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Analyses of Results FromCardiovascular Safety Trials WithDPP-4 Inhibitors: CardiovascularOutcomes, Predefined SafetyOutcomes, andPooledAnalysis andMeta-analysisDiabetes Care 2016;39(Suppl. 2):S196–S204 | DOI: 10.2337/dcS15-3024
The U.S. Food and Drug Administration requires that the cardiovascular (CV)safety of all new drugs for diabetes be demonstrated through pooled analyses ofphase III studies or specifically designed trials. This requirement prompted severalplacebo-controlled, noninferiority CV safety trials in high-risk patients; to date, allcompleted trials showed that dipeptidyl peptidase (DPP)-4 inhibitors do notincrease or reduce the risk of major CV events. These results apparently contrastwith those of pooled analyses and meta-analyses of previous, smaller trials withmetabolic end points, which had suggested a reduction of risk. However, thedesign of CV trials, which were required to demonstrate safety, is not adequate(for duration, management of concurrent therapies, etc.) for the assessment ofpotential therapeutic benefits. In addition, CV safety trials enroll patients at highrisk of CV events, who are different from those included in earlier trials withmetabolic end points. Differences in characteristics of patients enrolled probablyaccount for most of the discrepancy in CV outcomes between CV safety studiesand earlier trials. The availability of several large-scale trials with longer durationprovides the unique opportunity for assessment of the safety of DPP-4 inhibitorsnot only with respect to major CV events but also with reference to other safetyissues. For example, CV safety trials can be a source of information for pancreatitis,cancer, or hypoglycemia.
In December 2008, the U.S. Food and Drug Administration (FDA) published guidanceprompting pooled analyses and meta-analyses of cardiovascular (CV) events (some-times with post hoc adjudication) observed in trials with metabolic outcomes (1). Ashift of emphasis occurred from short-term, HbA1c-centered phase II–III trials in“healthy” patients with type 2 diabetes to CV safety studies in a more vulnerablepopulation (2). Results from the first trials according to the FDA guidance werepublished in 2013: the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Out-comes Recorded in Patients with Diabetes Mellitus–Thrombolysis in MyocardialInfarction 53) and the EXAMINE (Examination of Cardiovascular Outcomes withAlogliptin versus Standard of Care) trials with the dipeptidyl peptidase (DPP)-4inhibitors saxagliptin and alogliptin, respectively (3,4). The publication of theresults of TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) (5)with sitagliptin, the presentation of the ELIXA [Evaluation of Lixisenatide in Acute
1Diabetology, Careggi Hospital, Florence, Italy2Internal Medicine, Hadassah Medical Center,Jerusalem, Israel3Endocrinology, University of Padua, Padua, Italy
Corresponding author: Edoardo Mannucci,[email protected].
This publication is based on the presentationsat the 5th World Congress on Controversies toConsensus in Diabetes, Obesity and Hyperten-sion (CODHy). The Congress and the publicationof this supplement were made possible inpart by unrestricted educational grants fromAstraZeneca.
© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.
Edoardo Mannucci,1 Ofri Mosenzon,2 and
Angelo Avogaro3
S196 Diabetes Care Volume 39, Supplement 2, August 2016
RECEN
TOUTC
OMESTUDIES
Coronary Syndrome] trial with theglucagon-like peptide 1 (GLP-1) receptoragonist lixisenatide, and the publicationof the BI 10773 (Empagliflozin) Cardio-vascular Outcome Event Trial in Type 2Diabetes Mellitus Patients (EMPA-REGOUTCOME) trial with the sodium–
glucose cotransporter 2 (SGLT2) inhibi-tor empagliflozin (6) followed in 2015.This wave of information on CV safetyof new antidiabetes drugs (ADD) is onlythe beginning (Fig. 1 and Table 1). In-terpretation of the “mountains” ofnew information provided by theselarge-scale studies presents new chal-lenges for the treating physician, the sci-entific world, the pharmaceutical industry,and eventually patients with diabetesthemselves (7).Unexpectedly, in the case of DPP-4
inhibitors the results of earlier trialshad suggested a reduction in the inci-dence of major CV events (8–10), whichwas not confirmed by the specifically
designed CV studies that followed (3–5). The reasons for this discrepancy arecontroversial and will be discussed inthe article.
Primary and Secondary Outcomes: CVSafety Outcomes
CV Outcome Versus CV Safety Trials
The intensification of diabetes treat-ment appears to improve CV outcomesonly in patients with recent-onset dia-betes and after a prolonged latency(11,12). The FDA guidance requires therecruitment of patients at high CV risk,often with prolonged diabetes duration,advanced age, and renal failure (1), whoare the least likely to benefit from anyintervention regarding CV risk factors. Inaddition, most of those patients alreadyreceive multiple treatments for CV dis-ease prevention. In the Steno-2 trial, theuse of statins at the end of the interven-tion in the intensive versus conventionaltreatment arms was 0 vs. 3% at baseline
and 85 vs. 22% at the end of the inter-vention stage of the trial, respectively(13). In SAVOR-TIMI 53, EXAMINE, andTECOS, statins were used at baseline by78.3, 90.4, and 79.9% of the trial pop-ulation, respectively (3–5). The resid-ual CV risk left, in spite of statintreatment, was smaller, and thereforeany CV superiority was more difficultto prove.
