Transcript Richard Aguilar 3 - National Hispanic Medical Association

Efficacy and safety of linagliptin in Hispanic/Latino
patients with type 2 diabetes: a pooled analysis
from six randomized placebo-controlled phase 3
trials
Jaime A. Davidson1, Rosemarie Lajara2, Richard Aguilar3,
Michaela Mattheus4, Maximilian von Eynatten4
1University
of Texas Southwestern Medical Center, Dallas, TX, USA; 2Diabetes
America, Plano, TX, USA; 3Diabetes Nation, Sisters, OR, USA; 4Boehringer
Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 5Boehringer
Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
18th National Hispanic Medical Association’s (NHMA) Annual Conference; 27-30 March 2014; Washington, D.C.
Author disclosure information

This study was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI)

Richard Aguilar: advisory panels and speaker’s bureau for Boehringer Ingelheim, Amylin,
Eli Lilly, Takeda, Novo Nordisk, and Janssen Pharmaceuticals; consultant for Boehringer
Ingelheim, Amylin, and Takeda

Jaime Davidson: advisory panels for Boehringer Ingelheim, AstraZeneca,
Bristol-Myers Squibb, Johnson & Johnson Lifescan, Merck-Sharp & Dohme, Roche, Allergan,
Janssen Pharmaceuticals, Roche Diagnostics; advisory panels and speaker’s bureau for
Sanofi, Novo Nordisk, Eli Lilly; speaker’s bureau for Merck-Serono and Novartis; consultant
for Animas

Rosemarie Lajara: scientific advisor for Eli Lilly and Dexcom; scientific advisor and speaker’s
bureau for Boehringer Ingelheim, Novo Nordisk, and Sanofi; speaker’s bureau for Amylin,
AstraZeneca, and Abbott

Michaela Mattheus and Maximilian von Eynatten are employees of Boehringer Ingelheim

The authors were fully responsible for all content and editorial decisions, were involved at
all stages of slide development, and have approved the final version

Medical writing assistance during the preparation of these slides was supported financially
by BIPI and provided by Ann Kerrigan of Envision Scientific Solutions

Portions of these data were previously presented at the American Association of Clinical
Endocrinologists (AACE) 22nd annual meeting, May 1-5, 2013, Phoenix, AZ, USA
Global diabetes epidemic
Diabetes caused
5.1 million deaths
in 2013. Every six
seconds a person
dies from diabetes
IDF Diabetes Atlas, 6th Edition (2013)
% of people aged ≥20 years
Proportion of adults with diagnosed diabetes: US national survey
data 2007-2009
15
11.8
10
Risk was 66%
higher among
Hispanics
7.1
5
0
Non-Hispanic whites
Hispanics

Hispanic/Latinos also at increased risk of diabetes-related complications and mortality

A combination of genetic, socioeconomic, and cultural factors underlie the increased
diabetes burden in this group

Evidence for the efficacy and safety of glucose-lowering agents in this group is scarce
National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011.
Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.
Linagliptin
 Dipeptidyl peptidase (DPP)-4 inhibitor with a unique xanthine-based structure1
– Glucagon-like peptide (GLP)-1 is an incretin hormone released from the gut in response to food
– GLP-1 mediates glucose-dependent insulin release and glucose-dependent glucagon suppression
– DPP-4 inhibitors block the degradation of GLP-1, thereby increasing endogenous GLP-1 levels
–
and lowering blood glucose level
Linagliptin is a highly selective DPP-4 inhibitor and has been shown to have the highest potency
within its class
 Linagliptin does not undergo major hepatic metabolism and is mainly excreted
unchanged via bile and gut1,2
 Once-daily dosing with no dose adjustment in renal or hepatic impairment2
 Improves glucose control with very low risk of hypoglycemia and neutral effect
on body weight2
1
2
Deacon and Holst. Expert Opin Investig Drugs. 2010;19:133-140
Tradjenta. US prescribing information. Revised June 2013
Hypothetical case-based question
 Martina is a 44-year-old mother of Mexican origin raising 2 teenagers while
working part-time. She was diagnosed with type 2 diabetes at 40 and has
been treated with metformin 500 mg BID since then. She is 5’1” and
weighs 164 lbs. (BMI 31 kg/m2). Her blood pressure is 120/80 on Lisinopril
20 mg once daily. She states that she has been busy; she does not have
time to eat properly like she should, and that the metformin sometimes
upsets her stomach. She also notes that she sometimes forgets her evening
metformin dose. She tried adding some “yerba buena’’ tea from Mexico to
help control her “sugars” and she is here today for a check-up; her HbA1c is
8.3%, essentially unchanged from her results 3 months earlier, 8.4%.
 What therapy changes would you recommend for Martina’s T2D?
A.
None, continue metformin and refer for diabetes education
B.
Increase metformin dose
C.
Add a DPP-4 inhibitor
D.
Add a sulfonylurea
E.
Add an SGLT-2 inhibitor
Safety and efficacy of linagliptin in Hispanic/Latino patients with T2D

