Exploration of metformin-based drug combination for mitigating diabetes-associated atherosclerotic diseases

Abstract

Diabetes mellitus is a substantial global health threat due to its high prevalence and its serious complications. The hyperglycemic state causes damage to vascular endothelial cells and disturbance of lipid metabolism, thus contributing to the development of vascular disorders, especially atherosclerotic diseases. Aggressive glycemic control combined with vascular intervention is critical to the prevention and treatment of diabetes-associated atherosclerosis. It is suggested that metformin should be combined with hypoglycemic agents with proven vascular benefits for treating type 2 diabetes (T2DM) complicated with atherosclerotic diseases. Clinical studies indicates that the preferred combination is metformin with either glucagon-like peptide-1 receptor agonist or sodium/glucose cotransporter-2 inhibitor, which could offer additional vascular benefits and reduce the risk of atherosclerotic complications. Likewise, combination therapy with metformin and hypolipidemic agents has also shown additive effects on glucose control and lipid-lowering in patients with both diabetes and dyslipidemia, whereas extensive clinical trials using atherosclerotic-associated outcomes are required to support the vascular benefits. Moreover, co-administration of metformin with systemic antioxidant or anti-inflammatory therapy may also provide additional vascular benefits as indicated by several animal studies. For instance, a recent study found that additional supplementation of cholecalciferol and taurine enhanced metformin efficacy in controlling diabetes while reducing the risk of associated atherosclerotic complications. However, these potential benefits remain need validation by the evidence from clinical studies. Despite the limitations, such as heterogeneity across different patient populations, and deficiency in long-term outcomes, such efforts can contribute to finding optimal drug combinations to improve the management of T2DM and reduce its atherosclerotic complications.

Key Words: Diabetes; Atherosclerotic diseases; Metformin; Drug combination; Hypoglycemic agent; Hypolipidemic agent; Antioxidant agent

Core Tip: The hyperglycemic state can actually induce atherosclerosis development or further accelerate its progression, which leads to cardio-cerebrovascular diseases associated with high morbidity and mortality. As metformin is the preferred first-line drug to manage type 2 diabetes, metformin combined with either hypoglycemic agents, hypolipidemic agents, or systemic antioxidant/anti-inflammatory agents, have been investigated to provide additional vascular benefits. It is quite clear that such exploration can contribute to finding a better drug combination to mitigate diabetes-associated atherosclerotic diseases.

TO THE EDITOR

Type 2 diabetes mellitus (T2DM), along with its complications, have become a global public health issue because of its high prevalence and serious threat to human health[1,2]. Diabetic complications are usually classified by the involvement of organs, e.g., diabetic cardiopathy, encephalopathy, nephropathy, foot, and retinopathy[3-5]. These diabetic complications have a high degree of pathological commonality at the vascular level, and thus all can be considered a kind of macro/microvascular disease[6,7]. As a typical microvascular complication, atherosclerotic diseases occurred more than twice as frequently in T2DM patients than in non-diabetes patients[8]. Insights into the pathological mechanisms underlying diabetes-associated atherosclerotic diseases have achieved remarkable advances. Although mechanism research stimulates drug development, treatment options for such complications remain limited. Metformin is considered a first-line drug for T2DM, whereas it has limited effect for longer duration and atherosclerotic complication, thus necessitating the use of additional drugs. Thus, metformin-based drug combination has been investigated to provide additional vascular benefits. In this editorial, we focus on the general pathological mechanism of diabetes-associated atherosclerotic disease, and recent progress in the exploration of metformin-based pharmacological intervention for alleviating this complication.

PATHOLOGICAL MECHANISM OF DIABETES-ASSOCIATED ATHEROSCLEROTIC DISEASE

Insulin resistance remains a core defect in T2DM. It promotes lipid synthesis in hepatocytes and lipolysis in adipocytes, resulting in elevation of circulating fatty acids and triglycerides (TG). These substances disturb the regular oxidation process of fatty acids, promoting endoplasmic reticulum stress, apoptosis, and vascular remodeling[9,10]. Additionally, lipotoxicity can induce mitochondrial dysfunction and increased mitophagy, and these changes lead to increased reactive oxygen species (ROS) production and decreased ATP production, posing a significant threat to vascular health[11]. In the state of insulin resistance, attenuated insulin may promote vascular stiffening through the increased production of vasoconstrictor factors, such as endothelin[12,13]. Therefore, insulin resistance is considered a substantial risk factor for the development of excessive vascular stiffening and consequent atherosclerotic disease.