The FDA requirements for new ADDdevelopment programs were to excludean unacceptable increased relative CVrisk with an upper limit of 95% CI of,1.3 (1). For this reason, trials are de-signed to show noninferiority betweentreatment arms with respect to CVevents while maintaining similar glycemiccontrol (14): investigators are free tomodify glucose-lowering medicationsother than the experimental drug in or-der to maintain good glycemic controlin both treatment groups, and in fact,between-group differences in HbA1c
Figure 1—Timing of CV safety trials with drugs for type 2 diabetes.
care.diabetesjournals.org Mannucci, Mosenzon, and Avogaro S197
Table
1—CompletedandongoingCV
safety
trials
withADDs
GroupofADD
andtrial
Tested
drug
(comparator
ifnotplacebo)
Patien
ts(N
)MainCVinclusion
criteria
HbA1cinclusion
criteria(%
)BackgroundADDs
Start–actual/planned
completion,m
ean
durationoffollow-up
Prim
aryoutcome
(number
oftarget
even
ts)
DPP
-4inhibitors
SAVOR-TIM
I53
Saxagliptin
16,492
$50
y.o+established
CVDor
$55
(M)o
r$60
(F)y.o+CVDrisk
factors
6.5–12
duringthe
last6months
Allother
than
incretin
based
5/201
0–5/201
3,2.1
years
CVdeath,nonfatalM
I,nonfatalstroke
(1,040
)
EXAMINE
Alogliptin
5,38
0ACSwithin
15–90
days
6.5–11
Allother
than
incretin
based
10/2009
–6/20
13,
1.5years
CVdeath,nonfatalM
I,nonfatalstroke
(550
)TECOS
Sitagliptin
14,724
PreexistingCVD
6.5–8
Mono-ordualtherapy:
metform
in,SU,p
ioglitazone,
insulin
12/2008
–6/20
13,
3.0years
CVdeath,n
onfatalM
Iorstroke,
hospitalizationforUAP(1,300
)
CAROLINA
Linagliptin
(glim
epride)
6,00
0CVDhistory,en
d-organ
dam
age,
$70
y.o,o
rCVDrisk
factors
6.5–8.5or6.5–7.5if
withSU
/glinides
Drugnaıve
ormono-ordual
therapy:metform
in,SU,A
GI
10/201
0–9/20
18
CVdeath,n
onfatalM
Iorstroke,
hospitalizationforUAP(631
)CARMELINA
Linagliptin
8,30
0Albuminuria+CVDorR
F+specific
albuminuria
6.5–
10.0
Allother
than
incretin
based
andSG
LT2Inh
7/201
3–1/201
8CVdeath,n
onfatalM
Iorstroke,
hospitalizationforUAP
OMNEO
N01
8MK31
02(once
weekly)
4,00
0PreexistingCVD
6.5–10
or7–10
(insulin,SU,glinides)
Allother
than
incretin
based
10/201
2–10
/201
7CVdeath,n
onfatalM
Iorstroke,
hospitalizationforUAP
GLP-1
receptor
agonists
ELIXA
Lixisenatide
6,06
8ACS,18
0days
5.5–
11.0
Allother
than
incretin
based
6/201
0–2/201
5,
25.7
months
CVdeath,n
onfatalM
Iorstroke,
hospitalizationforUAP(844
)LEADER
Liraglutide
9,34
0$50
y.o+priorCVD
even
ts/PAD/CRF/
CHFor
$60
y.o+CVDrisk
factors
.7.0
Allother
than
incretin
based
9/201
0–10
/201
5,all
patients
atleast3.5years
CVdeath,n
onfatalM
I,or
nonfatalstroke
(611
)
SUSTAIN
6SemaglutideQW
3,29
7$50
y.o+priorCVDor
$60
y.o+subclinicalCVD
.7.0
Drugnaıve
ormono-ordual
oraltherapy,long-actingor
premixinsulin
2/201
3–1/201
6,upto
148weeks
CVdeath,nonfatalM
I,ornonfatalstroke
EXSC
ELExen
atideQW
14,000
none
6.5–10
0–3oralA
DDs(includingDPP
-4Inh),insulin
+0–
2oralA
DDs
6/201
0–1/201
8,upto
7.5years
CVdeath,n
onfatalM
I,or
nonfatalstroke
FREEDOM
CVO
ITCA65
0exen
atide
Q3–6months
4,00
0History
ofCAD,cerebrovascular
disease,o
rPA
D.6.5
Allother
than
incretin
based
3/201
3–7/201
8,2
years
CVdeath,n
onfatalM
Iorstroke,
hospitalizationforUAP
REW
IND
DulaglutideQW
9,62
2$50
y.o+established
CVD,$55
y.o+subclinicalvasculardisease,
or$60
y.o+$2CVDrisk
factors
#9.5
0–2oralA
DDs6
basal
insulin
6GLP-1
RA
7/201
1–4/201
9,upto
8years(expectedmean
of6.5years)
CVdeath,nonfatalM
I,ornonfatalstroke
AlbiglutideCV
safety
trial
AlbiglutideQW
9,40
0$40
y.o+established
CVD
.7
Allother
than
GLP-1
RA
7/201
5–5/201
9CVdeath,n
onfatalM
I,or
nonfatalstroke
SGLT2inhibitors
EMPA
-REG
OUTC
OME
Empagliflozin
(2[10mg,25
mg]:1)
7,03
4.18
y.o,established
CVD
7–10
(7–9ifADD
naıve)
ADD-naıve
patients,allADDs,
ortheircombination
7/201
0–4/201
5CVdeath,nonfatalM
I,orn
onfatal
stroke
($69
1)
CANVAS
Can
agliflozin
(2[100
mg,30
0mg]:1)
4,40
7.30
y.owithestablished
