Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update
Abstract
:1. Introduction
2. Materials and Methods
3. Epidemiology and Pathophysiological Pathway
4. Oxidative Stress in Diabetic Cardiomyopathy and β-Cell Dysfunction
- Subnormal expression of antioxidants (SOD, CAT, GPx) in β-cells due to hyperglycemia, high FFA-induced ROS and reactive nitrogen species (RNS) accumulation [19].
- Chronic exposure of β-cells to oxidative stress inhibits insulin secretion by opening ATP-sensitive K+ channels and suppressing calcium influx, which results from the ROS-induced overproduction of cyclin-dependent kinase inhibitor p21 [20].
- Chronic exposure of β-cells to elevated FFA, which decreases mitochondrial membrane potential and leads to uncoupled protein-2 accumulation, can also activate β-cell ATP-sensitive K+ channels to inhibit insulin production [21].
- Reduced transcriptional activity of insulin genes by nuclear accumulation of pancreas duodenal homeobox factor 1, which is a key transcription factor responsible for maintaining β-cell function) by oxidative stress [22].
- Excessive long-chain acyl CoA will be generated in the process of increased β-cell fatty acid metabolism, which can keep β-cell ATP-sensitive K+ channels open to suppress ATP generation and insulin secretion [25].
- ROS overproduction reduces insulin secretion by suppressing the expression of MaFA, a member of the fundamental leucine zipper family of transcription factors involved in the transcription of insulin genes [22].
5. Oxidative-Stress-Mediated Cardiac Hypertrophy/Heart Failure and Diabetes
- NOX proteins: ROS-generating enzymes
- b.
- Metabolic disorders: obesity and diabetes
- c.
- Mitochondrial dysfunction
- d.
- Inflammation
- e.
- Dysregulated autophagy and protein homeostasis
6. Anti-Diabetic Drug Categories and Their Action on Oxidative Stress
6.1. Metformin
6.2. Thiazolidinediones
6.3. Sulfonylureas
6.4. Meglitinides
6.5. Alpha Glucosidase Inhibitors
6.6. Insulin
6.7. Dipeptidyl Peptidase 4 Inhibitors
6.8. Sodium–Glucose Cotransporter-2 (SGLT-2) Inhibitors
6.9. Studies on the Effect of SGLT2 Inhibitors on Cardiovascular Outcomes and Heart Failure
6.10. Glucagon-Likepeptide-1 (GLP-1) Receptor Agonists
7. Conclusions
8. Strengths and Limitations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
(in alphabetical order) | |
ACE | Acarbose cardiovascular evaluation |
AGE | Advanced glucose end-products |
AMPK | Adenosine monophosphate-activated protein kinase |
ARNI | Angiotensin receptor neprilysin inhibitor |
CAD | Coronary artery disease |
CKD | Chronic kidney disease |
CANVAS | Canagliflozin Cardiovascular Assessment Study |
CANSAS-R | Canaglifozin Cardiovascular Assessment Study-Renal |
CARMELIN | Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes |
CAROLINA | Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes |
CREDENCE | Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation |
CV | Cardiovascular |
CVD-REAL | Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors |
CVOTs | Cardiovascular outcome trials |
DAPA-HF | Dapagliflozin in patients with HF and reduced ejection fraction |
DECLARE-TIMI 58 | Program, Dapagliflozin Effect on Cardiovascular Events-Thrombolysis In Myocardial Infarction |
DEFENCE | effectiveness on vascular endothelial function and glycemic control |
DEFINE-HF | Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction |
DEVOTE | A Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine |
DM | Diabetes mellitus |
DNA | Deoxyribonucleic acid |
DPP4 | Dipeptidyl peptidase 4 |
DREAM | Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication |
ELIXA | Evaluation of Lixisenatide in Acute Coronary Syndrome |
EMMY | Impact of Empagliflozin on cardiac function and biomarkers of heart failure in patients with acute myocardial infarction |
