Women and Diabetes Preventing Heart Disease in A New Era of Therapies

Women and Heart Disease
Women and Diabetes: Preventing Heart Disease in a New Era of Therapies

Giuseppe Galati ,1 Pierre Sabouret ,2 Olga Germanova 3
and Deepak L Bhatt 4
1. Heart Failure Unit and Division of Cardiology, Cardiothoracic and Vascular Department, San Raffaele Hospital and Scientific Institute
(IRCCS), Milan, Italy; 2. Heart Institute, Cardiology Department, Pitié-Salpétrière, Sorbonne University and Collège National des
Cardiologues Français, Paris, France; 3. Department of Diagnostic Medicine and Imaging, Samara State Medical University, Samara, Russia;
4. Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, US
Abstract
Despite major advances in cardiovascular research over the past decade, women with type 2 diabetes have a high risk of cardiovascular events.
Several factors contribute to the poor prognosis for women, including higher levels of frailty and comorbidities, but their cardiovascular risk
is underestimated and there is suboptimal implementation and uptitration of new evidence-based therapies, leading to high morbidity and
mortality. Recent studies highlight the need for better management of diabetes in women that can be pursued and achieved in light of recent
results from randomised controlled trials demonstrating evidence of the benefits of new therapeutic strategies in improving cardiovascular
outcomes and quality of life of women covering the entire cardiovascular continuum. This review critically discusses the multiple benefits for
women of new pharmacological treatments, such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter type 2 inhibitors
(SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, icosapent ethyl and bempedoic acid in preventing cardiovascular
events, and treatments, such as angiotensin receptor neprilysin inhibitors, SGLT2i, vericiguat and omecamtiv mecarbil, for preventing heart
failure.
Keywords
Women’s health, cardiovascular prevention, heart failure, diabetes, sodium–glucose cotransporter type 2 inhibitors.
Disclosure: PS has received personal fees from Amgen, Bayer, Novartis, Sanofi-Regeneron, Servier and Vifor. DLB is on advisory boards for Cardax, CellProthera, Cereno
Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma and Regado Biosciences; is on
the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care and TobeSoft; is chair of the American Heart Association Quality Oversight
Committee; is on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude
Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute,
Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo) and Population Health Research Institute; has received honoraria from
American College of Cardiology, Baim Institute for Clinical Research (RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive
committee funded by CSL Behring), Belvoir, Canadian Medical and Surgical Knowledge Translation Research Group, Duke Clinical Research Institute (including for the
PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life
Sciences, Population Health Research Institute (for COMPASS, funded by Bayer), Slack Publications, Society of Cardiovascular Patient Care, WebMD; declares Clinical
Cardiology, NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee; has received research funding from Abbott, Afimmune, Amarin,
Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories,
Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron,
Roche, Sanofi, Synaptic and The Medicines Company; has received royalties from Elsevier; is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude
Medical (now Abbott) and Svelte; is a trustee of American College of Cardiology; and has unfunded research from FlowCo, Merck and Takeda. All other authors have no
conflicts of interest to declare.
Received: 13 May 2021 Accepted: 27 July 2021 Citation: European Cardiology Review 2021;16:e40. DOI: https://doi.org/10.15420/ecr.2021.22
Correspondence: Giuseppe Galati, Heart Failure Unit and Division of Cardiology, Cardiothoracic and Vascular Department, San Raffaele Hospital and Scientific Institute
(IRCCS), Via Olgettina 60, 20132 Milan, Italy. E: galati.giuseppe@hsr.it
Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial
purposes, provided the original work is cited correctly.
During the past decade, new therapeutic strategies have been cardiovascular (CV) benefits of using new pharmacological treatments,
progressively showing a reduction in major adverse cardiac events whose implementation in clinical practice would address an urgent need
(MACE). Nevertheless, women with type 2 diabetes (T2D) remain at very for the reduction of morbidity and mortality in women with T2D.
high risk of events, not only due to the disease but also because their risk
is underestimated, leading to a suboptimal initiation and uptitration of Prevention
new evidence-based therapies. This risk causes the progressive CV events remain high in people with diabetes, especially in women.2
development of structural cardiac disease and invariably to heart failure Indeed, recent RCTs report a high rate of MACE (MI, stroke and CV death)
(HF) and advanced HF, covering the full spectrum of American Heart under optimal medical therapy (OMT), highlighted by a rate of 9.4–14.9%
Association/American College of Cardiology HF staging.1 This article for 3–4 years follow-up.3–5 To optimise CV prevention in women, three
reviews the main randomised clinical trials (RCTs) that prove the significant specific periods present themselves as an appropriate time to check
© RADCLIFFE CARDIOLOGY 2021

Access at: www.ECRjournal.com
Women and Diabetes
clinical status and provide healthy lifestyle advice: when discussing disease (ASCVD) but also for HF, because diabetes causes structural
contraceptive choices; before, during and after pregnancy; and during the myocardial, coronary and vascular disease, and leads to chronic
menopause. neurohormonal activation of the angiotensin–aldosterone system and
sympathetic nervous system that in the long run is deleterious and causes
A primary care visit for contraception is a good opportunity to check the hydrosaline retention, congestion and translates to a high risk of CV
clinical status of the patient and to provide key messages promoting death.8
healthy habits, including food intake, physical activities, stress
management and lifestyle. Information about T2D and its associated risks Optimal management of diabetes in women is challenging due to the
should be given to help reduce the risk of CV events. under-representation of women in RCTs and registries, highlighting the
need of dedicated studies for women (Table 1). Ageing and the high
During pregnancy, detection of diabetes is crucial, because gestational prevalence of comorbidities also represent documented barriers to
diabetes is a strong risk factor for future MACE. A glucose screening test optimal management. Nevertheless, underestimation of the CV risk and
should be performed for every pregnancy. If diabetes is suspected, the therapeutic inertia contribute to the poorer prognosis of women with
diagnosis should be confirmed with a 2-hour glucose tolerance test. diabetes which has been underlined by several registries, where the
Management of gestational diabetes includes a healthy diet, regular detection of CV risk is inadequate and women receive fewer recommended
exercise (150 minutes per week of moderate-intensity activity) and, if treatments with the target dose when compared to men. Recently, new
needed, metformin ± insulin with advice and information on preventing therapeutic classes have emerged which provide additional CV and renal
episodes of hypoglycaemia. An ultrasound exam between gestational benefits. The development of new classes acting not only on glycaemic
weeks 18 and 20 will detect potential abnormalities in the foetus. Further control but also by multiple mechanisms already represent valid options
ultrasound scans at weeks 28, 32 and 36 to monitor the growth of the to further reduce CV events in women. The modern approach should not
foetus and the volume of amniotic fluid are recommended, in combination only focus only on HbA1c level but much more on a holistic strategy to
with regular visits from week 38 onwards. The optimal time for delivery is improve life expectancy and quality of life (QoL).
usually considered to be between weeks 38 and 40. After 40 weeks and
6 days, induction of labour or a caesarean are the two medical options to The glucagon-like peptide-1 receptor agonists (GLP-1 RA) are the first class
be discussed. Earlier delivery is recommended in cases where diabetes with further CV benefits reported in several RCTs, with heterogeneity
control is poor despite diet and pharmacological options, in order to between molecules, whereas CV and renal benefits have been proven
protect both the baby and the mother. with several sodium-glucose cotransporter 2 inhibitors (SGLT2i) in EMPA-
REG Outcome, EMPEROR-Reduced (empagliflozin), CANVAS Program and
It is recommended that the baby is fed within 30 minutes of delivery, then CREDENCE (canagliflozin), DECLARE-TIMI 58, DAPA-HF (dapagliflozin),
every 2–3 hours until the baby’s glycaemic levels become stable.6 The SCORED and SOLOIST-WHF (sotagliflozin), and seem homogenous, even
glycaemia of the newborn is tested starting 2–4 hours after birth until it if only sotagliflozin provided a stroke reduction.3–5,9 Once again, women
becomes stable. If the glycaemic levels of the newborn are not well are under-represented in these RCTs, but the reported results were
controlled, a temporary transfer to the neonatal unit may be required for homogenous among groups with no sex differences.
closer monitoring. After discharge, the baby should have a new glycaemic
test 6–12 weeks after birth. New Anti-diabetic Classes That Act on Glycaemic
Levels and Reduce Cardiovascular Events
An early test to check new diabetes in a woman who has had gestational Sodium–Glucose Cotransporter 2 Inhibitors
diabetes is mandatory due to the increased risk of developing T2D. At 10 SGLT2is act by inhibiting glucose reabsorption in the kidneys, which
years follow-up, after adjustment for ethnicity and age, gestational increases urinary excretion of glucose and allows for better glycaemic
diabetes is associated with an increased relative risk of CV morbidity control in people with T2D. SGLT2i work independently of insulin
between 1.8 and 2.3.7 Therefore, long-term monitoring of women who regulation and β-cell function. Major RCTs have reported CV benefits and
have had gestational diabetes is highly recommended, with a calcium renal protection with five SGLT2is (empagliflozin, canagliflozin,
coronary score performed after the age of 40 to better define the CV risk. dapagliflozin, ertugliflozin and sotagliflozin). Recent meta-analyses
reported that SGLT2is not only reduce the risk of new-onset HF,
The third crucial period is the transition leading to menopause when the risk hospitalisations for HF (HHF), protect from worsening renal function and
of CV events increases whereas management remains poor. Hypertension, end-stage renal disease (ESRD), but also reduce all-cause as well as CV
dyslipidaemia, obesity and other issues with the metabolic syndrome death, with similar benefits in patients in primary or secondary prevention
represent the main risk factors for T2D in the peri-menopausal period, but and with and without a history of HF.10,11 Moreover, these meta-analyses
these remain insufficiently detected and treated in women. Hypertension is report a reduction in MI by 25% compared to OMT – with a specific benefit
a very strong risk factor at this stage and the control of blood pressure is regarding this endpoint proved by canagliflozin in the CREDENCE trial and
pivotal. Although hormone replacement therapy is effective for decreasing sotagliflozin in the SCORED trial – without apparent benefits in stroke
vasomotor symptoms linked to menopause, this option is not recommended reduction, except for the recent SCORED trial, requiring further
due to its negative effects on the CV system.6 Collaboration between GPs, investigation to better understand the underlying mechanisms providing
cardiologists and gynaecologists is crucial to better identify high-risk peri- these benefits.9 The magnitude of benefits varied according to baseline
menopausal women. Collaboration centred on the individual woman, with CV risk and renal function. Furthermore, two SGLT2i demonstrated
shared decision-making, would provide better detection and long-term efficacy in HF not only in patients with diabetes but also in the pre-
management of women with diabetes to prevent MACE. specified group of non-diabetic patients.
This call for action for women with diabetes is motivated by the cumulative The same limitations concerning women’s inclusion and sample size
data that shows they have a very high risk not only for atherosclerotic CV were observed and no heterogeneity was found according to sex for
EUROPEAN CARDIOLOGY REVIEW