The hyperglycemic state results in the excessive formation of free radicals due to the autoxidation of glucose and non-enzymatic glycation of proteins[14]. Meanwhile, antioxidant defenses are compromised. Thus, the levels of free radicals, which are termed ROS, are drastically elevated. ROS causes damage to cellular organelles and enzymes (i.e., mitochondrial electron transport chains), disrupts intercellular junctions, and increases cellular permeability, which consequently promotes microvascular disease progression[15]. Moreover, ROS in turn results in lipid peroxidation (LPO) and iron overload[16]. LPO products react with cellular macromolecules (i.e., DNA, proteins), consequently leading to vascular endothelial cell impairments. On the other hand, both LPO and free iron are pivotal participants in the development of cell ferroptosis, which is a crucial pathogenic factor newly identified in diabetes and cardiac ischemia[17].

Advanced glycation end-products (AGEs) are the most important products of diabetic glycotoxin. AGEs participate in diabetes-related disorders via two important mechanisms. The first mechanism involves the covalent crosslinking of proteins, lipids, and DNA, and the disruption of their biological functions[18]. Another mechanism involves the interaction of AGEs with their cell surface receptors (RAGEs), namely the AGE–RAGE axis[19]. A major end-result of AGEs action is the overproduction of ROS to induce oxidative stress[20]. Activation signals induced by oxidative stress in turn trigger the assembly of cytosolic NLRP3 inflammasome complexes, resulting in inflammation and chronic tissue destruction[21]. In addition, AGEs increase the expression of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF-α), and activate inflammatory signaling pathways, leading to vascular inflammation[22,23]. To sum up, insulin resistance, oxidative stress, and inflammatory response in the state of diabetes cause dysfunction of vascular endothelial cells, increase lipid accumulation, disrupt intercellular junctions, and increase cytomembrane permeability, which in turn accelerate atherosclerotic diseases.

METFORMIN PLUS OTHER HYPOGLYCEMIC AGENTS

Various hypoglycemic agents with different action mechanisms are currently available for T2DM patients. Metformin has usually been recommended as the first-line drug for T2DM[24]. However, it has limited evidence of cardiovascular benefits in the reported data. Moreover, therapeutic strategies for glucose control alone hardly met the clinical expectation of reduced atherosclerotic events[25]. Therefore, metformin in combination with other drugs has been investigated to provide additional vascular benefits.

Insulin is traditionally used as the last resort among pharmaceutical options for T2D patients. However, safety concerns remain surround its long-term use, particularly cardiovascular risk due to direct vascular injury and indirect effects such as hypertension and dyslipidemia[26-28]. In addition, sulfonylureas can carry detrimental risks of mortality in patients with T2DM[29]. By contrast, α-glucosidase inhibitor acarbose can not only prevent diabetes development in patients with impaired glucose tolerance, but also significantly reduce the number of cardiovascular events[30]. Indeed, the use of acarbose as an add-on remedy to metformin was associated with lower risks of major atherosclerotic events and ischemic stroke as compared to the use of sulfonylurea as an add-on remedy[31]. Dipeptidylpeptidase-4 (DPP-4) inhibitors increase endogenous glucagon like-peptide-1 (GLP-1) levels, leading to increased release of insulin and subsequent decreased glucose levels. Animal and in vitro experiments suggested that vascular stiffening and endothelial function were improved by DPP-4 inhibition with linagliptin[32,33]. Likewise, DPP-4 inhibitors sitagliptin and saxagliptin have been demonstrated protective effects on endothelial function in patients with T2DM in the setting of metformin background therapy[34,35].

Cardiovascular outcome trials have reported that GLP-1 receptor agonists (GLP-1RA; i.e., liraglutide, semaglutide, albiglutide, dulaglutide) and sodium-glucose co-transporter 2 inhibitors (SGLT-2i; i.e., empagliflozin, canagliflozin, dapagliflozin) reduced cardiovascular events in people with T2DM who had either established cardiovascular disease or cardiovascular risk factors[36-42]. Noticeably, the participants in these outcome trials mostly had a setting of concomitant metformin use, which has fueled the supposition that the cardiovascular benefits of these agents occur in the presence of metformin. Therefore, either GLP-1RA or SGLT-2i is suggested the preferred add-on therapy to metformin for treating T2DM complicated with high risk for or established atherosclerotic cardiovascular disease[43].

