ArticlePDF Available

Abstract and Figures

During the latest European Society of Cardiology (ESC) congress, impressive results have been reported regarding the clinical benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with reduced ejection fraction (HFrEF) in the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPERORReduced) and Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF) trials. Previous CV benefits also have been reported with Dulaglutid, Liraglutid and Semaglutid for the GLP1-RA class. Nevertheless, some clinical issues remain unresolved.
This content is subject to copyright.
Published online: December 30, 2020
Reviews in Cardiovascular Medicine
Rev. Cardiovasc. Med. 2020 vol. 21(4), 489–492
©2020 Sabouret et al. Published by IMR Press.
Editorial
New anti-diabetic agents: major advances with
unanswered questions
Pierre Sabouret1,*, Pier Paolo Bocchino2and Giuseppe Biondi-Zoccai3,4
1Heart Institute and ACTION Group, Pitié-Salpétrière, Sorbonne University, 47-83 Boulevard de l'Hôpital, 75013, Paris,
France
2Division of Cardiology, Department of Medical Sciences, University of Turin, “Città della Salute e della Scienza” hospital,
10100, Turin, Italy
3Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100, Latina, Italy
4Mediterranea Cardiocentro, 80100, Napoli, Italy
*Correspondence: cardiology.sabouret@gmail.com (Pierre Sabouret)
DOI:10.31083/j.rcm.2020.04.220
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Keywords
Diabetes mellitus; SGLT2i; GLP1-RA; heart failure; chronic kidney dis-
ease
During the latest European Society of Cardiology (ESC)
congress, impressive results have been reported regarding the
clinical benefits of sodium-glucose cotransporter 2 inhibitors
(SGLT2i) in heart failure with reduced ejection fraction (HFrEF)
in the EMPagliflozin outcomE tRial in Patients With chrOnic
heaRt Failure With Reduced Ejection Fraction (EMPEROR-
Reduced) and Dapagliflozin on the Incidence of Worsening Heart
Failure or Cardiovascular Death in Patients With Chronic Heart
Failure (DAPA-HF) trials (McMurray et al.,2019;Packer et al.,
2020). A meta-analysis addressing the combined 8474 patients
from both trials showed a 13% relative risk reduction (RRR) of
total mortality (HR [hazard ratio], 0.87; 95% CI [confidence in-
terval], 0.77-0.98), a 14% RRR of cardiovascular death (HR, 0.86;
95% CI, 0.76-0.98), a 25% RRR of cardiovascular death or hos-
pitalizations for heart failure (HR, 0.75; 95% CI, 0.68-0.84) and
a 38% RRR of the composite renal endpoint (HR, 0.62; 95% CI,
0.63-0.90) in the treatment group compared to placebo at a me-
dian follow-up time of 16 months in EMPEROR-Reduced and 18
months in DAPA-HF (Zannad et al.,2020).
After the encouraging results from Empagliflozin, Cardiovas-
cular Outcomes, and Mortality in Type 2 Diabetes (EMPAREG-
OUTCOME) and Dapagliflozin Effect on Cardiovascular Events-
Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58)
trials in diabetic patients with HFrEF (Kato et al.,2019;Zinman et
al.,2015), EMPEROR-Reduced and DAPA-HF demonstrated that
the magnitude of benefits were similar in both diabetic and non-
diabetic HFrEF patients, thus underlining that SGLT2i benefits are
not only mediated by the anti-diabetic pharmacological properties
of these drugs but other biological mechanisms are at work (Mc-
Murray et al.,2019;Packer et al.,2020). Notwithstanding, these
results should not obscure the clinical efficacy of glucagone-like
peptide-1 receptor agonists (GLP1-RA), which come as another
emerging class of anti-diabetic drugs (Gerstein et al.,2019;Marso
et al.,2016b,a).
Despite promising data from randomized controlled trials
(RCT) on SGLT2i and GLP1-RA, some issues remain unresolved.