Women and Diabetes
Table 1: Women’s Benefit in Randomised Controlled Trials Dedicated to Prevention for Different Class of Drugs
Trial Total Population, Primary Endpoint CV Death Selected Major

Women Enrolled, Secondary
n (%) Outcome Benefit
SGLT2is
EMPA-REG OUTCOME3 Total 7,020 CV death + non-fatal MI + non-fatal stroke HR 0.62; 95% CI [0.49–0.77]; HHF
Women 2,004 (28.5%) HR 0.86; 95% CI [0.74–0.99]; p=0.04 for p<0.001 HR 0.65; 95% CI [0.50–0.85];
superiority RRR 38% p=0.002
RRR 14% RRR 35%
CANVAS4 Total 10,142 CV death + non-fatal MI + non-fatal stroke: HR 0.87; 95% CI [0.72–1.06]; HHF
Women 3,633 (35.8%) HR 0.86; 95% CI [0.75–0.97]; p=0.02 for p=not significant HR 0.67; 95% CI [0.52–0.87]
superiority RRR 23%
RRR 14%
DECLARE-TIMI 585 Total 17,160 CV death or HHF HR 0.98; 95% CI [0.82−1.17] HHF
Women 6,422 (37.4%) HR 0.83; 95% CI [0.73–0.85]; p=0.005 p=not significant HR 0.73; 95% CI [0.61–0.88]
RRR 17% RRR 27%
Co-primary efficacy endpoint: CV death + MI +
ischaemic stroke
HR 0.76; 95% CI [0.84–1.03]; p=0.17 (not
significant)
SCORED9 Total 10,584 CV death + HHF + urgent visit for HF HR 0.90; 95% CI [0.73–1.12]; Total HHF + urgent visit for HF
Women 4,754 (44.9%) HR 0.74; 95% CI [0.63–0.88]; p=0.0004 p=not significant HR 0.67; 95% CI [0.55–0.82];
RRR 26% p<0.001
Co-primary endpoint: CV death + MI + stroke RRR 33%
HR 0.84; 95% CI [0.72–0.99]; p=0.035
RRR 16%
GLP1-RA
LEADER12 Total 9,340 CV death + non-fatal MI + non-fatal stroke HR 0.78; 95% CI [0.66–0.93]; MI
Women 3,337 (35.7%) HR 0.87; 95% CI [0.78–0.97]; p=0.01 for p=0.007 HR: 0.86; 95% CI [0.73–1.00];
superiority RRR 22% p=0.046
RRR 13% RRR 14%
REWIND14 Total 9,901 CV death + non-fatal MI + non-fatal stroke HR 0.91; 95% CI [0.78–1.06]; MI
Women 4,589 HR 0.88; 95% CI [0.79-0.99]; p=0.026 p=not significant HR 0.88; 95% CI [0.79–0.99];
(46.3%) RRR 12% p=0.026
RRR 12%
SUSTAIN-615 Total 3,297 CV death + non-fatal MI + non-fatal stroke HR 0.98; 95% CI [0.65–1.48]; MI
Women 1,215 (36.8%) HR 0.74; 95% CI [0.58–0.95]; p<0.001 for p=not significant HR 0.74; 95% CI [0.51–1.08];
non-inferiority p= not significant
RRR 26% RRR 26%
PCSK9i
FOURIER18 Total 27,564 CV death + MI + stroke + hospitalisation for UA HR 1.05; 95% CI [0.88–1.25]; MI
Women 6,769 (24.6%) + coronary revascularisation p=not significant HR 0.73; 95% CI [0.65–0.82];
HR 0.85; 95% CI [0.79–0.92]; p<0.001 p<0.001
RRR 15% RRR 27%
ODYSSEY-OUTCOME19 Total 18,924 Coronary heart disease-death, non-fatal MI + HR 0.88; 95% CI [0.74–1.05]; MI
Women 4,762 (25.2%) ischaemic stroke + hospitalisation for UA p=not significant HR 0.86; 95% CI [0.77–0.96]
HR 0.85; 95% CI [0.78–0.93]; p<0.001 RRR 14%
RRR 15%
ORION 10 and 1122 Total 3,178 LDL cholesterol decrease NA* NA*
Women 935 (29.4%) HR 0.50; p<0.01 for superiority
RRR 49.9 %
Icosapent Ethyl
REDUCE-IT23 Total 8,179 CV death + non-fatal MI + non-fatal stroke + UA HR 0.80; 95% CI [0.66–0.98]; MI
Women 2,357 + coronary revascularisation p=0.03 HR 0.69; 95% CI [0.58–0.81];
(28.8%) HR 0.75; 95% CI [0.68–0.83]; p<0.001 RRR 20% p<0.001
RRR 25% RRR 31%
Bempedoic Acid
CLEAR HARMONY26 Total 2,230 Any adverse event NA* NA*
Women 602 (27%) HR 0.95; p=0.91
RRR 5%
*Trials designed for safety and lipid level reduction. CV = cardiovascular; GLP-1 RA = glucagon-like peptide-1 receptor agonists; HF = heart failure; HHF = hospitalisation for heart failure; NA = not
available; PCSK9i = proprotein convertase subtilisin/kexin type 9; RRR = relative risk reduction; SGLT2i = sodium-glucose co-transporter type 2 inhibitors; UA = unstable angina.