1
Analysis approach: pooled analysis of Phase 3 RCT
Monotherapy (18 wks)
Barnett et al. Diabetes Obes Metab. 2012
2
Monotherapy (24 wks)*
Haak et al. Diabetes Obes Metab. 2012
3
Add-on to metformin (24 wks)
Taskinen et al. Diabetes Obes Metab. 2011
4
Add-on to sulfonylurea (18 wks)
Lewin et al. Clin Ther. 2012
5
Add-on to metformin + sulfonylurea (24 wks)
Owens et al. Diabet Med. 2011
6
Add-on to basal insulin ± metformin and/or
pioglitazone (24 wks)
Data from 745 patients (who selfidentified ethnicity as Hispanic or
Latino) were pooled from six
phase 3 trials in which
participants received linagliptin
(5 mg/day) or placebo as
monotherapy, or in combination
with other common oral
antidiabetes drugs (as stable
background therapy)
Yki-Järvinen et al. Diabetes Care. 2013

Primary endpoint in all studies
HbA1c change from baseline to week 18 or 24
* Patients were assigned to 1 of 6 treatment arms, including initial combination therapy. Only linagliptin monotherapy and placebo arms
were included in this analysis
Baseline characteristics
Linagliptin
Placebo
478
267
Sex, n (%)
Male
Female
213 (44.6)
265 (55.4)
117 (43.8)
150 (56.2)
Country, n (%)
Argentina
Brazil
Canada
Mexico
Peru
United States
271 (56.7)
22 (4.6)
3 (0.6)
126 (26.4)
3 (0.6)
53 (11.1)
155 (58.1)
25 (9.4)
0 (0.0)
49 (18.4)
2 (0.7)
36 (13.5)
Age, years, mean (SD)
57.4 (10.0)
56.8 (9.7)
BMI, kg/m2, mean (SD)
30.3 (5.0)
31.4 (4.6)
467
264
HbA1c, %, mean (SD)
8.25 (0.85)
8.23 (0.92)
FPG, mg/dL, mean (SD)
161.4 (46.3)
156.1 (44.4)
24 (5.1)
125 (26.8)
318 (68.1)
19 (7.2)
57 (21.6)
188 (71.2)
Patients, n (treated set)
Patients, n (full analysis set)
Time since diagnosis, n (%)
≤ 1 year
> 1 to 5 years
> 5 years
Change in HbA1c (%) over time (18-week data set)
Adjusted mean
change (95% CI):
−0.63 (−0.77, −0.48)
P<0.0001
Data based on six clinical trials. Full analysis set, last-observation carried forward. Analysis of covariance model
included continuous baseline HbA1c and fixed effects for treatment, study, and washout. The OBSMARGIN option
was used for the computation of least squares means coefficients.
Change in HbA1c (%) at 24 weeks
Data based on four clinical trials. Full analysis set, last-observation carried forward. Analysis of covariance model
included continuous baseline HbA1c and fixed effects for treatment, study, and washout. The OBSMARGIN
option was used for the computation of least squares means coefficients.
Placebo-adjusted mean change in HbA1c in different subgroups
Full analysis set, last-observation carried forward. Interactions of treatment-by-subgroup were added to the ANCOVA
and an equal weighting option was used for the computation of least squares means coefficients.
Safety (treated set)
Linagliptin (n=478) Placebo (n=267)
Any adverse event (AE), %
67.6
68.9
Investigator-defined drug related AE, %
15.1
18.7
AE leading to discontinuation, %
2.1
3.0
Serious AE, %
Fatal
Drug-related serious AE
3.6
0.2
0.4
3.0
0.0
0.4

Two patients who received linagliptin experienced a serious AE that was considered
related to the study drug (one case of bronchial hyperactivity and one case of
pancreatitis)

A single patient in the linagliptin arm died due to cardiorespiratory arrest. The cause
of death was judged unrelated to study drug