Indeed, even if these drugs have proven cardioprotective effects,
the underlying mechanisms of action are not yet perfectly under-
stood Fig. 1. The class effect also remains uncertain due to the
pharmacological differences among individual drugs and the het-
erogeneity of the results from RCTs. Moreover, it is still debated
which class provides the greatest prevention against ischemic
events. Indeed, only 3 RCTs, namely EMPAREG-OUTCOME,
Liraglutide Effect and Action in Diabetes: Evaluation of Cardio-
vascular Outcome Results (LEADER) and Peptide Innovation for
Early Diabetes Treatment (PIONEER-6) demonstrated a reduction
of cardiovascular mortality in the treatment group compared to op-
timal medical therapy, whereas all the RCTs showed no difference
in non-fatal myocardial infarction rates between groups (Husain et
al.,2019;Marso et al.,2016a;Zinman et al.,2015). As for stroke,
only dulaglutide was proven to reduce stroke rates in the Dulaglu-
tide and cardiovascular outcomes in type 2 diabetes (REWIND)
trial (Gerstein et al.,2019), but this effect was not observed in other
GLP1-RA or SGLT2i trials. In REWIND, 58 (3.2%) stroke events
were reported in the dulaglutide group (n = 4949) compared to 205
(4.1%) in the placebo group (n = 4952) with a hazard ratio (HR)
of 0.76 (95% CI 0.62-0.94; P= 0.010). Ischemic stroke rates were
decreased by 25% (HR 0.75, 95% CI 0.59-0.94, P= 0.012) with
no impact on hemorrhagic stroke (HR 1.05, 95% CI 0.55-1.99; P
= 0.89) (Gerstein et al.,2020).
Concerning the renal outcomes, RCTs on individual SGLT2i
and GLP1-RA molecules demonstrated their protective role
against worsening renal function, likely due to an increase of natri-
uresis and glycosuria, reduced proteinuria, decrease in glomerular
Fig. 1. Overview of the effects of SGLT2i (A) and GLP1-RA (B) on heart, kidney and metabolic pathways. GLP1-RA, glucagone-like peptide-1
receptor agonists; HBA1c, glycated haemoglobin; HDL, high-density lipoprotein; SGLT2, sodium-glucose cotransporter 2.
oxidative stress leading to an improved glomerular renal function
Fig. 1 (Gerstein et al.,2019;Kato et al.,2019;Marso et al.,2016b,a;
Zinman et al.,2015). However, which drug class should be con-
sidered for first-line antidiabetic therapy in patients with chronic
kidney disease is still a matter of debate as the most protective
agents against worsening renal function are still argued.
Lastly, whether a combination therapy with these agents is ef-
fective on cardiovascular and/or renal outcomes in diabetic and
non-diabetic patients is yet to be assessed in clinical trials (Table 1)
and, should it be proved true, their safety and cost-effectiveness
will eventually need to be confirmed by post-marketing analyses.
Of note, retinopathy complications (vitreous hemorrhage, blind-
490 Sabouret et al.
Table 1. Trials evaluating the combination of GLP1RA with SGLT2i.
Study DURATION 8
(Packer et al.,2020)
DECREASE (IJzerman ,
2020)
EXANDA
(Kautzky-Willer ,
2020)
RESILIENT (Uni-
versitätsklinikum
Hamburg-
Eppendorf. ,
2020)
NCT03018665 (Wang ,2017)
Number 2017-004709-42 NCT03361098 NCT03007329 NCT03419624 NCT03018665
Treatment group ExenatideQW Exenatide BID ExenatideQW ExenatideQW Exenatide
+ Dapagliflozin + Dapagliflozin + Dapagliflozin + Dapagliflozin + Metformin
Comparator group Placebo + Placebo + Placebo + Placebo + BIAsp30
Dapagliflozin Dapagliflozin Dapagliflozin Dapagliflozin + Metformin
Patient’s T2 diabetes, T2 diabetes, T2 diabetes, T2 diabetes, T2 diabetes,
Characteristics HbA1c 8-12% BMI >
30 kg/m2
HbA1c 7-10%, BMI 30-40
kg/m2
HbA1c 6.5-11%,
BMI 25 kg/m2
HbA1c 8-11% BMI
30 kg/m2
HbA1c 8-14% BMI 24-40
kg/m2
Primary end-
points
Changes in HbA1c Differences in neuronal
activity in central reward and
satiety activity in response to
food
Change in hepatic
lipid content
Differences in
weight and HbA1c
Rate of Inducing Diabetes +
Change of Rate of Maintaining
Diabetes Remission + Time of
Maintaining Diabetes
Remission
Status Published Recruiting Recruiting Ongoing Recruiting
T2 : Type 2; HbA1c : glycosylated Hemoglobin; IR:insulin resistance.
ness or conditions requiring treatment with an intravitreal agent
or photocoagulation) may be higher with GLP1-RA as reported
for semaglutide compared to placebo in the Trial to Evaluate Car-
diovascular and Other Long-term Outcomes with Semaglutide in
Subjects with Type 2 Diabetes (SUSTAIN 6) (HR 1.76, 95% CI
1.11-2.78; P= 0.02) (Huang and Lee,2020;Marso et al.,2016a).