Women and Diabetes
this therapeutic class. Therefore, even if specific studies in women are Phase II clinical trials, and the on-going RCT Phase III ORION 4
warranted to better define the magnitude of benefits in this major (NCT03705234) is evaluating the clinical efficacy of inclisiran versus
population, it is already crucial that women with diabetes benefit early placebo in ASCVD patients, including women with diabetes.21 The results
from these two classes in the therapeutic strategy. Choice of the class are expected in 2025.
should be a shared decision according to the woman’s preferences
(one weekly injection versus one daily pill), BMI (as weight loss is more Icosapent Ethyl
pronounced with GLP-1 RA), HbA1c level (SGLT2is lower HbA11c by 0.4– Icosapent ethyl (EPA) is a purified eicosapentaenoic acid formulation
0.6%; GLP-1 RA by 0.8–1%), renal function, atherothrombotic profile and which reduces hepatic production and secretion of very low-density
documented HF. The optimal time to initiate treatment may be lipoproteins, increasing triglycerides clearance without major safety
discussed, but the strong trend in preventing CV events is to start as concerns. The clinical efficacy has been proven in the REDUCE-IT trial,
soon as possible to decrease the loading of glycaemia, dyslipidaemia which enrolled ASCVD patients (70.7%) or patients with diabetes and
and blood pressure. associated CV risk factors.22,23 Almost all patients (99.5%) were on statin
therapy with a triglyceride level of 3.5–12.9 mmol/l at inclusion, and 8,179
Glucagon-like Peptide-1 Receptor Agonists patients (2,357 women) were randomised to 4 g/day of EPA or placebo.
GLP-1 RA work via multiple mechanisms. Their incretin effect – a pleiotropic EPA reduced the primary composite endpoint (CV death, non-fatal MI,
mechanism – reduces gastric emptying, but mainly acts on plasma non-fatal stroke, coronary revascularisation or unstable angina) by 25%
glucose modulation through the stimulation of insulin release and RRR (p<0.0001) after a mean follow-up of 4.9 years. The clinical efficacy of
reduction of hepatic glucose release (partially mediated by suppressing EPA was more pronounced in people with diabetes without sex
glucagon secretion). GLP-1 RA initially have been approved for the differences, and seems to be unrelated either to achieved triglycerides or
treatment of T2D because their glucose-lowering effect was associated LDL cholesterol levels, suggesting other underlying mechanisms. As in
with a reduction in weight and blood pressure. Liraglutide was the first in Phase II trials, no major safety issues were reported, except a slight
class to report CV benefits in the LEADER trial, with a reduction of the increased risk of hospitalisation for AF (3.1% versus 2.1%; p=0.004). EPA
primary composite outcome (CV death, MI or stroke) by 13% in the therefore represents an option to reduce MACE in women with diabetes
liraglutide group (p<0.001 for non-inferiority; p=0.01 for superiority), a following the National Lipid Association statement.24
22% relative RR (RRR) for CV death (p=0.007), and a 15% RRR for all-cause
mortality (p=0.02).12,13 Further benefits have been reported in two Bempedoic Acid
additional RCTs (REWIND and SUSTAIN-6), with no sex differences Bempedoic acid (ETC-1002) inhibits adenosine triphosphate citrate lyase,
observed.14,15 Therefore, European Society of Cardiology (ESC)/ European which decreases cholesterol production in the liver. The decreased
Association for the Study of Diabetes (EASD) guidelines recommended cholesterol synthesis promotes LDL receptor upregulation and thereby
both classes early in the treatment algorithm, either as monotherapy or in decreases plasma LDL cholesterol. ETC-1002 is converted to its active
combination with metformin, without sex-related specificities.16 In the moiety in the liver by the very long-chain acyl-CoA synthetase-1, an
setting of HF and/or chronic kidney disease (CKD), SGLT2is provide more enzyme absent in skeletal muscle, which explains why ETC-1002 is not
benefits than GLP-1RA and are the preferred option for women with associated with muscle symptoms and can be particularly useful in
diabetes.17 patients with statin intolerance.25
New Therapies Providing Benefits in Women In summary, prevention in women with T2D remains suboptimal and may
with Diabetes Outside Glucose Metabolism be improved by combining these novel therapeutic strategies with non-
Proprotein Convertase Subtilisin/Kexin pharmacological measures. All these pharmacological agents have
Type 9 Inhibitors and Inclisiran proven clinical efficacy without serious safety issues. Further efforts are
These two classes of drugs inhibit the proprotein convertase subtilisin/ needed to promote widespread use of these strategies for women, who
kexin type 9 (PCSK9), which modulates the cholesterol level, mainly by are frequently under-treated despite recent educational campaigns to
reducing the numbers of LDL receptors on the plasma membrane. better assess and manage their CV risk. Dedicated studies in women with
diabetes are warranted.
Two RCTs evaluating PCSK9 inhibitors (FOURIER and ODYSSEY Outcomes)
reported CV benefits for a short-term follow-up (about 2 years), one in Heart Failure Management
ASCVD patients including chronic coronary stable patients, peripheral Even if good preventive therapies are started, T2D patients who are in
artery disease and people who have had a stroke, the other in patients Stage A maintain a high risk of developing structural heart diseases (Stage
with post-acute coronary syndromes.18–20 In patients with LDL cholesterol B) and progressing to overt HF (Stages C and D).1 As shown by a large
levels of 1.8 mmol/l or higher under maximal tolerated dose of statin number of registries and meta-analyses including millions of patients, this
therapy, both PCSK9is reduce the primary combined endpoint with a RRR portends a risk of 5-year mortality higher than many cancers and an
of 15%, without a warning signal on safety even for very low LDL extremely low QoL, influenced by the high rate of rehospitalisation and by
cholesterol levels. As the CV risk was higher in people with diabetes, the symptoms and reduced activity as measured by several dedicated
clinical benefits of PCSK9i were more pronounced without sex differences. questionnaires, such as the Kansas City Cardiomyopathy Questionnaire
Glycaemic parameters remained unchanged with either PCSK9is. (KCCQ).26–29 The major impact of HF development is even more ominous
in women. Indeed, as recently highlighted by reviews and meta-analyses,
Inclisiran is a small interfering RNA molecule, which targets the hepatic women receive later referrals to HF treatment centres compared with
production of PCSK9. Inclisiran induces gene silencing through repression men, are under-enrolled in dedicated HF RCTs, receive cardiac
of transcription of specific genes, promoting cleavage and elimination of resynchronisation therapy/ICD and left ventricular assist device/heart
PCSK9, and reduces LDL cholesterol by 50–70% without any safety transplant less frequently, have higher mortality on the heart transplant
signals to date. This safety and biological efficacy were first observed in waiting list and have worse QoL.30,31

