TABLE 1.
Cardiovascular and platelet effects of anti-diabetic agents.
| Molecule | Glucose lowering mechanism | Clinical cardiovascular effects | Platelet effects |
|---|---|---|---|
| Metformin | ↓ Hepatic gluconeogenesis | ↓ Cardiovascular endpoints (MI and stroke) and all-cause mortality (UKPDS) (King et al., 1999) | Preclinical |
| ↑ Muscle tissue and other insulin-dependent tissues glucose uptake | ↓ Macrovascular complications (MI, stroke, peripheral vascular disease) (HOME) (Kooy et al., 2009) | ↓ ADP, collagen and arachidonic acid-induced platelet aggregation (Tremoli et al., 1982; Gin et al., 1989) | |
| ↓ GI absorption of glucose | ↓ Production of superoxide anion (O2-) (Gargiulo et al., 2002) | ||
| ↓ PLT activation and extracellular mitochondrial DNA release | |||
| Clinical | |||
| ↓ 11-dhTXB2 urinary excretion (Formoso et al., 2008) | |||
| ↓ 8-iso-pg F2α excretion (Formoso et al., 2008) | |||
| ↓ Mean PLT volume (Dolasik et al., 2013) | |||
| Sulphonylureas | ↑ Insulin secretion (through pancreatic beta cells receptors) | ↓ Cardiovascular benefit vs metformin alone (UKPDS) (King et al., 1999) | Preclinical |
| ↑ Number of peripheral insulin receptors (through extra-pancreatic receptors) | ↑ Risk of cardiovascular hospitalization/mortality (Rao et al., 2008) | ↓ ADP-induced platelet aggregation | |
| ↑ Glucose intake by tissues | ↑ Risk of stroke and overall mortality, no effect on MACEs (Monami et al., 2013) | ↓ PLT adhesiveness (Klaff et al., 1981; Satoh et al., 1994) | |
| ↓ Hepatic glucose production | Neutral effect with regard of all-cause mortality, cardiovascular mortality, MI or stroke with second or third-generation molecules (varvaki Rados et al., 2016) | ↓ Oxidative stress (Klaff et al., 1981; Violi et al., 1982) | |
| ↓ Cyclooxygenase and lipoxygenase pathways (Satoh et al., 1994) | |||
| Clinical | |||
| ↓ PLT aggregation (de Bellis et al., 1984; Jennings et al., 1992; Konya et al., 2010) | |||
| Thiazolidinediones | ↓ Circulating fatty acids promoting ability to store lipids | Pioglitazone | Preclinical |
| ↓ Insulin resistance | Neutral effect on major cardiovascular end points (PROactive, Dormandy et al., 2005); ↓stroke or MI (IRIS) (Viscoli et al., 2014) | ↓ ADP-induced PLT aggregation (Li et al., 2005) | |
| ↑ Insulin sensitivity and glucose uptake in muscle | Rosiglitazone | ↓ P selectin levels (Bodary et al., 2005) | |
| ↑ risk of cardiovascular events (Selvin et al., 2008; Home et al., 2009); no increase in the incidence of MI or cardiovascular death; ↑ heart failure hospitalizations (RECORD) (Home et al., 2007; Home et al., 2009) | Clinical | ||
| ↓ Inflammation and macrophage recruitment (Yau et al., 2013) | |||
| ↓ E selectin (Hetzel et al., 2005), vWillebrand, SCD40L (Sidhu et al., 2003; schöndorf T. et al., 2011), PAI-1 (Derosa et al., 2005) | |||
| ↓ 11-dhTXB2 (Basili et al., 2006) | |||
| Acarbose | ↓ α-glucosidase in the intestinal tract | ↓ Risk cardiovascular events (STOP-NIDDM) (Chiasson et al., 2003) | Preclinical |