CVDor
.50
y.oand$2CVrisk
factors
7–10
.5AllADDs
12/200
9–6/20
17
CVdeath,nonfatalM
I,orn
onfatal
stroke
CANVAS-R
Can
agliflozin
5,86
5Established
vascularcomplication
or$2CVrisk
factors
7–10
.5ADD-naıve
patients,allADDs,
ortheircombination
1/201
4–1/201
7Number
ofpatients
with
progressionofalbuminuria
Con
tinu
edon
p.S199
S198 CV Safety Trials With DPP-4 Inhibitors Diabetes Care Volume 39, Supplement 2, August 2016
are small (3–5). Conversely, in superioritytrials the study is designed to highlightthe benefits of drug treatment: forexample, in lipid trials additional lipid-lowering therapies could not be modifiedduring the study, creating a sizable differ-ence in the surrogate marker (e.g., LDLcholesterol) that would hopefully lead toimproved CV outcome.
The FDA required the CV safety trialsto extend for a minimum of 2 years. Alonger trial duration increases the riskfor missing data (6), possibly affectingthe magnitude and even the directionof results (15). The short duration ofCV trials is also driven by market issues,such as patent duration, the extravagantcost of large clinical trials (the three cur-rently available trials with DPP-4 inhibi-tors alone, taken together, accumulated.85,000 patient-years of follow-up),and competition between pharmaceuti-cal companies.
In summary, these trials should becalled “CV safety trials” and not “CV out-come trials” owing to the trial goals anddesign, the patient population chosen,the minimization of glycemic differencesbetween treatment arms, and the rela-tively short duration. The recent findingof a significant benefit of empagliflozinin a similarly designed CV safety trial(6) was completely unexpected; despitethis unpredictable result, the design ofthose trials remains inadequate for ex-ploring treatment benefits.
Choosing the Primary Outcome: MACE
Versus MACE PlusdIs There a Difference?
The FDA guidance specifies that CV endpoints should be prospectively andblindly adjudicated by an independentcommittee in all trials of clinical devel-opment of new drugs. The CV end pointsthat must be adjudicated are CVmortality,myocardial infarction (MI), and stroke,combined in the composite end point, ma-jor adverse CV events (MACEs). Other CVend points specifically mentioned in theFDA guidance that can also be adjudicatedare hospitalization for acute coronarysyndrome (ACS), urgent revascularizationprocedures, “and possibly other end-points” (1). Some of the companies havechosen to add hospitalization for unstableangina, urgent coronary revascularization,and/or hospitalization for heart failure(hHF) to the definition of MACE (Table 1),although these end points are less “clear-cut” and more difficult to define; this
Table
1—Continued
GroupofADD
andtrial
Tested
drug
(comparator
ifnotplacebo)
Patien
ts(N
)MainCVinclusion
criteria
HbA1cinclusion
criteria(%
)BackgroundADDs
Start–actual/planned
completion,m
ean
durationoffollow-up
Prim
aryoutcome
(number
oftarget
even
ts)
CRED
ENCE
Can
agliflozin
3,62
7.30
y.o,urinaryACR30
0–2,00
0mg/g,eG
FR90
–30
mL/min/BSA
.Stab
lemaxim
um
tolerateddose
ofACEI
orARB
6.5–12
AllADDs
2/201
4–1/202
0ESRD,d
oublingofserum
creatinine,renalorCVdeath
DEC
LARE-TIMI
58Dapagliflozin
17,150
$50
y.o+established
CVDor
$55
(M)o
r$60
(F)y.o+CVDrisk
factors
6.5–12
AllADDsother
than
pioglitazone
4/201
3–4/201
9CVdeath,nonfatalM
I,ornonfatalstroke
Ertugliflozin
CVOT
Ertugliflozin
[2(5
mg,15
mg):1]
3,90
0.40
y.owithestablished
CVD
7–10
.5Naıve
orallA
DDs(specific
substudies)
11/201
3–6/20
20
CVdeath,nonfatalM
I,ornonfatalstroke
Other
drugs
DEV
OTE
Insulin
degludec
vs.
insulin
glargine
7,63
7$50
y.o+established
CVDor
renaldisease
or$60
y.o+CVD
risk
factors
$7or,7if.20
unitsinsulin/day
Oneormore
oralorinjectab
leADDs
10/201
3–12
/201
6CVdeath,nonfatalM
I,ornonfatalstroke
TOSC
A.IT
Pioglitazonevs.SU
(open
label)
3,37
150
–75
y.o,.