Women and Diabetes
Despite HF being more frequent in women than in men, women are After a mean follow-up of 18.2 months, dapagliflozin 10 mg/day versus
systematically under-enrolled in RCTs so that the specific benefits of HF placebo significantly reduced the primary endpoint: a composite of CV
drugs are less well known.32 In fact, women represent a specific population death and first HHF and urgent visit for worsening HF (WHF; (HR 0.74; 95%
in which not only the exact dosages (that can be lower or equal), but also CI [0.65–0.85] p=0.00001) with a RRR of 27% and a number needed to
the pathophysiological pathways (that can be involved with different treat (NNT) of 21. Note that WHF is considered an equivalent of HHF in the
magnitude or can even be different) of HF drugs are less studied and last ESC criteria for advanced HF. See Table 3 for the effect on other major
understood because women have been treated as ‘smaller men’ which is outcomes.38 Beyond the remarkable results achieved in reducing CV
evidently wrong. RCTs dedicated to HF usually enrol a maximum of 30% death and all-cause death, the secondary endpoint dedicated to QoL in
of women – at least in part due to under-enrolment of older patients, a HFrEF was significantly reduced, as demonstrated by the improvement in
higher percentage of whom are women. We strongly hope that will the total symptoms score of the KCCQ.39 In DAPA-HF there were no
change and we encourage researchers to conduct dedicated RCTs for differences regarding the incidence of the secondary endpoint ‘worsening
women or to enrol higher percentages of women to fill our knowledge renal function’ – a composite of sustained ≥50% reduction in eGFR, ESRD
gap. On the other hand, T2D patients are well represented in some of the or death from renal causes (HR 0.71; 95% CI [0.44–1.16]; p=0.17).
most recent HF RCTs (ranging from 34.9–49.8%), reflecting the percentage
of T2D in HF reported by large clinical registries (about 40%).33,34 By far the most remarkable result has been the pre-specified subgroup
analyses, which did not show any difference regarding the reduction of
After more than 30 years of triple therapy – angiotensin-converting primary endpoint between diabetic patients (HR 0.75; 95% CI [0.63–0.90])
enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB), β-blockers and non-diabetic patients (HR 0.73; 95% CI [0.60–0.88]). In particular,
and mineralocorticoid receptor antagonists (MRA) – ivabradine non-diabetic patients had a RRR of 27% for the primary endpoint,
represented a first, small improvement in reducing HHF and HF death representing the real and unexpected result of DAPA-HF. Importantly,
without any improvements on CV death and all-cause death.35 The real there was no difference between the magnitude of reduction of the
revolution in HF with reduced ejection fraction (HFrEF) therapy started in primary endpoint in patients with eGFR >60 versus <60 ml/min/1.73m2.
2014 with PARADIGM-HF, which proved a further reduction of major Consistently, dapagliflozin did not signal safety concerns, indeed, there
outcomes using the angiotensin receptor neprilysin inhibitor (ARNI) were no significant differences versus placebo in terms of volume
sacubitril/valsartan compared with the ACEi enalapril, and continued from depletion, renal adverse events, fractures, limb amputations, major
2019 to now with the new class of drugs SGLT2is and with the new drugs hypoglycaemia (also shown in patients without T2D), diabetic ketoacidosis,
vericiguat and omecamtiv mecarbil.36 urinary infections or all infections; whereas any serious adverse events
were significantly higher in the placebo than in the dapagliflozin group.
SGLT2is: The New Pillar of Cardiorenal These results represented a breakthrough in HFrEF management because
Benefit in HF and Chronic Kidney Disease dapagliflozin provided additional benefits on top of OMT (including 11% of
As previously mentioned, meta-analyses of RCTs dedicated to prevention patients on ARNI) irrespective of diabetic status and this is also valid for
in T2D have demonstrated a significant benefit on CV death and MACE, women.
but the magnitude of benefit was unexpectedly greater on the endpoints
of CV death and HHF, and significant for each individual RCT and not only The second RCT published on HF was EMPEROR-Reduced, dedicated to
in the pooled analysis.10 empagliflozin in HFrEF.40 EMPEROR-Reduced enrolled and randomised
3,730 patients with a similar design to DAPA-HF. However, EMPEROR-
Chronic Heart Failure with Reduced studied a population with a more compromised renal function
Reduced Ejection Fraction (mean eGFR 62 ml/min/1.7m2, 48.3% had eGFR<60 ml/min/1.73 m2) and a
Noticing this evident benefit, all the developers of SGLT2is designed RCTs more severe HFrEF, characterised by a lower mean LVEF (27.5%), higher
exclusively dedicated to HF patients with and without T2D, such as levels of median NT-pro-BNP (1,906 pg/ml), and an annual placebo event
EMPEROR-Reduced (empagliflozin in HFrEF), EMPEROR-Preserved rate of 20% (compared to the 15% of the population enrolled in DAPA-HF)
(empagliflozin in heart failure with preserved ejection fraction [HFpEF]), despite a better OMT, i.e. a greater percentage of patients in ARNI (19.5%;
CHIEF-HF (canagliflozin in both HFrEF and HFpEF), DAPA-HF (dapagliflozin Table 2). After a mean follow-up of 16 months, empagliflozin 10 mg/day
in HFrEF), DELIVER (dapagliflozin in HFpEF) and SOLOIST-WHF (sotagliflozin versus placebo on top of HFrEF standard of care, significantly reduced
in AHF).38,41,44,50 (HR 0.75; 95% CI [0.65–0.86]; p<0.001) the primary endpoint – a composite
of CV death and first HHF with a RRR of 25% and an NNT of 19 – the first
The first published RCT was DAPA-HF on dapagliflozin in HFrEF.37 DAPA-HF hierarchical secondary endpoint (total HHF; Table 3) and significantly
enrolled and randomised 4,744 patients with the following characteristics improved the second hierarchical secondary endpoint, the mean slope of
mean age 66.4 years, 23% women, T2D 41.8%, New York Heart Association change in eGFR (HR 1.3; 95% CI [1.10–2.37] p<0.001). The renal benefit has
(NYHA) stage II 67.5%, median N-terminal pro-B type natriuretic peptide (NT- also proved by the reduction of the composite renal endpoint (ESRD +
pro-BNP) was 1,437 pg/ml, mean estimated glomerular filtration rate (eGFR) sustained profound eGFR decrease) (HR 0.50; 95% CI [0.32–0.77]) with a
was 66 ml/min/1.73 m2, 40.2% had eGFR <60 ml/min/1.73 m2. Key inclusion RRR of 50%.
criteria are shown in Supplementary Material Table 1 and detailed
demographic and clinical characteristics are shown in Table 2. Considering Beyond the results achieved on primary and secondary endpoints,
OMT, patients were well treated: ACEi/ARB/ARNI pooled 94% (split: ACEi empagliflozin also showed a significant benefit on QoL in HFrEF measured
56%, ARB 28%, ARNI 11%), β-blockers 96%, MRA 71%, ivabradine 5%. The by the symptoms score of the KCCQ that was significantly better than
OMT percentages of DAPA-HF were even better than that of PARADIGM-HF. placebo (p=0.0058; absolute difference 1.7). As in DAPA-HF, the
Noticeably, as in PARADIGM-HF, the percentages of CRT/ICD were particularly prespecified subgroup analyses did not show any significant difference
low in DAPA-HF (7% and 26%, respectively), showing the intention to test the regarding the reduction or primary endpoint between diabetic patients
efficacy of the drug before the implantation of any devices (Table 2). (HR 0.72; 95% CI [0.60–0.87]; RRR 28%) and non-diabetic patients

Women and Diabetes
Table 2: Comparison of Different Populations Enrolled and of Different Outcomes in Major RCTs in Chronic HFREF
PARADIGM-HF37 DAPA-HF38 EMPEROR- GALACTIC-HF76 VICTORIA70

Reduced41
Main Baseline Characteristics of Different Populations Enrolled
Total population enrolled 8,442 4,744 3,730 8,256 5,050
Mean age, years 63.8 66.4 66.9 64.5 67.3
Women 22% 23% 24% 21.3% 23.9%
NYHA classification
Class II 70.9% 67.5% 75.1% 53.2% 59.0%
Class III 24.1% 31.6% 24.4% 43.8% 39.7%
Class IV 0.7% 0.9% 0.5% 3.0% 1.3%
LVEF (%; mean) 29.5 31.1 27.5 26.6 28.9
NT-pro-BNP, median, pg/ml 1,608 1,437 1,906 1,971 2,816
Previous HF hospitalisations
Any time 63% 47.4% 30.8% 74.4% 83.9%
≤12 months randomisation N/A 27% 30.8% 74.4% 83.9%
≤6 months randomisation 31.1% 16.4% N/A 54.6% 83.9%
≤3 months randomisation 19.1% 7.8% N/A 36.2% 66.7%
Currently hospitalised for AHF (worsening) N/A N/A N/A 25.2% N/A
Ischaemic aetiology 59.7% 56.4% 51.7% 54.0% 58.3%
Stroke 8.7% 9.9% 11.3% 9.1% 11.5 %
Hypertension 71.2% 74% 72.3% 70.3% 79.1%
Anaemia 20.3% 27.6% N/A N/A 20.9%
COPD 12.9% 12.3% 11.9% 16.3% 17.2%
AF/flutter 37% 38.3% 36.7% 42.1% 44.9%
Systolic blood pressure (mmHg mean) 121 122 122 117 121
Heart rate (beats/min mean) 72 71 71 72 73
eGFR (ml/min/1.73 m ) 2
Mean 70 65.8 62 60.3 61.5

<60 ml/min/1.73 m2 33% 40.2% 48.3% 52.5% 52%
T2D 34.9% 41.8% 49.8% 40.1% 46.9%
Comparison of HFREF GDMT
ACE-I/ARB 100% 83.7% 69.7% 67.4% 73.5%
ARNI N/A 10.7% 19.5% 19.3% 14.5%
β-blocker 93.6% 96.1% 94.7% 94.0% 93.1%
MRA 55.3% 71% 71.3% 77.0% 70.3%
Ivabradine 2% 5% N/A 6.5% N/A
SGLT2i N/A N/A N/A 2.7% N/A
ICD 14.9% 26.2% 31.4% 31.7% 27.8%
CRT 6.8% 7.5% 11.8% 14.0% 14.7%
Annualised Event Rate in the Comparator Group
CV death 7.5% 7.9% 8.1% 10.8% 13.9%
First HF hospitalisation 8.5% 9.8% 15.5% 15.2% 29.1%
All-Cause Death Observed in the Total Follow-up in the Comparator Group
Mean follow-up (months) 27 18.2 16.0 21.8 10.8
All-cause death 19.8% 13.9% 14.2% 25.9% 21.2%
AHF = acute heart failure; CV = cardiovascular; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronisation therapy; eGFR = estimated glomerular filtration rate; HF = heart failure;
LVEF = left ventricular ejection fraction; NT-pro-BNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; SGLT2i = sodium-glucose cotransporter type 2 inhibitors;
T2D = type 2 diabetes.
(HR 0.78;95% CI [0.64–0.97]; RRR 22%) and between patients with depletion, hypotension, bone fractures, limb amputations, severe
eGFR>60 versus <60 ml/min/1.73 m2. Empagliflozin showed the same hypoglycaemia (also in patients without T2D), diabetic ketoacidosis and
safety profile dapagliflozin in HFrEF, especially regarding volume urinary infections. As in the RCTs dedicated to prevention, empagliflozin