TOSCA.IT | The Thiazolidinediones Or Sulfonylureas and Cardiovascular Accidents Intervention Trial |
UGPD | University Group Diabetes Program |
Akt | Protein kinase B |
AMPK | AMP-activated protein kinase |
ASK1 | Apoptosis-signal-regulating kinase 1 |
BCL10 | B-cell lymphoma/leukemia 10 |
CARD9 | Caspase recruitment domain family member 9 |
CDC20 | Cell division cycle protein 20 homolog |
CHCHD3 | Coiled-coil helix coiled-coil helix domain-containing protein 3 |
CTRP3 | C1q-tumour necrosis factor-related protein 3 |
CTRP9 | C1q-tumour necrosis factor-related protein 9 |
ENDOG | Endonuclease G |
Erk1/2 | Extracellular signal-regulated kinase ½ |
FGF21 | Fibroblast growth factor 21 |
FNDC5 | Fibronectin type III domain containing 5 |
FOXO1 | Forkhead box O1 |
FOXO3a | Forkhead box O3 |
GSK3β | Glycogen synthase kinase 3 beta |
HDAC4 | Histone deacetylase 4 |
Hsp22 | Heat shock protein 22 |
JAK2 | Janus kinase 2 |
Jnk1/2 | c-Jun N-terminal kinases1/2 |
LC3 | Microtubule-associated proteins 1A/1B light chain 3B |
LKB1 | Loss of tumor suppressor liver kinase B1 |
LPS | Lipopolysaccharide |
LOX | Lysyl oxidase |
MAPK | Mitogen-activated protein kinase |
MICOS | Mitochondrial contact site and cristae organizing system |
mitoKATP | Mitochondrial ATP-sensitive potassium channel |
MnSOD | Manganese superoxide dismutase |
MnTBAP | Superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride |
MTG1 | Mitochondrial ribosome associated GTPase 1 |
mTOR | Mammalian target of rapamycin |
NCOA4 | Nuclear receptor coactivator 4 |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NOX | Nicotinamide adenine dinucleotide phosphate oxidase |
NOX2 | NADPH oxidase 2 |
NOX4 | NADPH oxidase 4 |
NOX5 | NADPH oxidase 5 |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
PI3K | Phosphoinositide 3-kinase |
PIKfyve | FYVE finger-containing phosphoinositide kinase |
PKA | Protein kinase A |
PPARα | Peroxisome proliferator-activated receptor alpha |
PPARγ | Peroxisome proliferator-activated receptor gamma |
PPARδ | Peroxisome proliferator-activated receptor delta |
ROS | Reactive oxygen species |
RPS6 | Ribosomal Protein S6 |
SAM50 | Sorting and assembly machinery 50 |
SFXN1 | Sideroflexin1 |
SIRT1 | Sirtuin 1 |
SIRT3 | Sirtuin 3 |
STAT3 | Signal transducer and activator of transcription 3 |
STVNa | Isosteviol sodium |
TAK1 | Transforming growth factor beta-activated kinase 1 |
TIM50 | Translocase of inner mitochondrial membrane 50 |
TLR4 | Toll-like receptor 4 |
TRPC3 | Transient receptor potential channel, canonical 3 |
4E-BP1 | Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 |
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Sodium–glucose cotransporter-2 (SGLT-2) inhibitors: Block renal glucose reuptake and promote loss of glucose in the urine, thus improving blood pressure via glucose and sodium excretion. |
Canagliflozin (Invokana) taken by mouth once daily Dapagliflozin (Farxiga, Forxiga) taken by mouth once daily Empagliflozin (Jardiance) taken by mouth once daily Ertugliflozin (Steglatro) taken by mouth once daily Ipragliflozin (Suglat) taken by mouth once daily Luseogliflozin (Lusefi) taken by mouth once daily Remogliflozin etabonate (Remo, Remozen) taken by mouth once daily Sotagliflozin (Zynquista) taken by mouth once daily Tofogliflozin (Apleway, Deberza) taken by mouth once daily |
Glucagon-like peptide-1 (GLP-1) receptor agonists: Increase insulin secretion and inhibit glucagon release via stimulation of the GLP-1 receptors |
Dulaglutide (Trulicity) taken by injection weekly Exenatide extended release (Bydureon) taken by injection weekly Exenatide (Byetta) taken by injection twice daily Liraglutide (Victoza) taken by injection daily Lixisenatide (Adlyxin) taken by injection daily Semaglutide (Ozempic) taken by injection weekly Semaglutide (Rybelsus) taken by mouth once daily |