Linagliptin and placebo were both weight neutral (adjusted means [SE] at week 24:
0.37 [0.15] kg and 0.21 [0.21] kg, respectively [P=0.5454])
Hypoglycemia (treated set)
 Two patients experienced severe hypoglycemia with linagliptin (both patients were
also receiving insulin and both patients recovered)
Study conclusions
 Linagliptin in Hispanic/Latino patients was well tolerated and
achieved clinically meaningful improvements in glycemic control
− Overall efficacy results were consistent among clinically
relevant subgroups of patients
− Overall, linagliptin was not associated with an increased risk
of hypoglycemia and was weight neutral
 Together, the above observations support the use of linagliptin
as a treatment option for this highly burdened population
Hypothetical case-based question
 Martina is a 44-year-old mother of Mexican origin raising 2 teenagers while
working part-time. She was diagnosed with type 2 diabetes at 40 and has
been treated with metformin 500 mg BID since then. She is 5’1” and
weighs 164 lbs. (BMI 31 kg/m2). Her blood pressure is 120/80 on Lisinopril
20 mg once daily. She states that she has been busy; she does not have
time to eat properly like she should, and that the metformin sometimes
upsets her stomach. She also notes that she sometimes forgets her evening
metformin dose. She tried adding some “yerba buena’’ tea from Mexico to
help control her “sugars” and she is here today for a check-up; her HbA1c is
8.3%, essentially unchanged from her results 3 months earlier, 8.4%.
 What therapy changes would you recommend for Martina’s T2D?
A.
None, continue metformin and refer for diabetes education
B.
Increase metformin dose
C.
Add a DPP-4 inhibitor
D.
Add a sulfonylurea
E.
Add an SGLT-2 inhibitor
BACKUP
Study design
Assessment of eligibility
Treatment-naïve patients /
patients pre-treated with a
permitted antidiabetic agenta
2 week placebo run-in
Patients pre-treated with nonpermitted antidiabetic agents
4 weeks washout followed by
2 weeks placebo run-in
Assessment of eligibility
Randomizationb
Linagliptin 5 mg
a Permitted
Placebo
antidiabetes agents: metformin (NCT00601250), metformin + sulfonylurea (NCT00602472), sulfonylurea
(NCT00819091), basal insulin ± metformin and/or pioglitazone (NCT00954447). b NCT00798161, patients were
randomized to 1 of 6 treatment arms, but only Hispanic/Latino patients from the linagliptin and placebo arms were
pooled for these analyses
Statistical methods

Efficacy analyses were performed on the full analysis set, including all patients
with a baseline value and ≥1 on-treatment value; missing data were replaced
using last observation carried forward (LOCF)

The primary analysis used analysis of covariance (ANCOVA) to compare change
in HbA1c and FPG for the linagliptin and placebo groups, with continuous
baseline HbA1c and fixed effects for treatment, study, and washout. The FPG
model also included continuous baseline FPG. The OBSMARGIN option for the
computation of LSMEANS was used

For subgroup analyses the effect of subgroup and the interaction of treatmentby-subgroup were added to the ANCOVA. An equal weighting option for the
computation of LSMEANS was used
Antidiabetes treatment at enrollment, n (%)
Linagliptin
n=467
Placebo
n=267
No treatment
20 (4.3)
16 (6.1)
Metformin
70 (15.0)
20 (7.6)
Sulfonylurea
35 (7.5)
16 (6.1)
Alpha-glucosidase inhibitor
1 (0.2)
0 (0.0)
Insulin
29 (6.2)
26 (9.8)
216 (46.3)
73 (27.7)
Metformin & glinide
1 (0.2)
0 (0.0)
Metformin & DPP-4 inhibitor
4 (0.9)
1 (0.4)
Metformin & insulin
79 (16.9)
98 (37.1)
Glitazone & insulin
2 (0.4)
3 (1.1)
Metformin, sulfonylurea, & alpha-glucosidase inhibitor
1 (0.2)
0 (0.0)
Metformin, glitazone, & insulin
9 (1.9)
11 (4.2)
Metformin & sulfonylurea
Adjusted mean change in FPG and PPG at 24 weeks
FPG
Data based on four clinical
trials. Full analysis set, last
observation carried forward.
ANCOVA model included
continuous baseline HbA1c
and FPG, and fixed effects for
treatment, study, and washout
PPG
Data based on a subset of
patients of one clinical trial
Pancreatitis

T2D increases the risk of acute pancreatitis

Postmarketing reports of acute pancreatitis, including fatal pancreatitis, have been reported
for DPP-4 inhibitors. The Warnings and Precautions section of DPP-4 inhibitor drug labels
contain warnings about the risk of acute pancreatitis

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year
exposure while being treated with linagliptin, compared with 3.7 cases per 10,000 patient year
exposure while being treated with comparator (placebo and active comparator, sulfonylurea).
Three additional cases of pancreatitis were reported following the last administered dose of
linagliptin (US prescribing information)

An observational study demonstrated a significantly increased risk of acute pancreatitis with
GLP-1 based therapies. However, data from randomized controlled trials and meta-analyses
have not shown any increase in the incidence of acute pancreatitis with DPP-4 inhibitors

These results must be confirmed by ongoing large cardiovascular outcomes trials
– No increased risk of pancreatitis or pancreatic cancer in two recently completed DPP-4
inhibitor trials [Scirica BM, et al NEJM 2013; White WB, et al. NEJM. 2013]

An FDA review is ongoing. For now, ‘’FDA believes that the current labeling for approved GLP-1
based therapies reflects the extent of our understanding of the safety signals at this point in
time’’ (Lisa Kubaska, FDA, CDER; http://www.medscape.com/viewarticle/808830)

For a comprehensive review and discussion of the evidence see: Scheen A. Expert Opinion on
Drug Safety, 2013