2years’diabetes
duration
7–9
.2months,
metform
in.2g
9/200
8–12
//20
18All-cause
mortality,nonfatalM
I,ornonfatalstroke,unplanned
coronaryrevascularization
ACEI,A
CEinhibitor;ACR,albumin-to-creatinineratio;AGI,a-glucosidaseinhibitors;ARB,angiotensinreceptorblocker;CAD,coronaryartery
disease;CANVAS,CANaglifl
ozincardioVascularAssessm
entStudy;
CANVAS-R,A
StudyoftheEffectsofC
anaglifl
ozinonRen
alEndpointsinAdultParticipan
tsWithType2Diabetes
Mellitus;CARMELINA,CArdiovascularandRen
alMicrovascularoutcomEstudywithLINAgliptinin
patientswithtype2diabetes
mellitus;CAROLINA,CARdiovascularOutcomeStudyofLINAgliptinVersusGlim
epirideinPatien
tswithType2Diabetes;C
HF,congestiveheartfailure;C
RED
ENCE,Canagliflozinand
Ren
alEven
tsin
Diabetes
withEstablished
Nep
hropathyClinicalEvaluation;CRF,chronicrenalfailure;CVD,CVdisease;DEC
LARE-TIMI58
,DapagliflozinEffect
onCardiovascuLA
REven
ts;DEV
OTE,D
egludec
CardiovascularOutcomes
Trial;eG
FR,estim
ated
glomerularfiltrationrate;ESR
D,end-stage
renaldisease;EXSCEL,EXe
natideStudyofC
ardiovascularEven
tLowering;F,female;Inh,inhibitor;LEADER
,Liraglutide
Effect
andActionin
Diabetes:EvaluationofcardiovascularoutcomeResultsd
ALongTerm
Evaluation;M,m
ale;
MI,myocardialinfarction;PA
D,p
eripheralarterialdisease;RA,receptoragonist;REW
IND,
ResearchingCardiovascularEven
tsWithaWeeklyINcretin
inDiabetes;R
F,renalfailure;TOSC
A.IT,Thiazolidined
iones
orSulphonylureas
andCardiovascularAcciden
tsInterven
tionTrial;UAP,
unstab
leangina
pectoris;y.o,years
old.
care.diabetesjournals.org Mannucci, Mosenzon, and Avogaro S199
increases overall event rates, thus reducingrequired sample size, but it limits the re-liability of results, augmenting backgroundnoise and biasing results in favor of “nodifference” between treatment arms (16).
Choosing the Trial Population and Its
Effect on Study Conduct and Results
In the FDA 2008 guidance (1), patientswith “higher CV risk” to be included inCV safety analysis were defined as “pa-tients with relatively advanced disease,elderly patients, and patients with somedegree of renal impairment.” Pharma-ceutical companies and researchers fol-lowed these instructions yet chosedifferent inclusion and exclusion criteriain different CV safety trials (Table 1).Patients in EXAMINE and ELIXA (4) hadexperienced recent ACS, whereas thosein TECOS had previous CV disease (5).Conversely, in the SAVOR-TIMI 53 trial21.7% of enrolled patients had no priorCV events but showed at least two riskfactors (17). The selection of a higher-risk population increases CV event rate,thus reducing the sample size and/orthe duration of the trial. For example,if the expected annual event rate is 3%instead of 2%, with a 5-year follow-up,the sample needed to prove CV safetyaccording to the FDA requirement is5,400 patients instead of 8,000 (16).However, the downside of usingsuch a specific high–CV risk populationis the external validity of trial results.Alogliptin was shown to be safe in pa-tients with ACS during the last 90 days(4), but the inference of those results topatients with stable CV disease, or withhigh CV risk without prior events is ofuncertain validity.