Women and Diabetes
Table 3: Women’s Benefit in RCTs Dedicated to HF for SGLT2is
Trial Primary Endpoint CV Death HF Events Total HHF and Total HHF All-cause
CV Death Mortality
Chronic HFrEF
DAPA-HF CV death + first HHF + urgent HR 0.82; 95% CI First HHF and urgent visits for 0.75; 95% CI HR 0.71; 95% CI HR 0.83; 95% CI
visits for WHF [0.69–0.98]; WHF [0.65–0.88]; [0.61–0.82]; p<0.01 [0.71–0.97)
HR 0.74; 95% CI [0.65-0.85] p=0.029 HR 0.70; 95% CI [0.59–0.83]; p=0.0002 RRR 29% p=0.022
p=0.00001 RRR 18% p=0.00003 RRR 25% RRR 17%
RRR 26% RRR 30%
EMPEROR- CV death + first HHF HR 0.92; 95% CI First HHF NA HR 0.70; 95% CI HR 0.92; 95% CI
Reduced HR 0.75; 95% CI [0.65–0.86]; [0.75–1.12]; p=not HR 0.69; 95% CI [0.59–0.81]; [0.58–0.85]; p<0.01 [0.77–1.10]; p=not
p<0.001 significant p<0.001 RRR 30% significant
RRR 25% RRR 8% RRR 31% RRR 8%
Acute HF
SOLOIST-WHF CV death + total HHF + urgent HR 0.84; 95% CI Total HHF + urgent visits for NA NA HR 0.82; 95% CI
visits for WHF [0.58–1.22]; p=not WHF [0.59–1.14]; p=not
HR 0.67; 95% CI [0.52–0.85]; significant HR 0.64; 95% CI [0.49–0.83]; significant
p=0.0009 RRR 16% p<0.001 RRR 18%
RRR 33% RRR 36%
CV = cardiovascular; HF = heart failure, HFrEF = heart failure with reduced ejection fraction; HHF = hospitalisation for heart failure; NA = not applicable; RCT = randomised clinical trial; RRR = relative
risk reduction; SGLT2i = sodium-glucose cotransporter type 2 inhibitors; WHF = worsening heart failure.
significantly increased genital infections compared to placebo, but these The first meta-analysis dedicated to SGLT2i in HFrEF showed that when
represented only 1.7% of patients in the empagliflozin arm (1,863); this considered together (empagliflozin and dapagliflozin) consistently reduce
data is not available for DAPA-HF. CV death (p=0.027 for efficacy; HR 0.86; 95% CI [0.76–0.98]; RRR 14%;
p=0.39 for heterogeneity), all-cause death (p=0.018 for efficacy; HR 0.87
Finally, in EMPEROR-Reduced, CV death and all-cause death were not 95% CI [0.77–0.98]; RRR 13%; p=0.39 for heterogeneity), CV death and
significantly reduced, so some authors have speculated about the impact first HHF (p<0.0001 for efficacy; HR 0.74; 95% CI [0.68–0.82]; RRR 26%;
of empagliflozin on mortality. The reasons of the lack of statistical p=0.89 for heterogeneity), CV death and total HHF (p<0.0001 for efficacy;
significance have been elegantly discussed in a recent editorial.41 HR 0.75; 95% CI [0.68–0.84]; RRR 25%; p=0.91 for heterogeneity), first
Previously, we mentioned that the population enrolled in EMPEROR- kidney composite outcome (p=0.013 for efficacy; HR 0.62; 95% CI [0.43–
Reduced had a higher annual placebo event rate of the primary endpoint 0.90]; RRR 38%; p=0.42 for heterogeneity). Furthermore, the effect on the
when compared to the population of DAPA-HF (24.7 versus 15.3 per 100 primary endpoint is independent of the fact that patients had T2D, were
person-years). A further analysis of the placebo event rate showed that receiving ARNI or had an eGFR >60 versus <60 ml/min/1.73 m2.42
the rate of CV death was nearly the same between the two RCTs (8.1
versus 7.9 per 100 person-years in the placebo group for EMPEROR- Acute Heart Failure
Reduced and for DAPA-HF, respectively) whereas the rate of first HHF of The other major RCT in HF is SOLOIST-WHF dedicated to sotagliflozin (an
EMPEROR-Reduced was significantly higher than in DAPA-HF (15.5 versus SGLT1i and SGLT2i) which enrolled a population with AHF.43 Following the
9.8 per 100 person-years; Table 2). This shows that in EMPEROR-Reduced encouraging results of EMPA-RESPONSE-AHF (a pilot study on
the higher primary endpoint rate was driven by an elevated rate of HHF empagliflozin in very early phases of AHF), SOLOIST-WHF enrolled 1,222
but not rate of death, and this higher primary endpoint rate led to a patients with the following characteristics: median age 70 years; 33.7%
shorter mean follow-up of this RCT when compared to DAPA-HF (16.0 women; NYHA II 45.2%, NYHA III 45.8% and NYHA IV 4.4%; median LVEF
versus 18.2 months). On the other side, the sample size of patients 35% (79.1% had an LVEF <50%, 20.9%, LVEF ≥50%); median HbA1c 7.1%;
enrolled in EMPEROR-Reduced was significantly smaller than in DAPA-HF median NT-pro-BNP was 1,799.7 pg/ml; median eGFR: 49.7 ml/min/1.73 m2;
(3,730 versus 4,744), this had the final effect to significantly reduce the and 47.1% had a history of AF (key inclusion criteria in Supplementary
statistical power of the RCT. Indeed, there were 111 fewer CV deaths and Material Table 1).44 Patients were very well treated: ACEi/ARB/ARNI pooled
90 fewer all-cause deaths in EMPEROR-Reduced than in DAPA-HF (389 99.4% (ACEi: 40.5%, ARB: 42.1%, ARNi: 16.8%), β-blockers 92.1%, MRA
versus 500 and 515 versus 605). 64.5%, loop-diuretic 95%, CRT/ICD 20.3%, any glucose-lowering
medications (metformin/insulin/GLP1-RA/dipeptidyl peptidase-4 inhibitors/
A further element aggravating this reduced statistical power on mortality sulfonylurea): 85.4%. Sotagliflozin could be started prior to discharge
was the higher study treatment discontinuation rate in EMPEROR- from the hospital until a maximum of 3 days post-discharge. Half of the
Reduced, compared with DAPA-HF (17.1% versus 10.7%). Considering the patients started the drug during HHF. After a median follow-up of 9.2
significant reduction of CV death in EMPAREG-OUTCOME that was not months, sotagliflozin 200 mg/day (uptitrated to 400 mg/day as tolerated)
seen in DECLARE-TIMI58, it is very likely that both drugs have the same versus placebo on top of HF treatments significantly reduced the primary
effect in reducing CV death in T2D and in HFrEF, and the differences endpoint, a composite of CV death + total HHF + urgent visits for WHF,
outlined above are related to the design and conduction of each trial. with a RRR of 33% and NNT of 4 (HR 0.67; 95% CI [0.52–0.85]; p=0.0009).
EMPEROR-Reduced demonstrated the efficacy of SGLT2i on a more The first secondary hierarchical endpoint: total HHF + urgent visits for
severe HFrEF population and provided complementary data to those of WHF was significantly reduced whereas CV death (the second secondary
DAPA-HF, strengthening the evidence of benefit of this class of drugs hierarchical endpoint) considered alone as well as all-cause death were
in HF. not significantly reduced (Table 3).