METFORMIN PLUS LIPID-LOWERING AGENTS

Atherogenic dyslipidemia is a key contributor to the increased cardiovascular risk associated with diabetes. The corresponding lipid profile of these patients is characterized by elevated TG and low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol levels. Statins and fibrates are two kinds of widely used lipid-lowering drugs, which also have been found to be beneficial in treating diabetics through a number of pleiotropic effects including the reduction of atherogenic dyslipidemia and inflammation process at the level of the vascular wall[44-46]. The study of Tousoulis et al[47] suggested that metformin and atorvastatin combination therapy had additive effect on the lipid-lowering, exerted a better response to glucose intake and reduced the post-glucose loading levels of TNF-α compared to metformin monotherapy. In addition, a recent phase III multicenter study found that addition of atorvastatin to metformin improved glycosylated hemoglobin and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients[48]. These findings suggested the promising application of this combination therapy in reducing the risk of atherosclerotic cardiovascular disease in patients with both diabetes and dyslipidemia. Likewise, both fenofibrate and gemfibrozil have been demonstrated the additive anti-atherogenic and anti-inflammatory effects in rat model of T2DM when add-on to metformin[49,50]. However, these benefits still need further investigation by clinical trials.

METFORMIN PLUS SYSTEMIC ANTIOXIDANT/ANTI-INFLAMMATORY AGENTS

Hyperglycemia-induced oxidative stress and inflammatory response have been implicated in diabetes-induced cardiovascular dysfunction. Studies suggest that the combinational use of metformin and antioxidant/anti-inflammatory agents could be effective in reducing diabetic cardiovascular events. Wu et al[51] found that salvianolic acid A combined with metformin exerted marked protection against macrovascular injury in diabetic mice. The mechanism was at least partly attributed to the activation of both metformin-mediated adenosine monophosphate-activated protein kinase (AMPK) and salvianolic acid A-mediated nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-response element pathways. Roxo et al[52] reported that the combination of metformin with natural antioxidant curcumin further decreased dyslipidemia, AGEs, and TBARS levels, increased PON1 activity in streptozotocin-diabetic rats, compared with metformin alone. These findings indicated that this combination might be effective for combating diabetic complications, mainly cardiovascular events. N-acetylcysteine (NAC) is an antioxidant known to protect against hyperglycaemic-induced oxidative stress by promoting glutathione generation. The study of Johnson et al[53] demonstrated the cardioprotective effect of NAC plus metformin against hyperglycemia-induced cardiac damage in an H9c2 cardiomyoblast model. The combination treatment was effective in diminishing oxidative stress, LPO, and apoptosis in cardiomyoblasts by increasing GLUT4 expression, promoting phosphorylation of AMPK while decreasing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Taurine is a semi-essential amino acid possessing anti-inflammatory and antioxidant properties, while cholecalciferol, the major form of vitamin D in humans, also has such activities. The supplementation of taurine and cholecalciferol with metformin in diabetic rats not only improved glycemic profile, but also resulted in reduction of LPO and atherosclerotic inflammatory process, which in turn may help to prevent the onset of plaque and all subsequent disorders[54]. However, currently these findings have not yet been translated to human subjects, and there is also a lack of supporting or contradicting evidence from retrospective studies. Although the positive results from animal experiments might not always translate to clinical practice, such exploration can promote progress in the treatment of diabetes-associated atherosclerotic diseases.

CONCLUSION

Diabetic atherosclerotic diseases represent a kind of typical microvascular complication that poses a substantial health threat to patients. Aggressive glycemic control combined with vascular intervention is critical to the prevention and treatment of this complication. Extensive studies have explored the general pathological mechanism of diabetes-associated atherosclerotic diseases, as well as the combination of metformin with either hypoglycemic agents or systemic antioxidant/anti-inflammatory agents to provide additional vascular benefits. The encouraging findings can contribute to finding a better drug combination to mitigate this complication.