Other CV Safety Issues: hHF
Unexpectedly, in the SAVOR-TIMI 53 trial,saxagliptin was associated with an in-creased rate of hHF (3.5 vs. 2.8%; hazardratio [HR] 1.27 [95% CI 1.07–1.51]; P =0.007) (3,18). This phenomenon oc-curred during the first year, with nosignificant difference thereafter. InEXAMINE, in which hHF was a compo-nent of a prespecified exploratory ex-tended MACE end point, there was nostatistically significant increase in therisk of first event of hHF with alogliptinversus placebo (3.1 vs. 2.9%; 1.07 [0.79–1.46]) (19). However, these results arestill not sufficient to exclude a small in-crease in risk (20). In TECOS, in whichhHF was a secondary outcome, the rate
of hHF in the sitagliptin arm (228 [3.1%])was not statistically or numerically differ-ent from that in the placebo arm (229[3.1%]) (HR 1.00 [95% CI 0.83–1.2] P =0.98) (5). The results of saxagliptin onhHF in the SAVOR-TIMI 53 trial couldbe a play of chance, a specific effect ofthat drug, or an effect of the class ofdrugs on specific (and still unidentified)subpopulations of patients. In fact, theTECOS and SAVOR-TIMI 53 populations,although similar in age (66 vs. 65.1 years)and diabetes duration (9.4 vs. 10.3years), differ in other features: for exam-ple, inclusion of patients without priorCV disease (0 vs. 21.6%), HbA1c (7.2 vs.8.0%), ethnicity (whites 67.9 vs. 75.3%),renal impairment (estimated glomerularfiltration rate ,50 mL/min [9.3 vs.15.6%]), and/or use of insulin at baseline(23.2 vs. 41.4%).
None of the major CV safety trialswith DPP-4 inhibitors were specificallydesigned to assess the effect of thesedrugs on heart failure, which was a sec-ondary end point or part of a compositeend point. This is a typical case inwhich a meta-analysis can add relevantinformation (see below).
Other Predefined Safety Outcomes:Hypoglycemia, Weight Changes,Cancer, Pancreatitis, and FracturesCommon adverse events (AEs) can beeasily identified in phase II/III trials; con-versely, rare AEs can be missed by thosestudies due to insufficient sample sizeand/or duration of observation (21). Inaddition, most early trials with diabetesdrugs include only relatively healthypopulations, who may be at lower riskof AEs (22). Large-scale trials designedfor CV end points may yield importantresults for other safety issues.
Hypoglycemia
Targeting intensive glycemic controlsignificantly increases the risk of severehypoglycemia (23), which may increaseCV disease risk (24).
However, there is a consistent het-erogeneity in the incidence of severehypoglycemia among trials, which couldbe attributable to various factors suchas frailty, age, duration of disease,HbA1c targets, and therapeutic strategies.Severe hypoglycemia tends to be posi-tively associated with baseline HbA1c;the higher the starting HbA1c value ofthe patient, the higher the event rate ofsevere hypoglycemia.
Notably, incretin-based therapy shouldbe void of hypoglycemic risk owing to theability of these drugs to stimulate insulinsecretionwith a glucose-dependent effect.However, in SAVOR-TIMI 53, episodes ofsevere hypoglycemia were significantlymore frequent in the saxagliptin arm(2.1 vs. 1.7%, P = 0.047) (3), whereas anyhypoglycemic events were more frequentonly in patients with a baseline HbA1c,7%. Almost all episodes were observedin patients treated with sulfonylureas(SUs), especially in those with HbA1c,7%. In EXAMINE (4) and TECOS (5), noincrease in rates of hypoglycemia wasreported with alogliptin and sitagliptin,respectively.
Weight Changes
The observed adherence to oral hypo-glycemic drugs in patients with type 2diabetes varies from 48.5 to 72.5%(25). Drug-induced weight gain is awell-known predictor of nonadherence(25). In addition, the increase in bodyweight induced by some glucose-loweringdrugs may have an adverse effect onquality of life and on some CV risk factors(26). Weight gain induced by treatmentintensification is influenced by theamount of HbA1c reduction, backgroundtherapy, and treatment strategy. Wheninsulin is added to backgroundmetforminand SUs,weight gain is almost 3 kg; whenTZDs are added the observed weightgain is .4 kg (27). In a meta-analysis of40 randomized controlled trials, the useof secretagogues (SUs plus meglitinides)added to background metformin was as-sociatedwith aweight gain of 1.9 kg (28).
Conversely, the use of DPP-4 inhibi-tors is not associated with weight gain:in SAVOR-TIMI 53, EXAMINE, and TECOS,no significant weight changes were ob-served. The main reasons for this may berelated to lesser degrees of serious hypo-glycemic events, to a delay in gastric emp-tying, and/or toa senseof satiety secondaryto a direct hypothalamic effect (29).