Women and Diabetes
Beyond the endpoints on major outcomes, sotagliflozin significantly A press release on EMPEROR-Preserved (a dedicated RCT of empagliflozin
improved QoL as reported by a 4.1 point increase in KCCQ (p=0.005) and in HFmREF and HFpEF) revealed that empagliflozin has met the primary
showed a significant renal benefit confirmed by the lower mean reduction endpoint of CV death and HHF (Supplementary Material Table 1).49 The
in the eGFR compared to placebo after the initial treatment period reduction of the primary endpoint is significant, so that this is the first RCT
(p=0.02). Similar to DAPA-HF and EMPEROR-Reduced, there were no in the history of cardiology that has a significant impact on prognosis in
major safety issues with sotagliflozin, with the difference of significant this population. Moreover, this will confirm that SGLT2is have multiple
increase of diarrhoea (6.9% versus 4.1%) and severe hypoglycaemia (1.5% benefits in HF irrespective of LVEF.
versus 0.3%) with respect to placebo.
Chronic Kidney Disease
SOLOIST-WHF was the first RCT in the history of cardiology to demonstrate As mentioned above, meta-analyses of RCTs dedicated to prevention in
a significant reduction of major combined endpoints such as total HHF + T2D provided another unexpected benefit – the significant reduction
CV death + urgent visits for WHF. Despite that, CV death, as well as all- (both for each RCT and for the pooled analysis) of the composite endpoint:
cause death, have not been significantly reduced when considered alone, worsening renal function + ESRD + renal death not only in patients with an
but the same considerations for EMPEROR-Reduced are even more valid established ASCVD but also in T2D patients without ASCVD.10 Equal to
for SOLOIST-WHF which was largely underpowered for mortality. Indeed, what happened for HF, the developers of these drugs designed and
loss of funding from the sponsor during enrolment – also affected by the conducted RCTs dedicated to patients with CKD, such as CREDENCE,
coronavirus disease 2019 pandemic – led to the trial enrolling only 1,222 DAPA-CKD, and EMPA-KIDNEY, the results of the first two RCTs are already
of the planned 4,000 patients and it being stopped earlier than planned. published and a detailed discussion of these trials is outside of the
purpose of this review.50,51 In summary, CREDENCE – dedicated to
The major conclusion is that in AHF an initiation of an SGLT2i in a late canagliflozin 100 mg/day in CKD – enrolled 4,401 patients with the
phase of hospitalisation provided significant benefits, and this is just the following main characteristics: mean age 63 years, 33.9% women, mean
beginning of evidence because RCTs with a similar design such as eGFR 56.2 ml/min/1.73 m2 (key inclusion criteria in Supplementary Material
EMPULSE (empagliflozin) and DAPA ACT HF-TIMI68 are ongoing, while Table 1).50 DAPA-CKD – dedicated to dapagliflozin 10 mg/day in CKD –
DICTATE-AHF is enrolling patients with AHF who will start dapagliflozin in enrolled 4,304 patients with the following main characteristics: mean age
the early phase of HHF.45 61.9 years, 33.1% women, mean eGFR 43 ml/min/1.73 m2, 67.5% T2D,
32.5% without T2D (key inclusion criteria in Supplementary Material
Heart Failure with Preserved Ejection Fraction Table 1).51 In short, these two RCTs showed a significant reduction in the
HFpEF is a multifaceted syndrome and over the past 20 years, several same primary endpoint – a composite of ESRD, doubling of serum
efforts have been made to identify, recognise and characterise this creatinine, renal death, and CV death. All the secondary endpoints were
complex syndrome that under this general label hides dozens of different significantly reduced as well, both for CREDENCE (CV death + first HHF,
diseases ranging from hypertensive heart disease, obesity, metabolic MACE, first HHF) and for DAPA-CKD (ESRD + renal-death + ≥50% sustained
syndrome, pulmonary hypertension to cardiac amyloidosis, hypertrophic eGFR decline, CV death + first HHF, all-cause death). The most important
cardiomyopathy and restrictive cardiomyopathies.46 result is probably that of DAPA-CKD because this was achieved irrespective
of diabetic status.
Several studies and registries showed that HFrEF and HFpEF number or
comorbidities are very similar and their number is related to the patient’s In conclusion, we can state that the four domains of SGLT2is are: T2D,
age. 33,34 Furthermore, HFpEF due to its kaleidoscopic nature had several CHF, AHF and CKD (Figure 1) and after the publication of EMPEROR-
problems of definition so that recently the Heart Failure Association of the Preserved we will probably be able to add a fifth domain of HFpEF.
ESC redefined the diagnostic criteria to reduce the possibility of
misdiagnosis.47 However, the complexity of HFpEF has never been Recently, we published a review in which we discussed the multiple
correctly assessed over time and consequently a large number of mechanisms of cardiorenal benefits of this class of drugs with respect to
molecules have been tested in RCTs by the ‘all-comers’ or ‘one-size-fits- the previous review we underline a recent discovery of a new mechanism
all’ approach, with several failures. As a major consequence, no therapies that can be highly beneficial particularly to women.52,53 Indeed, two
have been shown to convincingly modify prognosis in HFpEF. separate research groups were able to demonstrate (in human, mouse
and pig models) that SGLT2i activate, both in HFrEF and in HFpEF, the
This has pushed researchers to better identify specific phenotypes and to pathway of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/
develop specific therapies for different phenotypes or different aetiologies protein kinase G (PKG) that provokes the titin phosphorylation and ends in
of HFpEF. One of the clearly identified phenotypes is constituted by reducing cardiomyocyte stiffness and interstitial myocardial fibrosis, with
women with the metabolic syndrome (or even T2D) who develop particular benefit on diastolic function.54,55 Moreover, this pathway has
concentric hypertrophy without chamber dilatation and dominant diastolic important effects on vessel function and remodelling (see vericiguat) and
dysfunction.48 this can be highly beneficial in particular for women that are older than
men at HF diagnosis and have a more compromised vascular function.
In this area, pooled data from SOLOIST + SCORED in HFpEF patients were
presented. The opportunity given by this analysis is to have a larger Another important clue to underline is a recent subanalysis of DAPA-HF,
sample size (one derived from an RCT dedicated to chronic kidney which demonstrated that SGLT2is cause a ‘smart’ reduction of systolic
disease and the other one to HF, constituted by 739 HFpEF patients. blood pressure (SBP).56 In fact, they reduce SBP only in patients with
Sotagliflozin significantly reduced the endpoint total CV death, HHF and hypertension but in hypotensive patients (SBP ≤110 mmHg) they do not
urgent heart failure visits, with RRR 37% (HR 0.63; 95% CI [0.45–0.89]; have any impact on blood pressure. This is a particular advantage in
p=0.009). The same happened with the 456 HFmrEF, with RRR 39% (HR specific groups of HFrEF patients who have low SBP and cannot tolerate
0.61; 95% CI [0.40–0.94]). ACEi/ARB/ARNI or high doses of β-blockers. Women in clinical practice are

Women and Diabetes
Figure 1: The Four Domains of Sodium–Glucose Cotransporter Type 2 Inhibitors
AHF CKD
SGLT2i
CHF T2D
HFrEF
AHF = acute heart failure; CHF = chronic heart failure; CKD = chronic kidney disease; HFrEF = heart failure with reduced ejection fraction, SGLT2i = sodium–glucose cotransporter type 2 inhibitors;
T2D = type 2 diabetes.
more exposed and often present with lower SBP than men so drugs with but after this RCT, ARNI have been recommended globally from all the
minimal or no impact on that offer a specific practical advantage. international HF guidelines in substitution of an ACEi/ARB in chronic HFrEF
as a class I indication.
Sacubitril/Valsartan: A Drug with
Potential Higher Impact on Women The RCTs TITRATION, PIONEER-HF and TRANSITION extensively proved
Chronic Heart Failure with Reduced Ejection the safety of this drug when compared to an ACEi both in the chronic
Fraction and Acute Heart Failure ambulatory HFrEF setting and in the AHF hospitalised setting in terms of
The multiple benefits of the ARNI sacubitril/valsartan have been well worsening renal function, renal adverse events, hyperkalaemia and
established since 2014 when PARADIGM-HF was published.36 The design angioedema.57–59 Hypotension and symptomatic hypotension are more
of this RCT is similar to DAPA-HF. PARADIGM-HF is the largest RCT by frequent than with ACEi/ARB, but in those RCTs this did not lead to drug
population enrolled in the history of HFrEF so far, enrolling 8,442 patients, discontinuation and has been managed with lowering ARNI dosage. A
22% of whom were women. The major clinical and demographic slower uptitration regimen – as TITRATION showed – reduces the
characteristics are summarised in Table 2. After a mean follow-up of 27 incidence of hypotension and this is even more useful in women with
months, sacubitril/valsartan (uptitrated to 200 mg twice a day) versus HFrEF who often have lower blood pressure in the clinical scenario.57
enalapril on top of HFrEF standard of care, significantly reduced the
primary endpoint: a composite of CV death and first HHF (HR 0.80; 95% PIONEER-HF and TITRATION showed important benefits in terms of efficacy
CI [0.73–0.87]; p<0.0001), with RRR 20% and NNT 21, as well as the split in key secondary exploratory endpoints (CV death and HHF), so that they
separate components of the primary endpoint, i.e. CV death (HR 0.80; are suggested in recent ACC and CCS guidelines as first-line treatments in
95% CI [0.71–0.89]; p<0.001, RRR 20%) and the first HHF (HR 0.79; 95% CI the AHF setting. PROVE-HF and EVALUATE-HF proved that ARNI improve
[0.71–0.89]; p<0.001, RRR 21%].36 Also, the secondary endpoint all-cause cardiac remodelling in terms of ventricular volume reduction and systolic
death has been significantly reduced (HR 0.84; 95% CI [0.76–0.93]; function improvement. More trials (PARADISE-MI and LIFE) were presented
p=0.0009, RRR 16%). Beyond this major outcome, sacubitril/valsartan at the American College of Cardiology’s 2021 scientific session.60,61
compared to enalapril significantly reduced sudden cardiac death, total
HHF, total hospitalisations, as well as total emergency department Heart Failure with Mid-range (Mildly Reduced)
admissions for WHF, total stays in the intensive care unit and significantly and Preserved Ejection Fraction
improved symptoms (measured by NYHA) and QoL measured by KCCQ. A The most important RCT that showed particular benefit for women is
detailed analysis of PARADIGM-HF is outside of the scope of this review, PARAGON-HF, dedicated to sacubitril/valsartan versus valsartan in

