Comment
Reduction in heart failure outcomes with SGLT2 inhibitors
irrespective of glycaemic status
Dysglycaemia is a metabolic state characterised by
an HbA1c level above the normal range and includes
anyone with slightly elevated glucose concentrations,
impaired fasting glucose, impaired glucose tolerance,
or diabetes. Since the term was first coined in
1996,1 analyses of many prospective studies have
clearly shown a progressive relationship between
the degree of dysglycaemia and cardiovascular
outcomes, including coronary artery disease, stroke,
cardiovascular mortality, all-cause mortality, and
heart failure.2,3 These findings, meta-analyses of
glucose-lowering trials reporting reduced myocardial
infarctions,4 and Mendelian randomisation analyses
linking lifetime exposure to elevated glucose with
coronary artery disease5 and diastolic dysfunction6
are consistent with a causal relationship between
dysglycaemia and cardiovascular outcomes. Never­
theless, no compelling data have shown that short-
term glucose lowering reduces the incidence of heart
failure. This, and the fact that some glucose-lowering
drugs appear to increase its incidence, suggests it is
unlikely that glucose control alone could meaningfully
prevent heart failure in people with type 2 diabetes.
This view was apparently challenged by the addition
of SGLT2 inhibitors to the list of glucose-lowering
drugs, specifically by the large reductions in the
incidence of heart failure outcomes in people with
type 2 diabetes receiving SGLT2 inhibitors, and by
preliminary analyses implicating glucose lowering as
a possible mediator of these salutary effects.7 However,
more recent observations showing similar reductions
of heart failure outcomes with SGLT2 inhibitors
in people with and those without type 2 diabetes
suggested that the heart failure benefits of these
drugs were in fact unrelated to their glucose-lowering
effects.8 Analyses of the effect of SGLT2 inhibitors
on heart failure outcomes in people whose glucose
concentrations spanned the entire dysglycaemic range
would help to confirm this hypothesis.
These analyses, done previously in the Dapagliflozin
and Prevention of Adverse Outcomes in Heart
Failure (DAPA-HF) trial in patients with heart failure
and reduced ejection fraction,9 have now been
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extended to participants with heart failure and
a left ventricular ejection fraction of more than 40%
in the Dapagliflozin Evaluation to Improve the Lives of
Patients with Preserved Ejection Fraction Heart Failure
(DELIVER) trial. In The Lancet Diabetes & Endocrinology,10
Silvio E Inzucchi and colleagues first confirmed
a progressive relationship between the degree of
Shutterstock
dysglycaemia analysed both categorically (ie, as
normoglycaemia, prediabetes, or type 2 diabetes
based on ranges of the baseline HbA1c level) and Published Online
November 10, 2022
continuously (based on the actual HbA1c level) and https://doi.org/10.1016/
the subsequent occurrence of the primary composite S2213-8587(22)00313-8
outcome (worsening heart failure or cardiovascular See Articles page 869
death), its components, and all-cause mortality. They
then showed that the hazard ratios for these outcomes
with dapagliflozin versus placebo were similar within
all three glycaemia status subgroups (hazard ratio 0∙77
[95% CI 0∙57–1∙04], log-rank p=0·088, for patients
with normoglycaemia, 0∙87 [0∙69–1∙08], log-rank
p=0·21, for patients with prediabetes, and 0∙81
[0∙69–0∙95], log-rank p=0·0077, for patients with
type 2 diabetes; pinteraction=0∙82) and across HbA1c levels
that ranged from 5% to 10%, with no evidence of any
interaction (pinteraction=0∙85). Therefore, although higher
degrees of dysglycaemia are associated with higher
absolute rates of heart failure-related outcomes,9 the
salutary heart failure benefits of dapagliflozin, and by
extension other SGLT2 inhibitors, seem completely
unrelated to the degree of dysglycaemia.
These findings support several take-away messages
for a clinician treating patients with mildly reduced or
preserved ejection fraction. First, more than 70% of
these individuals have some evidence of dysglycaemia
and, therefore, are at particularly high risk for
recurrent heart failure or cardiovascular death. Second,
both patients with normoglycaemia and those with
dysglycaemia will have the same relative benefit when
prescribed an SGLT2 inhibitor. However, the high
risk of heart failure in patients with dysglycaemia
means that their absolute risk reduction with these
drugs is greater, and the number needed to treat to
prevent one event is therefore lower. Third, despite
its heart failure benefits, dapagliflozin does not
831
 Comment
eliminate the excess risk of heart failure associated
with dysglycaemia, a finding that strongly supports
ongoing research into cardioprotective therapies
for people with dysglycaemia. Finally, and perhaps
most importantly, the benefits of SGLT2 inhibitors
on heart failure outcomes must be completely
unrelated to its glucose-lowering properties. This is
not to say their glucose-lowering properties do not
matter. They do, and glucose reduction is an added
bonus in patients with diabetes. However, as the
authors of DELIVER point out, SGLT2 inhibitors also
rapidly affect haemodynamic pathways (consistent
with rapid reductions in outcomes that are apparent
within weeks) and have other metabolic, cellular,
and organ-specific effects that, once fully elucidated,
might reveal new preventive methods for major
cardiorenal outcomes.
HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes
Research and Care. He reports research grants from Eli Lilly, AstraZeneca,
Novo Nordisk, and Sanofi; honoraria for speaking from AstraZeneca,
Boehringer Ingelheim, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Roche, Sanofi,
Jiangsu Hanson, and Carbon Brand; and consulting fees from Abbott, Eli Lilly,
Novo Nordisk, Sanofi, Kowa, Pfizer, Hanmi, and Viatris. NS declares consulting
fees, speaker honoraria, or both from Abbott Laboratories, Afimmune,
Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals,
Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi,
and grant support paid to his university from AstraZeneca, Boehringer
Ingelheim, Novartis, and Roche Diagnostics.
*Hertzel C Gerstein, Naveed Sattar
gerstein@mcmaster.ca
The 2022 hormone therapy position statement of The
North American Menopause Society: no news is good news
The 2022 position statement of The North American
Menopause Society (NAMS) on hormone therapy1 is an
excellent read that keeps alive discussion on a topic of
interest for a wide audience of practitioners in the field
of women’s health. Indeed, menopause is a universal
process among women at midlife (ranging 46–52 years
globally) and some of them might have distressing
symptoms and develop risk factors for chronic condi­
Shutterstock
tions with an impact on healthy longevity.2
After so many years of bad news deriving from the
Published Online original analysis of the Women’s Health Initiative
October 18, 2022
https://doi.org/10.1016/
hormone therapy trial,3 reassuringly, the new NAMS
S2213-8587(22)00285-6 statement reinforces the key concepts of the 2017
statement—such as, women who have recently
832
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January 02, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
Population Health Research Institute, McMaster University and Hamilton
Health Sciences, Hamilton, ON L8S 4K1, Canada (HCG); School of
Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK (NS)
1 Gerstein HC, Yusuf S. Dysglycaemia and risk of cardiovascular disease.
Lancet 1996; 347: 949–50.
2 Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and
cardiovascular risk in nondiabetic adults. N Engl J Med 2010; 362: 800–11.
3 Gerstein HC, Swedberg K, Carlsson J, et al. The hemoglobin A1c level as
a progressive risk factor for cardiovascular death, hospitalization for
heart failure, or death in patients with chronic heart failure: an analysis
of the Candesartan in Heart failure: Assessment of Reduction in Mortality
and Morbidity (CHARM) program. Arch Intern Med 2008; 168: 1699–704.
4 Control Group, Turnbull FM, Abraira C, et al. Intensive glucose control
and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;
52: 2288–98.
5 Ross S, Gerstein HC, Eikelboom J, Anand SS, Yusuf S, Pare G. Mendelian
randomization analysis supports the causal role of dysglycaemia and
diabetes in the risk of coronary artery disease. Eur Heart J 2015;
36: 1454–62.
6 Vaitinadin NS, Shi M, Shaffer CM, et al. Genetic determinants of body
mass index and fasting glucose are mediators of grade 1 diastolic
dysfunction. J Am Heart Assoc 2022; 11: e025578.
7 Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce
cardiovascular mortality? Insights from a mediation analysis of the
EMPA-REG OUTCOME Trial. Diabetes Care 2018; 41: 356–63.
8 Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in
patients with heart failure: a comprehensive meta-analysis of
five randomised controlled trials. Lancet 2022; 400: 757–67.
9 Petrie MC, Verma S, Docherty KF, et al. Effect of dapagliflozin on
worsening heart failure and cardiovascular death in patients with heart
failure with and without diabetes. JAMA 2020; 323: 1353–68.
10 Inzucchi SE, Claggett BL, Vaduganathan M, et al. Efficacy and safety of
dapagliflozin in patients with heart failure with mildly reduced or
preserved ejection fraction by baseline glycaemic status (DELIVER):
a subgroup analysis from an international, multicentre, double-blind,
randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2022;
published online Nov 10. https://doi.org/S2213-8587(22)00308-4.
undergone menopause with moderate or severe
symptoms are appropriate candi­ dates for hormone
therapy.4 Such a simple procla-mation will substantially
benefit the wellbeing and health of women in their
midlife by removing excessive fears and offering a
balanced perspective in daily clinical practice.
The availability of Women’s Health Initiative
findings, with extended post-intervention follow-
up and stratification by age and other important
variables, and data from recent hormone therapy
trials, led the advisory panel of clinicians and research
experts to formulate almost overlapping conclusions
with the 2017 position statement.1,4 A recent review
on concepts, controversies, and management of
www.thelancet.com/diabetes-endocrinology Vol 10 December 2022