Cancer and Pancreatitis
Type 2 diabetes may be associated withincreased risk of malignancies (30);in addition, it is possible that someglucose-lowering drugs increase the riskfor all cancers or specific forms of cancer.Such a concern has been raised also forGLP-1 receptor agonists and DPP-4 in-hibitors. GLP-1 receptor activation di-rectly promotes cell proliferation andenhances cell survival in several tissues
S200 CV Safety Trials With DPP-4 Inhibitors Diabetes Care Volume 39, Supplement 2, August 2016
(31). It has been observed that GLP-1–based therapies can induce histologicalchanges suggestive of pancreatic dam-age in rodents (32). An analysis of AEsreported to the FDA suggested that GLP-1receptor agonists and DPP-4 inhibitorscould be associated with pancreatitisand pancreatic cancer (33), but that re-sult could have been heavily affected byunderreporting and reporting bias. Infact, cohort studies failed to detect anysignal of risk either for pancreatitis or forpancreatic cancer (34).Reassuring findings are also available
from SAVOR-TIMI 53, EXAMINE, andTECOS, which did not report any signifi-cant increase in risk of either pancreatitisor pancreatic cancer, although a modesttrend toward an increased incidence ofpancreatitis was reported in TECOS (3–5).Finally, it has been observed in pre-
clinical studies that the incidence ofthyroid C-cell tumors is increased inrodents treated with GLP-1 analogs(35). Notably, in mouse and rat thyroidgland C cells, GLP-1 receptor densitiesare much higher than in humans andprimates (36). The available CV safetytrials confirm the safety of DPP-4 inhibitorsin this respect; in fact, no case of thyroidmedullary carcinoma was reported inSAVOR-TIMI 53, EXAMINE, or TECOS (3–5).
Pooled Analyses and Meta-analyses:Combining CV Outcome Studies andTrials With Other OutcomesMeta-analyses are typically performedwhen there is a multiplicity of availablestudies that either provide inconsistentresults or lack adequate statisticalpower because of insufficient samplesize. CV trials performed with moleculesof the same class, which can be assumedto have a similar profile of action on CVrisk, can be combined in a meta-analysis,thus increasing their power to detecteven small differences between treatmentgroups. However, it is unlikely that such ameta-analysis would provide any relevant
additional information on the effect ofDPP-4 inhibitors on major CV events, inwhich the sample size was calculated tohave an adequate power to explore theprincipal end point (i.e., MACE).
On the other hand, a meta-analysisof CV trials could be useful for the ex-ploration of secondary end points or ofindividual components of the principalend points, for which each trial is under-powered. A typical example is hHF,which was significantly increased withsaxagliptin in the SAVOR-TIMI 53 trial(3). In the CV trial with alogliptin, thedifference between treatment groupsfor hHF was not statistically significant,but this could have been the conse-quence of a smaller overall number ofevents, with a lower statistical power(19); on the other hand, no such effectwas detected with sitagliptin in TECOS(5). A meta-analysis of all available trialswith DPP-4 inhibitors (including thosewith a non-CV end point, but not TECOS,whichwas unavailable at the time) con-firmed an increased risk for heart fail-ure (37). However, when trials with anon-CV end point (i.e., phase II–IIIstudies) were considered separately,no signal of risk was detected, with nosignificant difference across molecules(37). This result is consistent with thehypothesis that the increased risk ob-served with saxagliptin in SAVOR-TIMI53 may have been related to the charac-teristics of the patients enrolled. In thecase of heart failure with DPP-4 inhibi-tors, the number of available large-scaletrials is insufficient to draw definitiveconclusions through meta-analysis. Fur-ther insight may be provided by a pooledanalysis of patient-level data from the CVsafety trials (SAVOR-TIMI 53, EXAMINE,and TECOS), exploring the effect ofDPP-4 inhibitor treatment on differentsubgroups of patients categorized fortheir baseline characteristics, with themolecule used as a categorical covariate.However, such an analysis would pose
many technical and organizational chal-lenges, considering differences in proto-cols across studies.
Information on CV events provided bymeta-analyses and pooled analyses isparticularly relevant when no CV out-come study is yet available. Under cur-rent regulations, most new drugs aremarketed on the basis of a clinical pro-gram composed of studies with meta-bolic end points, with a large-scale,noninferiority CV study performed onlyafter marketing, to confirm the safety ofthe drug. While long-term studies areongoing, combined analyses of shorter-term trials can provide some insights onpossible CV actions of new treatments.In the case of DPP-4 inhibitors, pooledanalyses of CV events in randomizedphase II–III studies have been publishedfor all molecules (38–42); all these anal-yses yielded risk estimates,1, althoughdifferences from comparator groupswere not statistically significant (Table2). Data from different analyses arenot comparable, because the definitionof events and the trial entry criteria areheterogeneous. In addition, in some ofthe analyses CV events had not beenadjudicated (38).
