DPP-4 inhibitor use and risk of diabetic retinopathy: a new safety issue of a safe drug Nam Hoon Kim

Transcription

1 DPP-4 inhibitor use and risk of diabetic retinopathy: a new safety issue of a safe drug Nam Hoon Kim Endocrinology of Metabolism, Korea University College of Medicine

2 Conflict of interest disclosure None Committee of Scientific Affairs

3 Contents Issue 1: DPP-4 inhibitor and pancreatitis/pancreatic cancer Issue 2: DPP-4 inhibitor and risk of heart failure DPP-4 inhibitor and risk of diabetic retinopathy Case/control study data using a NHIS cohort

4 DPP-4 inhibitor The first agent of the class sitagliptin was approved by the FDA in 2006 Vildagliptin (EU approved in 2007) Saxagliptin (FDA approved in 2009) Linagliptin (FDA approved in 2011) Gemigliptin (approved in Korea in 2012) Anagliptin (approved in Japan in 2012) Teneligliptin (approved in Japan in 2012) Alogliptin (FDA approved in 2013) Trelagliptin (approved in Japan in 2015) Omarigliptin (approved in Japan in 2015) Evogliptin (approved in Korea in 2015) Generally safe - No hypoglycemia - No weight gain - Safely use in renal impairment - Safely use in liver dysfunction - Safely use in the elderly

5 FDA adverse event reporting system (AERS) database

6 Examination of pancreata from organ donors with T2DM treated by incretin therapy increased exocrine cell proliferation (P<0.0001) increased exocrine cell dysplasia (increased pancreatic intraepithelial neoplasia, P<0.01) Diabetes 2013;62:

7 Major CV outcome studies TECOS SAVOR-TIMI 53

8 EXAMINE GLP-1R agonists trial LEADER Liraglutide (n=4668) Placebo (n=4672) P value Acute pancreatitis 18 (0.4) 23 (0.5) 0.44 Chronic pancreatitis 0 2 (<0.1) 0.16 Pancreatic cancer 13 (0.3) 5 (0.1) 0.06 SUSTAIN-6 Semaglutide (n=1648) Placebo (n=1649) Acute pancreatitis 9 (0.5) 12 (0.6) Pancreatic cancer 1 (<0.1) 4 (0.2) EXSCEL Exenatide XR (n=7344) Placebo (n=7372) Pancreatitis 26 (0.4) 22 (0.3) Pancreatic cancer 15 (0.2) 16 (0.2)

9 Combined analysis of 3 trials Diabetes Care 2017;40:

10 SAVOR-TIMI 53 More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; HR, 1.27 (1.07 to 1.51); P = 0.007).

11 EXAMINE Overall, alogliptin was not associated with an increased risk of hospitalization for HF (HR 1.19 [ ]), But the risk differed among patients with (HR 1.00 [ ]) and without (HR 1.76 [ ]) a history of HF Lancet 2015;385:

12 A Meta-analysis BMJ 2016;352:i610

13 DPP-4 substrates Endor Rev 2012;33:

14 DPP-4 inhibitor and diabetic retinopathy A few experimental or clinical data showed the beneficial effects of DPP-4 inhibitors on diabetic retinopathy. Diabetes Care 2014;37:

15 However, no study has so far evaluated the effects of DPP-4 inhibitors on retinopathy end points in diabetic patients. Recently, some preclinical and clinical data suggest a possible association between dipeptidyl peptidase-4 (DPP-4) inhibitor use and increased risk of diabetic retinopathy (DR).

16 TECOS 21.4%

17 Sci Rep 2016;6:29393

18 DPP-4 inhibitor activates SDF-1α-Src-VE cadherin axis Hypothesis that DPP-4 inhibitors aggravate diabetic retinopathy DPP-4 DPP-4 inhibitor SDF-1α CXCR4 R Src Phosphorylation of vascular endothelial cadherin (VE-cadherin) Angiogenesis Vascular permeability DR, HF

19 DPP-4 inhibitor aggravated vascular leakage in the retina

20 Other DPP-4 inhibitor trials SAVOR-TIMI (saxagliptin): no DR data presented. EXAMINE (alogliptin): no DR data presented.

