Correspondence
bempedoic acid and 1·0% of patients
receiving placebo, and renal failure
occurred in 1·1% of patients receiving
bempedoic acid and 0·9% of patients
receiving placebo; 0·2% of patients in
both treatment groups had an eGFR less
than 15 mL/min per 1·73m² at any time
during the trial.2 These small changes in
creatinine and BUN are reversible and
are probably related to inhibition of
the renal transporter OAT2.2
Modest changes in weight in
people with diabetes and prediabetes
with bempedoic acid have been
reported.3 This finding could be due
to the role of ATP citrate lyase, the
molecular target of bempedoic acid,
in lipid and carbohydrate metabolism,
which is supported by Mendelian
randomisation data.5 Groothof and
Bakker question whether the small
changes in creatinine and weight
could be associated with muscle
loss. We assessed the correlation of
weight change with renal laboratory
parameters in patients on the basis
of glycaemic status and baseline
BMI. The Spearman correlation
r values were all less than 0·1,
suggesting that less than 1% of the
change in renal laboratories were
explained by change in weight. At
36 months, patients treated with
bempedoic acid with a baseline
BMI less than 25 kg/m² had a mean
change in bodyweight of 0·43 kg (vs
0·66 for placebo), with a 6% mean
increase in creatinine (vs 3% for
placebo). Patients with baseline BMI
of 30 kg/m² or more had a mean
change in bodyweight of –2·28 kg
(vs –1·37 kg for placebo) and a 7%
mean increase in creatinine (vs 4%
for placebo). Finally, bempedoic acid
is a prodrug that requires enzyme
activation by very long chain acyl-
coenzyme A synthetase 1, which is
present in liver cells but absent from
muscle tissue. Muscle-related side-
effects have been balanced with
placebo in phase 3 trials. 1,2,4 Thus,
the comprehensive clinical data
suggest that the small changes in
creatinine and BUN do not appear
www.thelancet.com/diabetes-endocrinology Vol 12 April 2024
to be of clinical significance and are
independent of the small changes in
weight seen in people with obesity.
KKR reports unrestricted research grants in the past
3 years, paid to Imperial College London, from
Amgen, Sanofi, Regeneron, Daiichi Sankyo, and
Ultragenix; consulting fees from Novartis, Daiichi
Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Lilly,
Silence Therapeutics, AstraZeneca, New Amsterdam
Pharma, Bayer, Beren Therapeutics, Cleerly,
EmendoBio, Scribe, CRISPR, Vaxxinity, Amarin,
Regeneron, Ultragenix, Cargene, and Resverlogix
for being a member of steering committees and
executive committees of clinical trials and for roles
as principle investigator and national lead
investigator; attends advisory boards, provides
advice on data, its interpretation, and future lines
of research, and lecture fees from Novartis,
Boehringer Ingelheim, AstraZeneca, Novo Nordisk,
Viatris, Amarin, Biologix Pharma, Sanofi, Amgen,
Esperion, Daiichi Sankyo, and Macleod Pharma;
holds stock options from New Amsterdam Pharma
and PEMI31; and is European Atherosclerosis
Society President (unpaid). NL and LB are
employees of Esperion Therapeutics. SEN received
grant support from Esperion Therapeutics for the
CLEAR Outcomes Trial; and the Cleveland Clinic
Center for Clinical Research has received funding to
perform clinical trials from Abbvie, AstraZeneca,
Arrowhead, Amgen, Bristol Myers Squibb, Eli Lilly,
Medtronic, MyoKardia, New Amsterdam
Pharmaceuticals, Novartis, and Silence
Therapeutics, in which SEN is involved in these
clinical trials but receives no personal remuneration
for his participation.
*Kausik K Ray, LeAnne Bloedon, Na Li,
Steven E Nissen, on behalf of the
co-authors
k.ray@imperial.ac.uk
Centre for Cardiovascular Disease Prevention,
Department of Primary Care and Public Health,
Imperial College London, London, UK (KKR);
Esperion Therapeutics, Ann Arbor, MI, USA (LB, NL);
Cleveland Clinic, Cleveland, OH, USA (SEN)
1 Nissen SE, Lincoff AM, Brennan D, et al.
Bempedoic acid and cardiovascular outcomes
in statin-intolerant patients. N Engl J Med
2023; 388: 1353–64.
2 Bays HE, Bloedon LT, Lin G, et al. Safety of
bempedoic acid in patients at high
cardiovascular risk and with statin
intolerance. J Clin Lipidol 2023; published
online Oct 31. https://doi.org/10.1016/j.
jacl.2023.10.011.
3 Ray KK, Nicholls SJ, Li N, et al. Efficacy and
safety of bempedoic acid among patients
with and without diabetes: prespecified
analysis of the CLEAR Outcomes randomised
trial. Lancet Diabetes Endocrinol 2024;
12: 19–28.
4 Bays HE, Banach M, Catapano AL, et al.
Bempedoic acid safety analysis: pooled data
from four phase 3 clinical trials. J Clin Lipidol
2020; 14: 649–59.
5 Ference BA, Ray KK, Catapano AL, et al.
Mendelian randomization study of ACLY and
cardiovascular disease. N Engl J Med 2019;
380: 1033–42.