Pooled analyses, which combinepatient-level data, can be performed onlyby companies that hold the property ofdata collected during clinical developmentof new drugs. Independent researchers,without access to patient-level data, canonly pool trial-level results from studiesin a post hoc meta-analysis, which allowsthe combination of trials with differentdrugs from the same class, estimating anoverall class effect. Since some of the trialssubmitted to regulatory authorities remainunpublished, it is important that all dis-closed trials, including those not publishedin medical journals, are included in themeta-analysis. Notably, in such analysisonly the crude number of events is avail-able, whereas time to event remains un-known; this produces an imprecision in risk
Table 2—Pooled analyses of major CV events based on patient-level data from phase II–III trials with DPP-4 inhibitors
Reference Drug # Studies# Patients
(drug/comparator)# Events
(drug/comparator) AdjudicatedRisk estimate(HR [95% CI])
Engel et al. (38), 2013 Sitagliptin 25 7,726/6,885 40/38 No 0.83 [0.53–1.30]
Iqbal et al. (39), 2014 Saxagliptin 20 5,701/3,455 43/31 Yes 0.75 [0.46–1.21]
Rosenstock et al. (40), 2015 Linagliptin 19 5,847/3,612 60/62 Yes 0.78 [0.55–1.12]
Schweizer et al. (41), 2010 Vildagliptin 25 7,509/6,061 81/91 Yes 0.84 [0.62–1.14]
White et al. (4), 2013 Alogliptin 11 4,162/1,855 13/10 Yes 0.63 [0.00–1.41]
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estimates,which is negligible in short-termstudies but which can be relevant if theduration of treatment is very long. Thelack of adjudication of events and the shortduration of treatment are also major limi-tations for post hoc meta-analyses. Fur-thermore, it is possible that some trialswith unfavorable results for experimentaldrugs remain undisclosed or that CV out-comes are only partially reported, thusproducing a systematic bias. All thesemethodological issues suggest cautionin the interpretation of results frompost hoc meta-analyses. However, it isnotable that all post hoc analyses (8–10,43) reported a significant reductionin the incidence of major CV events,with risk estimates ranging from 0.36to 0.71 (Table 3); the only exceptionis a meta-analysis that included twoCV studies (SAVOR-TIMI 53 and EXAMINE)along with earlier trials, with theformer largely driving the overall result(44). One of the largest of those meta-analyses (8) also reported a significantreduction of all-cause mortalitydtheonly end point unaffected by eventadjudication.
Why Are the Results of PooledAnalyses and Meta-analyses of EarlyTrials Different From Those of StudiesWith a CV End Point?The difference in results betweenpooled analyses and meta-analyses ofearly studies, on one side, and CV trials,on the other, is quite substantial. Themethodological limitation of pooledanalyses and meta-analyses summa-rized above, although relevant, doesnot seem sufficient for inducing such alarge distortion. It has been suggestedthat differences in results could be de-termined by the duration of trials, withDPP-4 inhibitors producing a benefitin the short-term, which is lost withlonger-term treatment (45). This viewis not confirmed by CV trials, in whichno evidence of a temporary benefit ispresent in the first few months afterrandomization; in addition, a signifi-cant reduction of major CV events isobserved in non–CV outcome trialswith DPP-4 inhibitors with duration oftreatment .52 weeks (46). Anotherpossible explanation for the observeddifference is the diversity in the charac-teristics of enrolled patients. Subjectsrecruited in CV studies, who areselected for high CV risk, are typically
older with longer duration of diabetes,greater impairment of renal function,higher comorbidity, and higher numberof concomitant treatments than thoseparticipating in earlier trials with meta-bolic end points. It is possible that DPP-4inhibitors produce a CV benefit in rela-tively low-risk patients, whereas theyare neutral in subjects at very high riskor with prior CV events.
The enrollment of subjects at high CVrisk is a practical strategy for yielding ahigh number of events with a limitedsample size and duration of observation.It is also reasonable to verify safety inthose patients who are at greatest riskof adverse outcomes. On the otherhand, patients enrolled in CV trialswith DPP-4 inhibitors are scarcely/hardly representative of those actuallyreceiving a prescription of those drugsin clinical practice.
ConclusionsThe results of the first CV trials withDPP-4 inhibitors (3–5) did not meet theexpectations of many clinicians, whohoped for a demonstration of a CV bene-fit, as suggested by meta-analyses of pre-vious, shorter-term studies (8–10,43).However, CV trials provided exactly theresult that they had been designed for:noninferiority versus placebo. CV trialsin diabetes simply demonstrate thatdrugs do not catastrophically increaseCV risk. The unexpected finding of a sig-nificantly beneficial effect of the activedrug, as with empagliflozin (6), giventhe design of those studies, is almost acase of serendipity.
The explanation of differences in CVoutcomes between earlier studies andCV safety trials is complex. Our opinionis that methodological issues are not
sufficient to account for such differ-ence and that themore favorable resultof an earlier trial is the effect of theenrollment of younger, healthier pa-tients with fewer complications, with alower proportion of subjects receivingother medications for the reduction ofCV risk. However, available data arenot sufficient to confirm such a hypoth-esis, which could be proven onlythrough a specifically designed CV out-come trial in patients with diabetes atlow riskdwhich is very unlikely to beever performed.
CV trials provide a huge amount ofsafety data. Large-scale trials of appropri-ate duration, although designed formajorCV events, yield relevant information onother safety end points (for example,withDPP-4 inhibitors, pancreatitis). Exposureof several thousand patient-years to anexperimental drug also warrants the de-tection of relatively infrequent AEs. How-ever, in this latter case, unless results areconsistent across trials with molecules ofthe same class, the interpretation of re-sults can be overwhelmingly difficult. Thisis what happened for the unexpected(and problematic) finding of increasedhHF with saxagliptin in SAVOR-TIMI 53.
