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 risk 1 Prompted by 1-2 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 expectations 1 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 1 st safety communic ation about saxagliptin and heart failure And then this year…
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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
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.
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
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.