INTRODUCTION:

Diabetes mellitus (DM) is a condition associated with hyperglycaemia in which the fasting plasma glucose levels are considered to be more than or equal to 200mg per dL administration of 75g oral glucose measured in a time period of 2 hours ¹. The accompanied lifestyle disturbances include increase in the urine output (glucosuria), rise in excess of lipids and fats (hyperlipidaemia), excretion of nitrogen from the body (negative nitrogen balance) and higher concentrations of ketones in the blood (ketonemia) resulting in complications such as atherosclerosis, retinopathy, neuropathy and peripheral vascular insufficiency². Diabetes patients are prone to severe risk of cardiovascular diseases due to changes associated with the disease in their physiological system³. The International Diabetes Federation estimates that by 2035, about 592 million (1 in 10 persons) would be diagnosed by DM⁴.

The studies of CVD associated DM are 1.7 times higher than compared with patients without DM. About 16-31% increase is seen in patients with DM associated CVD. Silent Ischemia’s are prevalent in patients with DM^5-⁶.

Among the different types of DM, DPP-IV (Dipeptidyl peptidase IV inhibitors) is used in the treatment of noninsulin - dependent diabetes mellitus (NIDDM) that is type 2 which accounts for 90% and continues to increase at an alarming rate⁷^-8. The insulin in the circulation is found to be low; normal or even high and reduction in beta cell mass is moderate or less and generally occurs in the later phase of life of about 45 years of age. There is an increased risk of cardiovascular diseases such as myocardial infarction, stroke, heart failure in diabetic patients⁹.

Symptoms recognised for DM associates CVD with its hyperglycaemia, hyperinsulinemia or insulin resistance leading to heart failure. Metabolic disturbances due to DM leads to decreased glucose alteration, increased free fatty acids leads to disturbed cellular activity, cardiomyocyte hypertrophy and AGE deposition leads to structural alterations, diabetes associated hypertension causes hypertensive cardiomyopathy, fibrosis causes for neurohormonal activation being causative factors for failure in the functioning of heart¹⁰.

DPP-IV inhibitors are a class of prescription medicines that are used with diet and exercise to control high blood sugar in adults with type 2 diabetes^11-12. The enzyme DPP-IV leads to rapid degeneration of endogenous GLP-1 (glucagon-like peptide-1). The direct effects of DPP-IV on immune cells and the indirect effects through GLP-1-dependent and -independent pathways suggest effects of DPP-IV inhibition may have beneficial effects beyond glycaemic control in improving CVD and renal outcomes. DPP-IV inhibitors include the following class of drugs: sitagliptin, vildagliptin, saxagliptin, teneligliptin, alogliptin, linagliptin (Figure:1). In this review, we focus on the efficiency of DPP-IV inhibitors and its mechanism in the treatment of DM associated CVD.

Figure 1: Approved DPP-IV inhibitors by FDA and EU from 2006-2015

Diabetes Mellitus and CVD:

Adults with DM has a higher rate of cardiovascular risk with symptoms for heart disease and stroke two to four times higher than with non-diabetics¹³. The National Cholesterol Education Program (NCEP) considers diabetes as equivalent to coronary heart disease¹⁴. This is due to the associated co-morbidities of the disease¹⁵^.DM with obesity, hypertension, oxidative stress, metabolic disturbances and dyslipidaemia that increases the risk of CVD¹⁶. Several putative actors such as insulin resistance, glycaemic control produces low-grade inflammation are linked to atherosclerosis¹⁷.

Oxidative stress due to DM results in inflammation due to the cytokines release, that activates macrophages leading to production of inflammatory mediators that affects the endothelial dysfunction or causes cardiovascular autonomic neuropathy that leads to sudden death¹⁸. Coronary heart disease and Ischemic stroke are risk factors of DM with a two-fold risk is observed leading to death¹⁹.

Hypertension is considered as a major risk factor associated with vascular complications and co-morbidities. Oxidative stress, inflammation and fibrosis are associated with micro and macrovascular complications that results in vascular remodelling and dysfunction in hypertension.