| ↓ Salivary α-glucosidase | ↓ Progression of carotid intima-media thickness (markolf Hanefeld et al., 2004) | ↓ PLT-bound fibrinogen and ↓ P selectin platelet exposure (Schäfer et al., 2004) | |
| ↓ Pancreatic α-amylase | ↓ Platelet-monocyte aggregates formation (Kaplar et al., 2001) | ||
| ↑ GLP-1 | Clinical | ||
| ↓ PLT activation and oxidative stress markers (Santilli et al., 2010) | |||
| Dipeptidyl peptidase-4 inhibitors | ↓ Breakdown GLP-1 and GIP | No clear benefit on MACEs incidence vs placebo (TECOS/EXAMINE/CAROLINA/TIMI) (White et al., 2013; Green et al., 2015; Marx et al., 2015; Udell et al., 2015) | Preclinical |
| ↑ cAMP formation and PKA activation (Steven et al., 2017) | |||
| ↓ Plasma fibrinogen and PAI-1 (Dardik et al., 2003) | |||
| ↓ Soluble levels of CD40 (Mason et al., 2011) | |||
| ↓ Inflammatory and thrombogenic gene expression (Maeda et al., 2012; Birnbaum et al., 2016) | |||
| ↓ Platelet mitochondrial respiration and platelet aggregation (Li et al., 2020) | |||
| Clinical | |||
| ↓ Intracellular free calcium and tyrosine phosphorylation→ ↓ PLT aggregation (Gupta et al., 2012) | |||
| Sodium–glucose cotransporter 2 inhibitors | ↓ Kidney sodium glucose cotransporters → urinary net loss of sodium and glucose | ↓ Incidence of MACE, cardiovascular death and hospitalization for HF (EMPA-REG OUTCOME, Zinman et al., 2015; CANVAS program, Neal et al., 2017, and DECLARE-TIMI 58, Wiviott et al., 2018) | Preclinical |
| ↓ ADP- induced PLT activation (Spigoni et al., 2020) | |||
| ↓ P selectin mRNA expression (Steven et al., 2017) | |||
| ↓ ROS and ↑ NO bioavailability (Smyth et al., 2017) | |||
| ↓ Advanced glycation end products, ↑ eNOS activation and ↓ interstitial and periarterial NO stress (Aroor et al., 2018) | |||
| GLP-1 receptor agonists | ↑ Insulin secretion and ↓ glucagon in a glucose-dependent manner | ↓ MACEs and ↓ fatal and non-fatal MI (ELIXA, LEADER, SUSTAIN- 6, EXSCEL, harmony outcomes, REWIND and PIONEER 6 (Kristensen et al., 2019) | Preclinical |
| ↓ Beta-cell apoptosis | ↓ Thrombin-, ADP-, and collagen-induced PLT aggregation mediated by cAMP-induced PKA activation and increased eNOS enzymatic activity (Cameron-Vendrig et al., 2016; Steven et al., 2017) | ||
| ↑ Beta-cell neogenesis | ↓ ROS production (Oeseburg et al., 2010; Ceriello et al., 2013) | ||
| ↓ Circulating lipoproteins | Clinical | ||
| ↓ Gastric emptying | ↑ cGMP production and ↑ VASP-ser239 phosphorylation and ↓ PI3-K/Akt and MAPK/erk-2 pathways → ↑ NO bioavailability and ↓ ROS production (Barale et al., 2017) | ||
| ↑ Satiety | ↓ Platelet P-selectin expression (Kahal et al., 2015) |
ADP, adenosine disphosphate; ERK, extracellular signal-regulated kinases; eNOS, endothelial nitric oxide synthase; GI, gastro intestinal; GIP, gastric inhibitory peptide; GLP-1, glucagon like peptide-1; HF, heart failure; MACEs, major adverse cardiac events; MAPK, mitogen-activated protein kinases; MI, myocardial infarction; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PG, prostaglandin; PI3K, phosphatidyl inositol-3 kinase; PKA, protein kinase A; PLT, platelet; ROS, reactive oxygen species; TXB, thromboxane; VASP, vasodilator-stimulated phosphoprotein.