Women and Diabetes
HFpEF.62 PARAGON-HF enrolled 4,822 HF patients with an LVEF >45% New Molecules with Impact on
(indicating a mix of HFmrEF and HFpEF), NYHA class II–IV, elevated level Quality of Life in HFrEF
of natriuretic peptides (with different cut-offs depending on the Vericiguat
occurrence of a recent HHF and the presence of AF), evidence of Vericiguat is a new drug that increases cGMP with a double mechanism,
structural heart disease, and on diuretic therapy (Supplementary one side directly stimulates the soluble guanylate cyclase (sGC) through a
Material Table 1). Noticeably, 51.7% of patients were women, NYHA class binding site independent of NO and the other sensitises sGC to
II 77.7% and NYHA class III 19.4%. After a median follow-up of 35 months, endogenous NO by stabilising the NO-sGC binding site. The final effect is
PARAGON-HF failed to demonstrate a significant reduction of the an important boost of the NO/cGMP/PKG pathway. We previously
primary endpoint of total HHF + CV death (HR 0.87; 95% CI [0.75–1.01]; mentioned this pathway because it is partially activated also by ARNI and
p=0.059; RRR 13%). The reasons for this lack of efficacy have been SGLT2i. However, vericiguat specifically activates this pathway that has
explored in several papers and discussed in heated debates, but beneficial effects both in diastolic and in systolic ventricular dysfunction
invariably lie in the elevated number of exclusion criteria (with 5,537 and in patients with HF in whom the oxidative stress leads to a reduction
patients excluded during the screening phase) who made the population of NO and to cGMP deficiency. VICTORIA trial – dedicated to vericiguat in
of PARAGON-HF far from the real population of HFpEF patients, the all- HFrEF – enrolled and randomised 5,050 patients (key inclusion criteria in
comers approach (that had already proved to be disastrous in HFpEF), Table 2).68,69
and a likely wrong primary endpoint that, unlike the DAPA-HF, did not
include urgent visits for HF (a recent post-hoc analysis showed that in Vericiguat was started at a dosage of 2.5 mg/day at randomisation and
this case, the reduction of primary endpoint would have been biweekly uptitrated in a blinded fashion to reach the target dose of 10 mg
significant).63–65 Interestingly, prespecified analyses, showed a per day (if tolerated based on mean SBP and clinical symptoms). After 10.8
significant benefit for two specific subgroups – HF with an LVEF <57% months of mean follow-up, vericiguat significantly reduced the primary
(substantially the HFmrEF population; HR 0.78; 95% CI [0.64–0.95]; endpoint: a composite of CV death and first HHF [HR 0.90 [0.82–0.98];
p=0.03 for interaction) and women (HR 0.73; 95% CI [0.59–0.90]; p=0.02, RRR 10%). However, the benefit was significant only for the first
p=0.017 for interaction). HHF (HR 0.90; 95% CI [0.81–1.00]; p=0.048, RRR 10%] but not for CV death
(HR 0.93; 95% CI [0.81–1.06]; p=0.269). The secondary endpoints
The women in the trial were older than men, had more HF symptoms confirmed the benefit on HHF, indeed total (first and recurrent) HHF were
(indicated by worsening NYHA class), a lower median NT-pro-BNP level, significantly reduced (HR 0.91; 95% CI [0.84–0.99]; p=0.023, RRR 9%) with
worse QoL measured by KCCQ, higher median LVEF (60% versus 55%) no effect on all-cause death (HR 0.95; 95% CI [0.84–1.07] p=0.38).
than men. Moreover, women had a lower mean eGFR, had a greater
incidence of obesity, had less coronary heart disease, T2D, and chronic Although at a first and superficial glance the results achieved in VICTORIA
obstructive pulmonary disease. More detailed analysis showed that the do not seem to be remarkable, the understanding of the characteristics of
higher benefit of ARNI in women than in men was covered mostly by HHF the enrolled population explains their important impact on HFrEF. Indeed,
with RRR of 33% (HR 0.67; 95% CI [0.54–0.84]; p=0.0048 for interaction), the population enrolled in VICTORIA had very severe HF when compared
without reduction in CV death (HR 1.05; 95% CI [0.78–1.41], p=0.37 for to all the recent RCTs dedicated to HFrEF (Table 2), which included 23.9%
interaction). The improvement in NYHA class was similar in women and of women, with higher NYHA III class 39.7%, mean LVEF 28.9%, very high
men, whereas the improvement in KCCQ seemed to be lower in women levels of median NT-pro-BNP = 2,816 pg/ml (double DAPA-HF and
than in men.66 significantly higher than the other RCTs), ~84% had an HHF within 6
months, with the remaining ~16% on IV diuretics managed as outpatients,
These results can be explained by the activation of different pathways in a compromised renal function superimposable to that of EMPEROR-
women or more likely by the activation of the same pathways but with Reduced (mean eGFR 61.5 ml/min/1.7m2, 52% had eGFR <60 ml/min/1.73
different strength and intensity in women than in men. Indeed, despite m2), and 46.9% with T2D. The HFrEF OMT was comparable to that of
worse symptoms and QoL, the lower median level of natriuretic peptides DAPA-HF and EMPEROR-Reduced and included 14.5% of patients on ARNI,
in women enrolled in PARAGON-HF was mostly driven by a higher 59.7% having triple therapy (ACE-I/ARB/ARNI, β-blocker, MRA), 27.8% with
prevalence of obesity and NT-pro-BNP is just a marker and the non-active an ICD and 14.7% with a CRT (Table 2).
part of the effective hormones (ANP/BNP). Other studies coming from a
subanalysis of PROVE-HF have demonstrated the greater importance of The HFrEF severity of VICTORIA’s population is well described by the
the increase of ANP level with sacubitril/valsartan and the increase of annualised event rate in the comparator group. indeed the annual rate of
cGMP.67 In women, there is the possibility that the decrease of oestrogen- CV death was two times higher than that of PARADIGM-HF, DAPA-HF, and
dependent stimulation of natriuretic peptides after menopause cause a EMPEROR-Reduced and the annual rate of first HHF rate was three times
further reduction of the NO/cGMP/PKG pathway, whose activation can be higher than that of PARADIGM-HF and DAPA-HF and twice as high as that
highly beneficial in women compared with men, and this benefit can be of EMPEROR-Reduced (Table 2). Add to this, the rate of all-cause death in
higher with the same serum and urinary levels of cGMP (therefore the the comparator group was 21.2% in 10.8 months similar to that of
same level of urinary cGMP in both sexes in PARAGON-HF does not PARADIGM-HF (19.8%) with the noticeable difference that this rate was
exclude this hypothesis). Finally, the inhibition by ARNI of neprilysin has achieved in 27 months. These numbers are close to the event rate that we
multiple benefits that we still only partially know because neprilysin observe in clinical registers and in our clinical practice in HFrEF patients
inactivates multiple biological substances with potentially different and explain what type of patients were enrolled in this trial. The benefit of
repercussions in each sex. VICTORIA on primary endpoint in terms of absolute RR was comparable to
that of DAPA-HF and was mostly due to the benefit on HHF.70 Furthermore,
Taking these considerations together, the use of ARNI in HFpEF in specific this benefit was achieved in a very short mean follow-up and it is likely
populations of women, such as those who are older and obese, can be that if the mean follow-up was longer, the benefit would have been even
considered to improve QoL by reducing HHF. greater.