Some of the other causes such as neuropathy, endothelial dysfunction, enhancement in coagulation causes for diabetes associated CVD²⁰.

DPP-IV inhibitors:

Gliptins or DPP-IV inhibitors are oral diabetic medication used in the treatment of type 2 DM. Some of the FDA approved glipitins include sitaglipitin, vildaglipitin, saxaglipitin, linaglipitin and aloglipiti²¹. Of these, sitaglipitin was the first DPP-IV inhibitor that received the approval in the year 2006 an it is also classified under safest DPP-IV inhibitor including saxagliptin, linagliptin and aloglipitin. Inhibitors of DPP-IV works by lowering blood glucose by stimulating insulin secretion, reducing glucagon concentration with delayed gastric emptying²². The incretin hormone immediately acts after intake of food within few minutes degrading essential enzymes GLP-1 and GIP whereas DPP-IV’s inhibition increases its concentration further increasing beta-cell insulin secretion²³.

Role of DPP-IV inhibitors in Cardioprotective effect:

The drugs that are used in the treatment of diabetes associates with cardiovascular diseases and heart failure. Thiazolidinediones are one such example of drugs that exacerbate heart failure by increasing sodium and water retention, thereby increasing the plasma volume²⁴. DPP-IV inhibitors on human cell lines and humans shows promising effect²⁵. studied the drug effects of vildagliptin in association with oxidative stress in humans and found that at a dose of 50mg twice daily for a period of about12 weeks showing lowered plasma levels of inflammation mediators like IL-6 and TNF-α markers of oxidative stress and inflammation. Aloglipitin was administered 25mg once daily about 12 weeks and effect were evidenced on vascular tone and dysfunction. eNOS is endothelial nitric oxide synthase, enzyme regulating vascular tone, blood flow and endothelial function²⁶. The mechanism involved is phosphorylation of eNOS in a GLP-1 dependent manner achieved at 50µM concentration as reported by²⁷. Linagliptin a xanthine related structure was administered at 5 mg once daily for a period of 6 months and is found to provide anti-inflammatory activity by preventing MAPK phosphorylation and activation of cAMP/PKA signalling and inhibits IL-6 and intranuclear p65 production showing anti-inflammatory pathway at a concentration of 50nM for 1hour²⁸. Sitagliptin was found to prove efficacy against oxidative stress and inflammation as shown in in-vitro studies conducted on human umbilical vein. Hu Y et.al., 2013 conducted clinical trials at a concentration range of 20nM–5µM for 16h, through GLP-1 dependent and independent manner it was found to reduce ICAM-1, VCAM-1, PAI-1 and NF-𝜅B expression. Gemigliptin prevents apoptosis of endothelial cells by activating AMPK phosphorylation in the study conducted on human umbilical vein endothelial cells at a concentration of 250µM for 1h²⁹. Teneglipitin is found to have cardiovascular protective effects by suppressing atherothrombosis progression and increasing plasma adiponectin wherein the mechanism is unclear. The patients were dosed at 20mg once daily for about 6 months³⁰.

DPP-IV inhibitor and Oxidative Stress:

Oxidative stress has a pivotal role in patients with diabetes and associated cardiovascular diseases causing for microvascular and macrovascular complications³¹. DM causes for release of superoxides in the mitochondria leading to tissue damage and also activates polyol pathway, advanced glycation end-product formation (AGE) pathway, increased receptor expression for AGE, protein kinase C activation (PKC) isoforms, hexosamine pathway activation and simultaneously inactivation of antiatherosclerosis enzymes, eNOS and prostacyclin synthase³².

Excessive production of ROS will lead to deleterious effects like damage of DNA, lipid, mitochondria and cell death³³. The dysfunction of mitochondria causes apoptosis through mitochondria dependent caspase cascade that release cytochrome c into cytosol³⁴. Glucagon like peptide (GLP-1), the incretin hormones stimulate insulin secretion and controls the glycaemic index, wherein GLP-1 is degraded by DPP-IV enzyme ³⁵.

