safety

Efficacy

Cost

Lifestyle/Other

Risks of poor DM control

Eating behaviors

Exercise

Lab monitoring

Blood sugar testing

Glucose/A1c targets

Lancets

Social support

Questions?

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

1/11/2017

13

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/canagliflozin-invokana-vokanamet-signal-of-increased-risk-of-lower-extremity-amputations-observed-in-trial-in-high-cardiovascular-risk-patients)

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.

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. Perkov ic 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 Prov ides 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 rev ises 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 rev iew. 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.

32. Suzuki S, Arnold LL, Pennington KL, et al. Effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the urine and urothelium of the rat. Toxicol Sci 2010;113:349-57.

33. Piccini C, Motola D, Marchesni G, et al. Assessing the association of pioglitazone use and bladder cancer through adverse drug event reporting. Diabetes Care 2011;34:1369-71.

34. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011;34:916-22.

35. Tuccori M, Filion KB, Yin H, et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541.

36. Ferwana M, Firwana B, Hasan R, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med 2013;30:1026-32.

37. Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 2015;314;265-77.

38. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone clinical trial in macrovascular events): a randomized controlled trial. Lancet 2005;366:1279-89.

39. Erdmann E, Harding S, Lam H, et al. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes, Obesity and Metabolism 2016;18:266-73.

40. American Diabetes Association. Promoting health and reducing disparities in populations. Sec. 1. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017; 40(Suppl. 1):S1–S129

References References

Photo/cartoon references

1. Three minion photo. http://www.steamworksstudio.com/bparty.html Accessed 1/1/2017

2. Minion wallpaper. http://weheartit.com/entry/73189313/in-set/11689299-minions?context_user=nelita_fer Accessed 1/1/2017

3. Blood pressure and cancer image. http://abcnews.go.com/Health/HypertensionNews/study-links-popular-blood-pressure-drugs-cancer/story?id=10909261 Accessed 1/1/2017

4. Heartburn and cancer image. http://www.cnn.com/2016/11/15/health/heartburn-medication-stroke-risk/ Accessed 1/1/2017

5. Statins and memory loss image. http://www.cbsnews.com/news/statins-and-memory-loss-should-you-worry/ Accessed 1/1/2017

6. “Please have a seat” photo. https://www.pinterest.com/kascott29/rx/ Accessed 1/1/2017

7. New Kids on the Block Photo. http://images4.fanpop.com/image/photos/22100000/nkotb-new-kids-on-the-block-22146585-1152-1156.jpg Accessed 12/2/2016.

8. Monopoly guy photo https://koshersamurai.files.wordpress.com/2012/12/monopoly-man-rich-guy.jpg accessed 1/1/2017.

9. Jardiance 10mg photo http://www.multivu.com/players/English/7617351-bi-lilly-empa-reg-cv-results/

10. SGLT Inhibitor Photos. http://www.mims.co.uk/sglt2-inhibitors-risk-diabetic-ketoacidosis/diabetes/article/1353980 Copyright Haymark Media Group. Accessed 12/3/2016

11. Darth Vader photo. http://www.ebay.com/itm/DARTH-VADER-STAR-WARS-LIFESIZE-CARDBOARD-STANDUP-STANDEE-CUTOUT-POSTER-FIGURE-/271239202903 Accessed 12/1/2016

12. Yoda photo https://en.wikipedia.org/wiki/Yoda Accessed 12/3/2016

13. Kylo Ren photo. https://twitter.com/kylor3n

14. Balancing hats photo. https://timemanagementninja.com/2014/03/how-many-hats-are-you-trying-to-wear/ Accessed 1/1/2017