Women and Diabetes
There were no major safety issues with vericiguat. In particular, there were Table 4: Pharmacological Pathways and
no significant differences in terms of syncope and hypotension, while there Indications of the New Medical Treatments
was an increase in the rate of anaemia (7.6% versus 5.7% of placebo).
Particularly, if the SBP was ≥90 and <100 mmHg the dosage was maintained, Indication Drugs Pathways
whereas in the case of SBP <90 mmHg the vericiguat dose was reduced. Type 2 diabetes SGLT2i Multiple (see text)
Therefore, this drug has no negative impact on hypotensive patients. GLP1-RA Multiple (see text)
Prevention and/or PCSK9i LDL-C reduction
In summary, this drug is highly beneficial in patients with recent HHF (<6 Dyslipidaemia Inclisiran LDL-C reduction
months) who have severe HF (as defined by the characteristics of the (Hypercholesterolaemia,
Icosapentyl ethyl VLDL and triglycerides
enrolled population) and present evident (clinical and laboratory) signs of Hypertriglyceridaemia)
reduction
congestion and can be considered in hypotensive patients not able to Bempedoic acid LDL-C reduction
tolerate ACEi/ARB/ARNI, as already discussed for SGLT2is. Furthermore,
Acute heart failure SGLT2i and SGLT1i Multiple (see text)
the selective activation and boosting of the NO/cGMP/PKG pathway
(sotagliflozin)
combines the myocardial benefits (inhibition of hypertrophy, fibrosis,
Chronic HFrEF ARNI Neprilysin inhibition/
inflammation and increase of coronary blood flow) that cause an
upregulation of natriuretic
improvement of diastolic function, ventricular-arterial coupling and an peptides
anti-remodelling effect with the vascular benefits (inhibition of RAAS inhibition
inflammation, vasodilative properties and positive effect on vasal NO/cGMP/PKG boosting
remodelling) that may have positive consequences, especially in women. SGLT2i Multiple (see text)
Vericiguat Selective stimulation of NO/
Recently our group provided a proof-of-concept study that demonstrated
cGMP/PKG
a compensatory active role of arteries in HF across the LVEF spectrum. Omecamtiv Mecarbil Selective cardiac myosin
New drugs, such as vericiguat specifically act on arterial function and can activation
be more beneficial in specific populations with a more compromised Chronic HFmrEF ARNI and SGLT2i Neprilysin inhibition/
arterial function – such as older women with HF and HFpEF patients.71 upregulation of natriuretic
peptides
Omecamtiv Mecarbil RAAS inhibition
NO/cGMP/PKG boosting
Omecamtiv mecarbil (OM), is a selective cardiac myosin activator that
increases cardiac contractility by specifically binding to myosin, stabilising Chronic HFpEF ARNI only in women Neprilysin inhibition/
upregulation of natriuretic
the pre-powerstroke state prior to onset of cardiac contraction with the
peptides
effect of increasing the number of myosin heads that can bind to the actin RAAS inhibition
filament and undergo a powerstroke once the cardiac cycle starts. Its NO/cGMP/PKG boosting
action can be described as ‘more hands pulling on the rope’. Moreover, OM
decreases the turnover of adenosine triphosphate in the absence of an SGLT2i and SGLT1i(?) Multiple (see text)
interaction with the actin filament, potentially increasing the overall Chronic kidney disease SGLT2i Multiple (see text)
energetic efficiency of the system by diminishing adenosine triphosphate ARNI = angiotensin receptor neprilysin inhibitor; cGMP = cyclic guanosine monophosphate;
use not associated with mechanical work.72 This peculiar mechanism does GLP-1 RA = glucagon-like peptide-1 receptor agonists; HDL-C = HDL cholesterol; HFmrEF = heart
failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction;
not increase myocyte calcium and does not increase myocardial HFrEF = heart failure with reduced ejection fraction; LDL-C = LDL cholesterol; NO = nitric oxide;
consumption of oxygen. This clearly differentiates this drug from other PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitors; PKG = protein kinase G;
inotropes (such as β-adrenergic receptor agonists, phosphodiesterase RAAS = renin–angiotensin–aldosterone system; SGLT2i = sodium-glucose cotransporter type 2
inhibitors; VLDL = very low-density lipoprotein.
inhibitors and levosimendan). OM has the final effect to increase the stroke
volume, the left ventricle ejection time and systole duration, also reducing
heart rate. OM has shown multiple benefits in HFrEF patients in Phase II cause death (HR 1.00 95% CI [0.92–1.09]; p=not significant). Beyond the
trials, which has led to the development of a large Phase III RCT.73,74 major outcome, QoL measured by KCCQ (another secondary endpoint)
was significantly improved. As we previously mentioned for VICTORIA, the
GALACTIC-HF – dedicated to OM in HFrEF – enrolled and randomised severity of the population enrolled in GALACTIC-HF is well described by
8,442 patients with a severe HF when compared to other recent RCTs the annualised event rate of CV death in the comparator group – 10%
(Supplementary Material Table 1 and Table 2): 21.3% were women, NYHA higher than in other recent HFrEF RCTs (only inferior to that of VICTORIA)
III represented 43.8% of patients, median LVEF was particularly low and of first HF event rate 15.2% (the same as EMPEROR-Reduced;
26.6%, median NT-proBNP was similar to that of EMPEROR-Reduced 1,971 Supplementary Material Table 1).
pg/ml, 54.6% had a recent HHF (within 6 months), interestingly 25.2% had
AHF, median eGFR:60.3 ml/min/1.73 m2, T2D patients were 40.1%. Patients Pre-specified group analysis showed that the benefit for primary endpoint
were very well treated as for other RCTs (Table 2).76 After 21.8 months of was particularly significant for people with a median LVEF <28.0% (HR
mean follow-up, OM – titrated from 25 to 50 mg twice daily to reach a 0.84; 95% CI [0.77–0.92], p=0.03 for interaction:).76 Regarding safety, OM
specific plasmatic concentration – significantly reduced the primary did not significantly increase ventricular tachyarrhythmias, torsades de
endpoint: a composite of CV death and first HF event (defined by an HHF pointes or QT prolongation, MI or any serious adverse events. Further,
or emergency department access for HF or urgent visit for WHF), HR 0.92 post-hoc analysis provided generator hypotheses of greater benefit in
95% CI [0.86–0.99]; p=0.025; RRR 9%. However, when considered alone more advanced HF populations (LVEF <28% plus one of the following:
none of the individual components of primary endpoint were significantly HHF within 3 months, NYHA III/IV, NT-pro-BNP >2,000 pg/ml, SBP
reduced (CV death: HR 1.01 95% CI [0.92–1.11]; p=0.86; first HF event: HR 2.85 mmol/l.) that need to be confirmed in future studies. On the other
0.93 95% CI [0.86–1.00], p=0.06) as well as the secondary endpoint all- hand, COSMIC-HF has also demonstrated that OM significantly increases

Women and Diabetes
stroke volume, systolic ejection time, reduces ventricular volumes, NT- Conclusion
pro-BNP levels and heart rate and these actions are demonstrated as also Cardiovascular risk remains high for women with diabetes and is
significant for the right ventricle.77 particularly underestimated – because the SCORE chart does not take
into account specific women’s risk factors, such as premature
In summary, this is the first inotrope in the history of cardiology that does menopause or peripartum complications, and this contributes to
not increase CV death and all-cause death, does not have any adverse inadequate prevention strategies in this population. The suboptimal
events and that is active (significantly reducing the primary endpoint) on a management of women with diabetes leads them to progress to overt
population of advanced HF acting on both ventricles without any reduction HF. New therapeutic approaches offered by new drugs have shown
of SBP. Further studies will clarify the benefits of OM, but its introduction evidence of multiple benefits on CV morbidity and mortality in women.
to HF therapies can be an added value in women with severe HF who are A better implementation of new pharmacological treatments both in CV
unable to tolerate ACEi/ARB/ARNI or high dosage of β-blockers because prevention and in HF is an unmet need for women with diabetes and
of hypotension. In this population of advanced HFrEF, a combination of requires a greater commitment from the medical community to improve
drugs without any effect on SBP, such as SGLT2i, MRA, vericiguat and OM women’s health.
should be considered, not only improving outcomes and QoL but also
generating amelioration myocardial and vascular function that makes it A specific focus on benefits of new drugs that potentially have greater
possible to start and titrate ACEi/ARB/ARNI. effect in women than in men – as may be the case for ARNI as shown in
PARAGON-HF – and on specific pathways, potentially more important in
Table 4 summarises the indications of the new medical treatments in women than in men – as is the case of NO/cGMP/PKG – can lead us to
women from prevention to heart failure management. develop a tailored-approach using ‘precision medicine’.
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collaboration to optimize cardiovascular prevention and Worsening heart failure episodes outside a hospital setting


Women and Diabetes Preventing Heart Disease in A New Era of Therapies

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Women and Heart Disease

Women and Diabetes: Preventing Heart Disease in a New Era of Therapies

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EUROPEAN CARDIOLOGY REVIEW

Trial Total Population, Primary Endpoint CV Death Selected Major

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PARADIGM-HF37 DAPA-HF38 EMPEROR- GALACTIC-HF76 VICTORIA70

Mean 70 65.8 62 60.3 61.5

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Table 3: Women’s Benefit in RCTs Dedicated to HF for SGLT2is

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Figure 1: The Four Domains of Sodium–Glucose Cotransporter Type 2 Inhibitors

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EUROPEAN CARDIOLOGY REVIEW

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