Gliptins are found to decrease levels of ROS, AGE, RNS³⁶. Wang et al. 2021 has proved ROS scavenging capacity of sitaglipitin in research associated with liver inflammation in diabetic mice. The mechanism by which DPP-IV inhibitors prevent oxidative stress is increasing eNOS phosphorylation increasing the endothelial vasodilatation and decreasing ischemia and preventing oxidative stress²⁶. Intracellularly, it increases cAMP and activates cAMP dependent protein kinase and SDF-1α. It increases lipid metabolism favouring endothelial and cardiovascular functions (Figure:2).

Fig 2: Overview of DPP-IV inhibitors in prevention of oxidative stress:

DPP-IV and cardioactive peptides:

The peptides like B-type natriuretic peptide (BNP) are produced primarily by the ventricles of the heart in a response to the internal stress produced in cardiac walls in conditions like heart failure, myocardial infarction, cardiac ischaemia, coronary artery disease etc³⁷. The role of cardioactive peptide is its efficacy in regulating blood pressure, heart rate, vascular tone and cardiac function³⁸. BNP is a cardioactive peptide that is released by the ventricles of the heart with vasodilatory activity promoting natriuresis, inhibits release of renin and aldosterone that relieves the cardiac strain³⁹. The enzyme DPP-IV cleaves and inactivates various peptides like BNP; therefore, inhibitors of DPP-IV increase the half-life of BNP in circulation and enhances its biological activity ⁴⁰.

Atrial natriuretic peptide (ANP) is a cardioactive peptide produced and released by atria of heart muscles in response to increased blood volume and atrial stretching. Natriuresis and diuresis lead to excretion of sodium and water by the kidneys that maintains blood volume and blood pressure. Physiological levels of ANP and BNP being low, they provide an improved regulation in heart failure⁴¹.

L. Pala et.al (2013) expressed the anti-thrombotic effects of DPP-IV that plays a role in CVS protection. Stromal cell-derived factor (SDF-1), a chemokine promotes angiogenesis. SDF-1 is a substrate of DPP-IV and SDF-1 engineered to work as a resistant to DPP-IV are found to increase blood flow in peripheral artery disease. It is found that, in-vitro and in-vivo parathyroid hormone (PTH) inhibits DPP-IV activity, thereby inactivating SDF-1 and protecting the heart from myocardial ischemia⁴².

The results of Cardiovascular outcome trials with incretin therapies reports that linagliptin has a better maintenance of glucose with HbA1c below 7.0% with a lower incidence of hypoglycaemic adverse events. Furthermore, a nationwide clinical study reported with a retrospective study in countries of Taiwan and China analysed that from a cohort study on 40,000 T2DM patients in an age group of 65 and above associated with a 21% decreased risk of myocardial infarction and stroke and a 46% decreased in mortality. The cohort study carried out showed decreased rate of hospitalisation of heart failure patients⁴³. Another study conducted by, de Boer et al. on linagliptin showed a decreased atherosclerosis⁴⁴.

Similarly, Intravascular Ultrasound study on the drug Sitagliptin reported reduction and decrease in coronary plaque volume and liquid plaque volume respectively with a decrease in non-HDL cholesterol⁴⁵. DPP-IV had been reported with potential anti-thrombotic and anti-platelet effects. They indicate platelet activation and aggregation and reduce the clot formation.

The incretin therapies inhibit DPP-IV increasing levels of GLP-1 leading to increased insulin secretion, decreased glucagon release and improved sugar control ⁴⁶. DPP-IV provides cardio protection by two different mechanisms, GLP-1R dependent and GLP-1R-independent. They provide increased angiogenesis thereby increasing the blood supply in areas of myocardium through intracellularly increasing cyclic adenosine monophosphate (cAMP) and activating c-AMP dependent protein kinase. Some of the concepts of CVS are unclear such as the effect of gastric inhibitory peptide on CV system, increased correlation between circulating GIP and atherosclerosis⁴⁷.

Inhibition of DPP-IV has a direct relation to GLP-1 pathway, where they increase the levels of GLP-1 in the bloodstream. This leads to improved cardiac function, vasodilation, anti-inflammatory and anti-apoptotic effects. GLP-1 increases the myocardial contractility, increases the coronary blood flow and improves the cardiac output. It reduces inflammation due to hardening of the arteries and protects the blood vessels and heart⁴⁸. It has shown to inhibit apoptosis protecting the heart cells against myocardial injury and cell survival.