Trial | Medication Used | Results | Meta-Analyses |
---|---|---|---|
EMPA-REG OUTCOME [40,76,77,78,79,80,81] | Empagliflozin vs. placebo |
| Savarese et al.: reduction in HF-associated readmissions and all composite post-acute HF period Fitchett et al.: regardless of the CV risk, the positive effects concerned all groups of patients |
EMPRISE [82] | Empagliflozin vs. sitagliptin |
| |
EMMY [83] | Empagliflozin vs. placebo |
| |
EMPEROR-PRESERVED [84] | Empagliflozin vs. placebo in patients with preserved ejection fraction |
| |
EMPEROR-REDUCED [85] | Empagliflozin vs. placebo in patients with reduced ejection fraction |
| |
EMPIRE-HF [86] | Empagliflozin vs. placebo in patients with reduced ejection fraction |
| |
CANVAS Programm [39,76,87,88] | Canagliflozin vs. placebo |
| Figtree et al.: canagliflozin reduced the risk of HF events in general in patients with type 2 DM, regardless of the presence of reduced or preserved ejection fraction |
CREDENCE [39,77] | Canagliflozin vs. placebo |
| |
CVD REAL [76] | SGLT-2 inhibitors vs. other anti-diabetic factors |
| |
DECLARE-TIMI 58 [39,76,89,90,91] | Dapagliflozin vs. placebo |
| Furtado et al.: reduced risk of MACE in DM patients compared to MI patients, similar risk reduction in cardiovascular mortality/heart failure hospitalization with a greater absolute risk reduction estimated at 1.9% for patients with prior MI vs. 0.6% in patients without prior MI Verma et al.: dapagliflozin had a positive effect in hospitalizations due to HF averse events and led to a greater reduction in HF complications or cardiovascular mortality in patients with HF with reduced ejection fraction (≤45%) in comparison with patients without reduced ejection fraction Kato et al.: dapagliflozin leads to a reduction of hospitalizations for HF regardless of the presence of reduced ejection fraction; the reduction of cardiovascular mortality and all-cause mortality was observed only in patients with reduced ejection fraction |
DAPA-HF [94,95,96,97,98] | Dapagliflozin vs. placebo |
| Kosiborod et al.: dapagliflozin improved health status and quality of life and reduced cardiovascular mortality Martinez et al.: safe use of dapagliflozin in elderly |
DEFINE-HF [99] | Dapagliflozin vs. placebo |
| |
VERTIS-CV [71] | Ertugliflozin vs. placebo |
|
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Koniari, I.; Velissaris, D.; Kounis, N.G.; Koufou, E.; Artopoulou, E.; de Gregorio, C.; Mplani, V.; Paraskevas, T.; Tsigkas, G.; Hung, M.-Y.; et al. Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update. J. Clin. Med. 2022, 11, 4660. https://doi.org/10.3390/jcm11164660
Koniari I, Velissaris D, Kounis NG, Koufou E, Artopoulou E, de Gregorio C, Mplani V, Paraskevas T, Tsigkas G, Hung M-Y, et al. Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update. Journal of Clinical Medicine. 2022; 11(16):4660. https://doi.org/10.3390/jcm11164660
Chicago/Turabian StyleKoniari, Ioanna, Dimitrios Velissaris, Nicholas G. Kounis, Eleni Koufou, Eleni Artopoulou, Cesare de Gregorio, Virginia Mplani, Themistoklis Paraskevas, Grigorios Tsigkas, Ming-Yow Hung, and et al. 2022. "Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update" Journal of Clinical Medicine 11, no. 16: 4660. https://doi.org/10.3390/jcm11164660
APA StyleKoniari, I., Velissaris, D., Kounis, N. G., Koufou, E., Artopoulou, E., de Gregorio, C., Mplani, V., Paraskevas, T., Tsigkas, G., Hung, M.-Y., Plotas, P., Lambadiari, V., & Ikonomidis, I. (2022). Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update. Journal of Clinical Medicine, 11(16), 4660. https://doi.org/10.3390/jcm11164660