Although the results of CV safetystudies could underestimate the actualbenefit of DPP-4 inhibitors on CVoutcomes, a recent study with a similardesign did show a significant reductionof CV morbidity and mortality with theSGLT2 inhibitor empagliflozin (6). Al-though the characteristics of patientsenrolled in this latter trial (5) are notexactly the same as in trials with DPP-4inhibitors (3–5), the fact that results withempagliflozin in patients with prior CVevents were much improved comparedwith than those observedwith saxagliptin,
Table 3—Post hoc meta-analyses of major CV events based on trial-level data withDPP-4 inhibitors
Reference # Studies# Patients
(drug/comp)# Events
(drug/comp)Risk estimate(HR [95% CI])
Not including CV safety trialsMonami et al. (37), 2014 63 23,562/16,509 263/232 0.71 (0.59–0.86)Patil et al. (43), 2012 18 4,998/3,546 45/56 0.48 (0.61–0.75)Wu et al. (9), 2014 8a 7,778 6/18a 0.36 (0.15–0.85)a
50b 10/12b 0.54 (0.25–1.19)b
Zhang et al. (10), 2014 12 5,505/5,477 25/43c 0.53 (0.32–0.87)c
Including CV safety trialsAgarwal et al. (44), 2014 80 40,749/32,592 NR 0.95 (0.86–1.04)
NR, not reported. aVersus metformin, monotherapy; bversus placebo, add-on to metformin;cversus SUs.
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alogliptin, or sitagliptin should be clearlyrecognized.Inevitably, information on safety is
excellent for newer agents but largelymissing for older drugs. This creates aninformation disequilibrium, for whichsafety issues have a greater probabilityof being raised for newer drugs, whilethey may remain unnoticed, or under-estimated, for older agents. Anotherproblem with the current approach isthat populations enrolled in CV trialscan be quite different from those that,on average, receive a prescription for adrug in the real-world. This can lead toan overestimation of safety issues withnewer agents.Finally, the most important drawback
of CV safety trials is their excruciatinglyhigh cost, which has an impact on theprice, and therefore the widespreadavailability, of newer agents. Further-more, pharmaceutical companies, beingforced to invest hugebudgets onplacebo-controlled CV trials, tend to shrink theirdevelopment programs on the side ofphase III active-comparator controlled tri-als, which are probably more useful forclinical decision making and which couldbe more cost-efficient.The decision of the FDA to require
safety data from large-scale, specificallydesigned trials had the merit of focusingthe attention of the scientific com-munity on the relevance of CV safetyof glucose-lowering drugs. At the sametime, the unintended negative conse-quences of this decision may outweighthe benefits. As an alternative, CV safetycouldbeassessed throughpooledanalysesof patient-level data from wider programsof active comparator-controlled phase IIItrials of appropriate duration, providedthat a relevant fraction of patients athigh CV risk is included and that MACEsare appropriately adjudicated. This wouldprobably require a safety criterion lessstringent than the present 1.3 for upperconfidence limit (1); however, additionalreal-world data could be obtained throughspecific programs for postmarketing sur-veillance, thus avoiding specific CV safetytrials.
Funding and Duality of Interest. E.M. hasreceived speaking and/or consulting honorariafrom AstraZeneca, Boehringer Ingelheim, EliLilly, Jannsen, Merck, Novartis, Novo Nordisk,Sanofi, and Takeda and research grants fromAstraZeneca, Boehringer Ingelheim, Eli Lilly,
Novartis, Novo Nordisk, Takeda, and Sanofi. O.M.has received speaking fees fromAstraZeneca andBristol-Myers Squibb, Novo Nordisk, Eli Lilly,Sanofi, Novartis, Merck Sharp & Dohme, andKyowa Hakko Kirin; consulting fees from NovoNordisk, Eli Lilly, Sanofi, Novartis, AstraZeneca,Boehringer Ingelheim, and Janssen; and researchgrants from AstraZeneca, Bristol-Myers Squibb,and Novo Nordisk. A.A. has received researchgrants from the Strategic Project DYCENDIfrom the University of Padova STPD11ALFEand has also received speaking honoraria fromNovartis, Eli Lilly, Novo Nordisk, Sanofi, BoehringerIngelheim, AstraZeneca, Mediolanum, Servier,Janssen, and Merck Sharp & Dohme; financialsupport for attending symposia from Novartis,Eli Lilly, NovoNordisk, Sanofi, Boehringer Ingelheim,and AstraZeneca; financial support for educa-tional programs from Novartis; consulting feesfrom Novartis, Eli Lilly, Novo Nordisk, Sanofi,Boehringer Ingelheim, AstraZeneca,Mediolanum,Servier, Janssen, andMerck Sharp&Dohme; andresearch grants from Boehringer Ingelheim andAstraZeneca. No other potential conflicts of interestrelevant to this article were reported.Author Contributions. E.M., O.M., and A.A.contributed to collection of relevant references,discussionof their clinical implications,writingofthe manuscript, and revision of the text.
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