21 LEADER (liraglutide) 15% N Engl J Med 2016;375:311-22

22 SUSTAIN-6 (semaglutide) N Engl J Med 2016;375:

23 A question based on preclinical and clinical evidences Logically, management of hyperglycemia with glucoselowering agents should be beneficial for diabetic retinopathy. However, incretin-based therapy or DPP-4 inhibitor therapy may increase the risk of diabetic retinopathy.

24 Population based cohort a retrospective matched cohort design using the National Health Insurance Service National Sample Cohort (NHIS-NSC ) all patients aged 20 years old or above with type 2 diabetes who were treated with oral glucose-lowering agents from Dec 1, 2008 (the release date of DPP-4 inhibitor in Korea), to Sep 30, 2013, were identified. Median follow-up time: 28.4 ( ) months. DPP-4 inhibitor, sulfonylurea, thiazolidinedione, and metformin were considered as oral glucose-lowering agents in this study. DPP-4 inhibitor: sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, and gemigliptin

25 Disposition of study subjects Subjects with type 2 diabetes who received treatment with oral glucose-lowering agents between Dec 2008 and Sep 2013 (n = 67,743) Ever use of DPP-4 inhibitors (n = 24,472) Never use of DPP-4 inhibitors (n = 43,271) Excluded (n=1,543): Age < 20 years (n = 43) Death on the first year (n = 18) not diagnosed with type 2 diabetes (n = 22) DR outcomes before the entry year (n = 1,465) Excluded (n=2,996): Age < 20 years (n = 200) Death on the first year (n = 191) not diagnosed with type 2 diabetes (n = 866) DR outcomes before the entry year (n = 1,826) Case pool: ever use of DPP-4 inhibitors (n = 22,929) Control pool: never use of DPP-4 inhibitors (n = 40,275) 1:1 matching on the index year, age, sex, duration of diabetes, and baseline retinopathy 1:1 matching by the year of the index date, age, sex, duration of diabetes, and presence of baseline retinopathy Case: ever use of DPP-4 inhibitors (n = 14,552) Matched control: never use of DPP-4 inhibitors (n = 14,552)

26 Outcome measures Vitreous hemorrhage (ICD-10 codes E10.32, E11.32, E13.32, E14.32, H43.1, or H45.0) Vitrectomy (S5121, S5122) or photocoagulation (S5160) Use of intravitreal agents Blindness (ICD-10 codes H54.0 or H54.4) Confounder variables evaluated included the patient s age at index date, sex, duration of diabetes, mean fasting glucose, presence of hypertension, and retinopathy at baseline. Stratified Cox proportional hazards regression analysis with timedependent covariates for these matched-pair data was performed

27 Baseline characteristics Case: ever use of DPP-4 inhibitor (n = 14,552) Matched control: never use of DPP-4 inhibitor (n = 14,552) p-value Index year, n (%) (0.7) 104 (0.7) (23.4) 3401 (23.4) (17.8) 2595 (17.8) (19.9) 2900 (19.9) (20.9) 3038 (20.9) (17.3) 2514 (17.3) Age group, n (%) 0.35* (0.8) 163 (1.1) (5.7) 697 (4.8) (17.6) 2646 (18.2) (28.3) 4120 (28.3) (23.9) 3480 (23.9) (19.1) 2466 (16.9) (4.6) 980 (6.7) Sex, n (%) Male 8004 (55.0) 8004 (55.0) Female 6548 (45.0) 6548 (45.0)

28 Case: ever use of DPP-4 inhibitor (n = 14,552) Matched control: never use of DPP-4 inhibitor (n = 14,552) p-value Duration of diabetes (years ) Mean (SD) 4.6 (3.3) 4.4 (3.4) <0.01 Median Min, Max (0.0, 11.7) (0.0, 11.7) < (37.7) 5484 (37.7) (22.2) 3226 (22.2) (32.4) 4721 (32.4) ) 1121 (7.7) 1121 (7.7) Baseline retinopathy, n (%) Yes 1998 (13.7) 1998 (13.7) No 12,554 (86.3) 12,554 (86.3) Hypertension, n (%) 0.04 Yes 9342 (64.2) 9169 (63.0) No 5210 (35.8) 5383 (37.0)