Future studies are warranted to better assess the pharmacolog-
ical properties, efficacy and safety of SGLT2i and GLP1-RA in
order to optimize the management of both diabetic patients and
non-diabetic individuals with heart failure against a background
of optimal medical treatmsent (Cosentino et al.,2020;Di Lullo et
al.,2020).
Author contributions
Pierre Sabouret and Giuseppe Biondi Zoccai conceived the
study. Pierre Sabouret and Pier Paolo Bocchino did the literary
search and wrote the first draft of the manuscript. All authors crit-
ically reviewed the manuscript. All authors read and approved its
final version.
Acknowledgment
There are no acknowledgments to disclose.
Funding
None.
Conflict of Interest
Dr. Sabouret reports consulting or lecture fees from Am-
gen, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, Pfizer,
Servier, Vifor, Sanofi Regeneron, outside the submitted work. Dr.
Biondi-Zoccai has consulted for InnovHeart, Milan, Meditrial,
Rome, and Replycare, Rome, all in Italy, outside the submitted
work. Dr. Bocchino has no conflicts of interest to declare.
Submitted: October 19, 2020
Revised: December 06, 2020
Accepted: December 08, 2020
Published: December 30, 2020
References
Cosentino, F., Grant, P. J., Aboyans, V., Bailey, C. J., Ceriello, A., Del-
gado, V., Federici, M., Filippatos, G., Grobbee, D. E., Hansen, T. B.,
Huikuri, H. V., Johansson, I., Jüni, P., Lettino, M., Marx, N., Mellbin,
L. G., Östgren, C. J., Rocca, B., Roffi, M., Sattar, N., Seferović, P.
M., Sousa-Uva, M., Valensi, P., Wheeler, D. C.; ESC Scientific Doc-
ument Group. (2020) 2019 ESC Guidelines on diabetes, pre-diabetes,
and cardiovascular diseases developed in collaboration with the EASD.
European Heart Journal 41, 255-323.
Di Lullo, L., Bellasi, A., Guastamacchia, E., Triggiani, V., Ronco, C.,
Lavalle, C., Di Iorio, B. R., Russo, D., Cianciolo, G., La Manna, G.
and Settembrini, S. (2020) Glifozines and cardiorenal outcomes. Min-
erva Cardioangiologica 68, 188-196.
Gerstein, H. C., Colhoun, H. M., Dagenais, G. R., Diaz, R., Lakshmanan,
M., Pais, P., Probstfield, J., Riesmeyer, J. S., Riddle, M. C., Rydén,
L., et al. (2019) Dulaglutide and cardiovascular outcomes in type 2
diabetes (REWIND): a double-blind, randomised placebo-controlled
trial. The Lancet 394, 121-130.
Gerstein, H. C., Hart, R., Colhoun, H. M., Diaz, R., Lakshmanan, M.,
Botros, F. T., Probstfield, J., Riddle, M. C., Rydén, L., Atisso, C. M.,
Dyal, L., Hall, S., Avezum, A., Basile, J., Conget, I., Cushman, W. C.,
Hancu, N., Hanefeld, M., Jansky, P., Keltai, M., Lanas, F., Leiter, L. A.,
Lopez-Jaramillo, P., Muñoz, E. G. C., Pogosova, N., Raubenheimer, P.
J., Shaw, J. E., Sheu, W. H. and Temelkova-Kurktschiev, T. (2020) The
effect of dulaglutide on stroke: an exploratory analysis of the REWIND
trial. The Lancet Diabetes & Endocrinology 8, 106-114.
Huang, C. Y. and Lee, J. K. (2020) Sodium-glucose co-transporter-2 in-
hibitors and major adverse limb events: A trial-level meta-analysis
including 51 713 individuals. Diabetes, Obesity and Metabolism 22,
2348-2355.
Husain, M., Birkenfeld, A. L., Donsmark, M., Dungan, K., Eliaschewitz,
F. G., Franco, D. R., Jeppesen, O. K., Lingvay, I., Mosenzon, O., Ped-
Volume 21, Number 4, 2020 491
ersen, S. D., Tack, C. J., Thomsen, M., Vilsbøll, T., Warren, M. L. and
Bain, S. C. (2019) Oral semaglutide and cardiovascular outcomes in
patients with type 2 diabetes. New England Journal of Medicine 381,
841-851.
