PMID- 36002856
OWN - NLM
STAT- MEDLINE
DCOM- 20220826
LR  - 20220831
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 21
IP  - 1
DP  - 2022 Aug 24
TI  - Transitioning to active-controlled trials to evaluate cardiovascular safety and 
      efficacy of medications for type 2 diabetes.
PG  - 163
LID - 10.1186/s12933-022-01601-w [doi]
LID - 163
AB  - Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) 
      therapies have mostly used randomized comparison with placebo to demonstrate 
      non-inferiority to establish that the investigational drug does not increase CV 
      risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and 
      sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. 
      Consequently, future T2DM therapy trials could face new ethical and clinical 
      challenges if CVOTs continue with the traditional, placebo-controlled design. To 
      address this challenge, here we review the methodologic considerations in 
      transitioning to active-controlled CVOTs and describe the statistical design of a 
      CVOT to assess non-inferiority versus an active comparator and if non-inferiority 
      is proven, using novel methods to assess for superiority versus an imputed 
      placebo. Specifically, as an example of such methodology, we introduce the 
      statistical considerations used for the design of the "Effect of Tirzepatide 
      versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with 
      Type 2 Diabetes" trial (SURPASS CVOT). It is the first active-controlled CVOT 
      assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate 
      CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent 
      insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an 
      active comparator with proven CV efficacy, dulaglutide. To determine the efficacy 
      margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV 
      outcome of death, myocardial infarction, or stroke (MACE-3), which is required to 
      claim superiority versus an imputed placebo, the lower bound of efficacy of 
      dulaglutide compared with placebo was estimated using a hierarchical Bayesian 
      meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed 
      so that when the observed upper bound of the 95% confidence interval of the 
      hazard ratio is less than the lower bound of efficacy of dulaglutide, it 
      demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV 
      benefit of dulaglutide as well as statistical superiority of tirzepatide to a 
      theoretical placebo (imputed placebo analysis). The presented methods adding 
      imputed placebo comparison for efficacy assessment may serve as a model for the 
      statistical design of future active-controlled CVOTs.
CI  - (c) 2022. The Author(s).
FAU - McGuire, Darren K
AU  - McGuire DK
AD  - Division of Cardiology, University of Texas Southwestern Medical Center and 
      Parkland Health and Hospital System, 5323 Harry Hines Blvd, Dallas, TX, 
      75235-8830, USA. darren.mcguire@utsouthwestern.edu.
FAU - D'Alessio, David
AU  - D'Alessio D
AD  - Division of Endocrinology, Duke University Medical Center, Durham, NC, USA.
FAU - Nicholls, Stephen J
AU  - Nicholls SJ
AD  - Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash 
      University, Melbourne, Australia.
FAU - Nissen, Steven E
AU  - Nissen SE
AD  - Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, 
      Cleveland, OH, USA.
FAU - Riesmeyer, Jeffrey S
AU  - Riesmeyer JS
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Pavo, Imre
AU  - Pavo I
AD  - Eli Lilly Regional Operations GmbH, Vienna, Austria.
FAU - Sethuraman, Shanthi
AU  - Sethuraman S
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Heilmann, Cory R
AU  - Heilmann CR
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Kaiser, John J
AU  - Kaiser JJ
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Weerakkody, Govinda J
AU  - Weerakkody GJ
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20220824
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 0 (Drugs, Investigational)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
SB  - IM
MH  - Bayes Theorem
MH  - *Cardiovascular Diseases/epidemiology
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Drugs, Investigational/therapeutic use
MH  - Glucagon-Like Peptide 1/adverse effects
MH  - Glucagon-Like Peptide-1 Receptor/agonists
MH  - Humans
MH  - *Hypoglycemic Agents/adverse effects
MH  - Randomized Controlled Trials as Topic
MH  - Sodium-Glucose Transporter 2 Inhibitors/adverse effects
MH  - Treatment Outcome
PMC - PMC9400320
OTO - NOTNLM
OT  - Antihyperglycemic
OT  - Cardiovascular
OT  - Imputed placebo
OT  - Non-inferiority trial
OT  - Type 2 diabetes mellitus
COIS- DKM reports honoraria, advisory board, and clinical trial executive committee 
      fees from Eli Lilly; fees for consultancy and/or clinical trial executive 
      committee from Boehringer Ingelheim, Sanofi, Novo Nordisk, AstraZeneca, Lexicon, 
      Eisai Inc., Esperion, Metavant, Applied Therapeutics, and Afimmune; clinical 
      trial data monitoring committee fees from Janssen Research and Development LLC, 
      CSL Behring, and GlaxoSmithKline; advisory committee and global advisory board 
      fees from Novo Nordisk and Merck Sharpe and Dohme; and clinical trial scientific 
      advisory committee fees from Pfizer. DD reports research grants and advisory fees 
      from Eli Lilly; research grants from Merck; consulting fees from Intarcia and Sun 
      Pharmaceuticals; and editorial fees from American Diabetes Association journals. 
      SJN reports research support, consulting and personal fees from Eli Lilly; grants 
      and personal fees from AstraZeneca, Amgen, CSL Behring, Esperion, and 
      Sanofi-Regeneron; grants from Anthera, Cerenis, Resverlogix, Novartis, and 
      InfraReDx; and personal fees from Akcea, Boehringer Ingelheim, Kowa, Merck, 
      Takeda, Pfizer, and Novo Nordisk. SEN reports grants from Eli Lilly, AstraZeneca, 
      Esperion Therapeutics, Amgen, and Novo Nordisk. Although SEN works closely with 
      pharmaceutical companies on the development of new therapies for cardiovascular 
      disease, he maintains a longstanding policy of requiring companies to donate all 
      related honoraria directly to charity so that he receives neither income, nor a 
      tax deduction. IP, SS, CRH, JJK and GJW are employees and stockholders of Eli 
      Lilly and Company. JSR was an employee of Eli Lilly and Company.
EDAT- 2022/08/25 06:00
MHDA- 2022/08/27 06:00
PMCR- 2022/08/24
CRDT- 2022/08/24 23:38
PHST- 2022/05/17 00:00 [received]
PHST- 2022/08/11 00:00 [accepted]
PHST- 2022/08/24 23:38 [entrez]
PHST- 2022/08/25 06:00 [pubmed]
PHST- 2022/08/27 06:00 [medline]
PHST- 2022/08/24 00:00 [pmc-release]
AID - 10.1186/s12933-022-01601-w [pii]
AID - 1601 [pii]
AID - 10.1186/s12933-022-01601-w [doi]
PST - epublish
SO  - Cardiovasc Diabetol. 2022 Aug 24;21(1):163. doi: 10.1186/s12933-022-01601-w.