29 Outcomes Composite outcome Never use of DPP-4 inhibitor Ever use of DPP-4 inh ibitor Person-years 35,906 36,216 No. of events Unadjusted HR (95% CI) ( ) Adjusted HR (95% CI) ( ) Vitreous hemorrhage No. of events Unadjusted HR (95% CI) ( ) Adjusted HR (95% CI) ( ) Vitrectomy or photocoagulation No. of events Unadjusted HR (95% CI) ( ) Adjusted HR (95% CI) ( ) Intravitreal injection No. of events Unadjusted HR (95% CI) ( ) Adjusted HR (95% CI) ( ) Blindness Results No. of events 7 5 Unadjusted HR (95% CI) ( ) Adjusted HR (95% CI) ( ) By stratified Cox`s proportional hazard regression analysis with variables of diabetes duration (year), and history of hypertension being adjusted.

30 A. Composite DR events B. Vitreous hemorrhage C. Vitrectomy or photocoagulation D. Use of intravitreal agents

31 Comparison of cumulative incidence for diabetic retinopathy with or without DPP-4 inhibitor use stratified by patient`s baseline retinopathy status.

32 Analyses by cumulative duration n Person-yea rs No. of eve nts Incidence per 1000 p erson-year s Unadjusted HR (95% CI) Adjusted HR* ( 95% CI) Never use of DPP-4 inhibitor 14,552 35, Ever use of DPP-4 inhib itor Cumulative duration of DPP-4 inhibitor use (m onths) 14,552 36, <12 months 14,552 12, months months months ( ) 1.32 ( ) 1.02 ( ) 0.88 ( ) 0.89 ( ) 1.08 ( ) 1.31 ( ) 1.00 ( ) 0.85 ( ) 0.86 ( )

33 Hazard rate by duration (hazard function) Incidence per 1000 person-years

34 Subanalysis by baseline retinopathy With baseline retinopathy (n = 3996) Without baseline retinopathy (n = 25,108) Never use of DPP- 4 inhibitor Duration of DPP-4 inhibitor use (mon ths) n No. of even ts Unadjusted HR (95% CI ) Adjusted H R* (95% CI) n No. of even ts Unadjusted HR (95% CI ) Adjusted H R* (95% CI) , <12 months ( ) 1.21 ( ) 12, ( ) 1.39 ( ) months ( ) 0.89 ( ) ( ) 1.00 ( ) months ( ) 0.68 ( ) ( ) 0.90 ( ) 36 months ( ) 0.73 ( ) ( ) 0.78 ( )

35 Risk of HF over time in SAVOR-TIMI This increased risk was clustered in the first year of follow-up (HR 1.46, [ ]) with no increase thereafter Circulation 2014;130:

36 Sitagliptin n Person-years No. of events Unadjusted HR (9 5% CI) Adjusted HR* (95 % CI) Never use of DPP-4 inhibitor (matched control) 11,026 28, Cumulative duration of sitagli ptin use (months) <12 months 11, ( ) 1.15 ( ) months ( ) 0.87 ( ) months ( ) 0.74 ( ) 36 months ( ) 0.89 ( ) Cumulative dose of sitagliptin (mg) <36,000 mg 11, ( ) 1.09 ( ) 36,000 72,000 mg ( ) 0.96 ( ) 72, ,000 mg ( ) 0.63 ( ) 180,000 mg ( ) 1.09 ( )

37 Summary This is the first large-scale population based study that investigated the DPP-4 inhibitor-related risk of DR. DPP-4 inhibitor therapy did not increase overall risk of diabetic retinopathy compared to other oral glucose lowering agents. However, it potentially exerts harmful effect on retinopathy aggravation in the early treatment phase.

38 A majority of DR events (71.5%) in the DPP-4 inhibitor case group occurred much earlier, <12 months after initiating treatment, and the risk of DR events was significantly higher, about 30% compared with that observed in the control group. It is not fully explained why the DR events were increased earlier, and diminished later, during DPP-4 inhibitor therapy. Close monitoring of retinal changes or symptoms right after starting DPP-4 inhibitors is warranted.

39 Conclusion Any safety issues of DPP-4 inhibitors or incretin-based therapy have not completely resolved. Retinopathy and heart failure issues may be laid on a same line, in terms of increased vascular permeability. DPP-4 inhibitor trials focusing on retinopathy end points will have an answer of this safety issue. we need further direct evidence from clinical trials.

40 Thank you for your attention