IJzerman, R. G. (2020) DECREASE: Dapagliflozin Plus Exenatide on
Central REgulation of Appetite in diabeteS typE 2 (DECREASE)
(Clinicaltrials.gov Identifier NCT03361098). Available at: https://cl
inicaltrials.gov/ct2/show/NCT03361098 (Accessed: 12 Decem-
ber 2020).
Kato, E. T., Silverman, M. G., Mosenzon, O., Zelniker, T. A., Cahn, A.,
Furtado, R. H. M., Kuder, J., Murphy, S. A., Bhatt, D. L., Leiter, L.
A., McGuire, D. K., Wilding, J. P. H., Bonaca, M. P., Ruff, C. T., De-
sai, A. S., Goto, S., Johansson, P. A., Gause-Nilsson, I., Johanson, P.,
Langkilde, A. M., Raz, I., Sabatine, M. S. and Wiviott, S. D. (2019)
Effect of dapagliflozin on heart failure and mortality in type 2 diabetes
mellitus. Circulation 139, 2528-2536.
Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter,
L. A., Lingvay, I., Rosenstock, J., Seufert, J., Warren, M. L., Woo,
V., Hansen, O., Holst, A. G., Pettersson, J. and Vilsbøll, T. (2016b)
Semaglutide and cardiovascular outcomes in patients with type 2 dia-
betes. New England Journal of Medicine 375, 1834-1844.
Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J.
F. E., Nauck, M. A., Nissen, S. E., Pocock, S., Poulter, N. R., Ravn, L.
S., Steinberg, W. M., Stockner, M., Zinman, B., Bergenstal, R. M. and
Buse, J. B. (2016a) Liraglutide and cardiovascular outcomes in type 2
diabetes. The New England Journal of Medicine 375, 311-322.
Kautzky-Willer, A. (2020) Effects of Combined Dapagliflozin and Exe-
natide Versus Dapagliflozin and Placebo on Ectopic Lipids in Patients
With Uncontrolled Type 2 Diabetes Mellitus. (EXENDA) (Clinicaltri-
als.gov Identifier NCT03007329). Available at: https://clinicaltria
ls.gov/ct2/show/NCT03007329 (Accessed: 12 December 2020).
McMurray, J. J. V., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod,
M. N., Martinez, F. A., Ponikowski, P., Sabatine, M. S., Anand, I. S.,
Bělohlávek, J., et al. (2019) Dapagliflozin in patients with heart failure
and reduced ejection fraction. The New England Journal of Medicine
381, 1995-2008.
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson,
P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., et al. (2020)
Cardiovascular and renal outcomes with empagliflozin in heart failure.
The New England Journal of Medicine 383, 1413-1424.
Universitätsklinikum Hamburg-Eppendorf. (2020) The Potential of Da-
pagliflozin Plus Exenatide in Obese Insulin-resistant Patients (Clini-
caltrials.gov Identifier: NCT03419624). Available at: https://clin
icaltrials.gov/ct2/show/NCT03419624 (Accessed: 12 December
2020).
Wang, G. X. (2017) A Study of the Effect of Glucagon-like Peptide
1(GLP-1) Receptor Agonist in Combination With Metformin Ther-
apy on Diabetes Remission in Subjects With Newly Diagnosed Type
2 Diabetes Who Are Overweight or Obese (Clinicaltrials.gov Identi-
fier: NCT03018665). Available at: https://clinicaltrials.gov/ct2/
show/NCT03018665 (Accessed: 12 December 2020).
Zannad, F., Ferreira, J. P., Pocock, S. J., Anker, S. D., Butler, J., Filip-
patos, G., Brueckmann, M., Ofstad, A. P., Pfarr, E., Jamal, W. and
Packer, M. (2020) SGLT2 inhibitors in patients with heart failure with
reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced
and DAPA-HF trials. The Lancet 398, 819-829.
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel,
S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., Broedl, U.
C. and Inzucchi, S. E. (2015) Empagliflozin, cardiovascular outcomes,
and mortality in Type 2 diabetes. New England Journal of Medicine
373, 2117-2128.