DPP-IV can exhibit CVS outcomes through GLP-1 independent mechanism by modulating oxidative stress, apoptosis, inflammation and endothelial dysfunction. Further clinical trials are required to validate this mechanism, as though the results are promising validation of data are unclear (Figure:3).

Figure 3: DPP-IV inhibitors in the protection of Cardioactive peptides

DPP-IV preventing CV inflammation:

Development and progression of cardiovascular diseases like atherosclerosis, myocardial infarction and stroke lead to CV inflammation.

Inhibition of cytokine release:

DPP-IV inhibitors reduce myocardial inflammation by inhibiting cytokine release activation of monocytes and chemotaxis. Cytokines are small proteins that are important signalling molecules in the immune system. The pro-inflammatory cytokines are suppressed by tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β). Cytokines promote inflammation and is involved in inflammatory disorders. Reduction of pro-inflammatory cytokines modulates inflammatory response^{49-50 .}

Immune cell modulation:

DPP-IV inhibitors activate the release of monocytes and macrophages which are key players of cytokines. By activation of immune cells, DPP-IV inhibitors block the release of cytokines and decrease the inflammatory response.

GLP-1 and inflammatory response:

DPP-IV inhibitors increase the level of incretin hormones, in particular GLP-1 which is found to have anti-inflammatory activity by the release of cytokines. Inhibition of degradation of GLP-1 indirectly is associated with inhibition of cytokine release and mitigates inflammation (Figure:4)

Figure 4: Anti-inflammatory activity of DPP-IV

Figure 5: Anti-apoptic activity of DPP-IV inhibitor

DPP-IV inhibitors and its anti-apoptic activity:

They act as inhibitors of cell death by decreasing oxidative stress and inflammation as a result of improved hyperglycaemia and also attributed to the effect of GLP-1 on the receptor of CVS. DPP-IV inhibitors are recognised with angiogenesis and anti-apoptic effect. It has a protective and antiapoptic effect by activating stromal cell derived factor-1α (SDF-1α)/ 3(Stat3) signaling pathway⁵¹.

There are two forms of DPP-IV, a membrane form and a soluble form. The latter is obtained by cleavage of membrane form of which the regulation is unknown. DPP-IV inhibitors increases the activity of SDF-1α on cardiomyocytes. It acts through CXCR4 (C-X-C- Chemokine receptor type 4) activates STAT3 (Signal Transducer and Activation of Transcriptor 3) signalling pathways leading to cardioprotection. STAT3 plays a role as a cardioprotective⁵². SDF-1α activity on myocardium is essential for cardioprotection. Akihiko Kubota et.al.2015 conducted three large-scale randomized trials and estimated efficiency in inhibition of DPP-IV. The drugs in the assessment included Saxaglipitin, Alogliptin and Sitaglipitin which was conducted in group of patients being 5000 in number. The study indicated the potential efficiency of DPP-IV inhibitor in the prevention of heart failure after MI (Figure 5).

CONCLUSION:

Diabetes mellitus associated cardiovascular diseases are emerging as a major threat to the society. Though newer drugs are in the process of discovery, it is time to study the effect of antidiabetic medications in the current treatment and its ability to act in the management of cardiovascular complications. The human trials on existing incretin therapies such as gliptins shows promising results in treating CVS diseases. Gliptins had been subjected to many different trials and has proven against oxidative stress and inflammation in heart. Oxidative stress is considered a role player in causing diabetes leading to cardiovascular complications. DPP-IV inhibitors are reviewed to play promising role by acting through GLP-1 and GIP pathways and plays role against oxidative stress, CV inflammation and apoptosis. Furthermore, its role in preventing homeostasis and maintaining CV haemodynamic and reported human clinical trials necessitates for further study on development of DPP-IV inhibitors.

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Received on 01.08.2023 Modified on 23.02.2024

Research J. Pharm. and Tech 2024; 17(8):3553-3559.

DOI: 10.52711/0974-360X.2024.00555