Bridging the worlds of
research and policy
making
The first Editorial of 2024 in
The Lancet Diabetes & Endocrinology
was entitled “From research to policy:
still a long way to go”.1 It explored
potential reasons why much research
in the field, despite its transformative
potential for impact, is not taken up
and implemented into health policy.
It also explored actions that both
researchers and journal editors might
take to improve the strike rate.
An additional contributor not
mentioned is worthy of consideration.
To accurately assess clinical and cost
effectiveness, impact on population
health, affordability, and value for
health systems and the populations
that they serve, policy makers need
some indication as to the effectiveness
of interventions when implemented
in the real world. Effect sizes can be
attenuated when pragmatic inter­
ventional implementation within
the real world is compared with
interventional testing in randomised
controlled trial (RCT) settings.
RCTs involve ideal circumstances
and ideal participants, often highly
selected from much larger potential
participant populations, to derive
maximum interventional efficacy.
Interventional implementation in the
real world involves the application
to populations at scale and therefore
must include affordable circumstances,
often involving lower unit costs than
those invested in the corresponding
RCTs, where participants who might
have the greatest interventional and
health needs have characteristics
that are very different to those
of the ideal participants involved
in RCTs. For example, those from
more socioeconomically deprived
communities, and those of non-White
ethnicity, are often under-represented
in RCTs.2 This discrepancy between
RCT and real-world results has been
previously described by Wareham as
229
 Correspondence
the efficacy versus effectiveness gap.3
Without any indication as to how
large the efficacy versus effectiveness
gap may be, policy makers must
either hope for the best when
translating RCT-tested interventions
into real-world delivery, or they
might consider piloting interventions
and evaluating them in real-world
For REDDIE see settings. Journal editors often
https://reddie-diabetes.eu place very high bars for publishing
cohort studies that result from
such evaluations of pilot studies,
so this important complementary
information to be considered
alongside RCT findings might be even
less visible to policy makers within
other health systems internationally.
There is an increasing appreciation
of the important contributions that
real-world observational data and
natural experimental evaluation
can make to the evidence base. 4
Over the last decade, the National
Health Service (NHS) in England
has implemented a number of
interventional programmes at scale.
For example, the NHS Diabetes
Prevention Programme involved
implementation of the interventions
tested in landmark type 2 diabetes
prevention RCTs into live clinical
environments, and now provides
rich data on effect size in the real
world, elucidates the differential
interventional effects according to
230
participant characteristics such as age,
socioeconomic status, and ethnicity,
and provides clear quantification of
the efficacy versus effectiveness gap,
as well as quantification of real-world
cost effectiveness.5,6
The European Commission Horizon
Europe 2022 Programme has funded
the Real-World Evidence for Decisions in
Diabetes (REDDIE) programme of work.
This will include assessment of efficacy
versus effectiveness gaps—it will use
data from four large national registries,
including the National Diabetes Audit
in England,7 to derive trial emulation
cohorts in whom the effectiveness
of therapeutic interventions in the
real world can be compared with
the efficacy demonstrated when the
same therapeutic interventions were
tested in RCT settings.
So in addition to improving the
quality of trials and trial reporting,
improving visibility of reported trials
to policy makers, and promoting
engagement between scientific
institutions and international policy
professionals, all of which were
highlighted in the recent Editorial,1
journal editors may also wish to
consider prioritising for publication
high-quality cohort studies, pilot
evaluations, and natural experiments
that build on existing published
RCTs. The Editorial suggested that
addressing diabetes remains a low
www.thelancet.com/diabetes-endocrinology Vol 12 April 2024
priority in policy makers’ agendas
around the world; perhaps this
reflects to some extent the paucity
of information on effectiveness of
interventions in the real world, and
the frequent lack of quantification of
the efficacy versus effectiveness gap.
JV was the national clinical director for diabetes and
obesity at NHS England from April, 2013, to
September, 2023.
Jonathan Valabhji
j.valabhji@imperial.ac.uk
Department of Metabolism, Digestion and
Reproduction, Faculty of Medicine, Imperial College
London, Chelsea and Westminster Hospital Campus,
London SW10 9NH, UK
1 The Lancet Diabetes & Endocrinology. From
research to policy: still a long way to go.
Lancet Diabetes Endocrino 2024; 12: 1.
2 Chan J, Blane D, Choudhary P, et al. Addressing
health inequalities in diabetes through
research: recommendations from Diabetes
UK’s 2022 health inequalities in diabetes
workshop. Diabet Med 2023; 40: e15024.
3 Wareham NJ. Mind the gap: efficacy versus
effectiveness of lifestyle interventions to
prevent diabetes. Lancet Diabetes Endocrino
2015; 3: 160–61.
4 Craig P, Campbell M, Bauman A, et al. Making
better use of natural experimental evaluation
in population health. BMJ 2022; 379: e070872.
5 Valabhji J, Barron E, Bradley D, et al. Early
outcomes from the English National Health
Service Diabetes Prevention Programme.
Diabetes Care 2020; 43: 152–60.
6 Bower P, Soiland-Reyes C, Heller S, et al. Diabetes
prevention at scale: narrative review of findings
and lessons from the DIPLOMA evaluation of
the NHS Diabetes Prevention Programme in
England. Diabet Med 2023; 40: e15209.
7 Holman N, Knighton P, Wild SH, et al. Cohort
profile: National Diabetes Audit for England
and Wales. Diabet Med 2021; 38: e14616.