492 Sabouret et al.
Article
Aim of the work We assessed the online efficacy of global awareness days (GADs) related to 5 rheumatological conditions: ankylosing spondylitis, fibromyalgia, gout, osteoporosis, and rheumatoid arthritis before and during the COVID-19 pandemic. Methods Google Trends was used to obtain global relative search volume (RSV) for each condition, for a 41-day period around each GAD, per annum, between the years 2015 and 2020, inclusive. A joinpoint (time-trend) analysis was subsequently used to identify statistically significant perturbations (p < 0.05) in the overall RSV trend for the 41-day period, per condition, per annum. Results Between the years 2015 and 2019, inclusive, we found that only 1 out of 5 rheumatological conditions was associated with 3 joinpoints centred around the respective GAD. In contrast, for 2020, 3 out of 5 conditions were associated with 3 joinpoints centred around the respective GAD (p < 0.001, p = 0.03, p = 0.04, for fibromyalgia, gout, and osteoporosis respectively). Conclusions GADs between the years 2015 and 2019, inclusive, were found to be inconsistent at increasing Google Interest (1 out of 5 conditions, per annum), but that GADs in 2020 were notably more consistent at increasing Google Interest (3 out of 5 conditions). This change in GAD efficacy described for 2020, at least in part, may be explained by the COVID-19 pandemic. Greater insight into how specific populations acquire health information could be leveraged into more effective health campaigns, with far-reaching benefits in screening, prevention, and early diagnosis.
Article
Full-text available
Background: In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. Methods: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. Results: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. Conclusions: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).
Article
Full-text available
Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.
Article
Background Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. Methods We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. Findings Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77–0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76–0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68–0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68–0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43–0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. Interpretation The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. Funding Boehringer Ingelheim.
Article
Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. Methods: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. Results: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. Conclusions: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
Article
Objective: Previous meta-analysis results showed that the use of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) is associated with an increased risk of lower extremity amputation. However, the effects of SGLT2i on specific lower extremity outcomes and whether outcome heterogeneity is based on key baseline characteristics remain unclear. Methods: We performed a quantitative meta-analysis of randomized, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched the PubMed, Embase, and Cochrane databases for trials published up until June 30, 2020. The efficacy outcomes analyzed included amputations and were stratified by several subgroup variables, including age, duration of diabetes, glucose control, renal function, established peripheral artery disease, and diabetes microvascular complications. This review is registered before completing the analysis. Results: Among 383 records identified, 6 studies assessing the following three SGLT2 inhibitors met our inclusion criteria: empagliflozin (EMPA-REG OUTCOME study), canagliflozin (CANVAS Program and CREDENCE study), dapagliflozin (DECLARE-TIMI 58 and DAPA-HF trials) and ertugliflozin (VERTIS CV study). Among a total of 51,713 participants, 858 required amputation operations. The event rates of amputation were 2.0 % (535/26,778) and 1.3% (323/24,927) in the SGLT2 inhibitors and control groups, respectively. The random effects model revealed that the SGLT2 inhibitors were not significantly associated with an increased risk of amputation with a substantial heterogeneity (pooled risk ratio [RR] 1.24, 95% confidence interval [CI] 0.96-1.60, I2 = 67.5%). This neutral effect of the SGLT2 inhibitors was also consistent across different levels of subgroups, including subgroups with or without established peripheral artery disease (PAD). Conclusion: SGLT-2 inhibitors are not associated with increased risks of amputation operations even among various high-risk subgroups, including patients with PAD. The amputation events primarily arise from critical limb ischemia and infection instead of acute limb ischemia. A multi-center study focused on major adverse limb events with a longer follow-up is needed to confirm these results and provide guidelines for clinical practice. This article is protected by copyright. All rights reserved.
Article
Diabetes mellitus, with its complications, is one of the major health problems in economically developed countries and its prevalence is constantly increasing. Kidneys and heart involvement represent main comorbidities in diabetic patients often leading to organ's failure. The treatments available until a few years ago are often associated with hypoglycemia, weight gain, gastro-intestinal disorders and other side effects together with serious averse effects on renal function. The new frontiers of diabetic cardionephropathy treatment are mainly focused on delay of heart and renal failure both on diabetic and non - diabetic patients ad it was shown by last data reports. In the following review, we'll focus on Gliflozins, one of the newest classes of hypoglycemic drugs that have shown to hold peculiar pharmacological properties in managing cardiac and renal complications.
Article
Background: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial. Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA1c was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m2. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group. Interpretation: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity. Funding: Eli Lilly and Company.
Article
Background: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). Interpretation: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. Funding: Eli Lilly and Company.
Article
Background Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. Methods We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). Results A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. Conclusions In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.)