A Comprehensive Review on Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: Mechanism, Therapeutic Applications, and Future Perspectives

Diabetes mellitus, especially type 2 diabetes (T2D), is a rapidly growing global health problem. As of 2021, the International Diabetes Federation (IDF) estimates that approximately 537 million adults have diabetes globally, and this number is forecast to rise to 783 million by 2045. This dramatic increase highlights the immediate public health requirements and emerging therapeutic opportunities urgently needed. Diabetes was the eighth leading cause of death in 2021 and drastically affects the quality of life for those who have this disease. Moreover, diabetes is very costly from an economic perspective: by 2021, global diabetes healthcare costs were over $966 billion, and this is expected to surpass $1 trillion according to estimates from the Global Burden of Disease study by 2045 [1], [2]. Different physiological mechanisms that govern the homeostasis of glucose, including incretin hormones, are involved in many aspects of glucose physiology. The two types of incretin hormones that have critical roles in incretin signaling, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), bind to specific members of the G-protein-coupled receptor (GPCR) family: the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively. Upon receptor binding, both of these hormones stimulate adenylate cyclase, resulting in the enhancement of cyclic adenosine monophosphate (cAMP) in β-cells. This sequence leads to glucose-dependent insulin secretion through sensitization, thus ensuring optimal maintenance of glucose levels. Still, this function is tightly regulated by dipeptidyl peptidase-4 (DPP-4), an enzyme that contributes to the rapid hydrolysis and inactivation of incretin hormones, resulting in decreased insulin secretion [3]. Dipeptidyl peptidase-4, or DPP-4, is the enzyme that hydrolyzes incretin hormones such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Dipeptidyl peptidase-4 (DPP-4) cleaves these hormones, acting in an inhibitory manner to regulate the physiological action of endogenous incretin. By cleaving these hormones, DPP-4 inhibits their functions, impacting physiological processes [4], [5]. The DPP-4 inhibitors, which are oral antidiabetic drugs of a specific class, have now become one of the main therapeutic categories for T2D. They work by blocking the action of the DPP-4 enzyme and increasing the half-life of endogenous GLP-1 and GIP. Hence, this leads these hormones to work for a longer time, and as a consequence, pancreatic β-cells become more sensitive to increases in blood glucose, causing the release of insulin and a decrease in glucagon. DPP-4 inhibitors have the advantage of decreasing glucagon by augmenting levels of incretin hormones, particularly driving insulin secretion in hyperglycemia to avoid glucagon overproduction. It has been observed that this group of drugs can block DPP-4 activity by over 80–90%, resulting in pronounced reductions in postprandial glucose levels and improved glycemic control [6], [7]. This article reviews the mode of action for DPP-4 inhibitors and their application in the treatment of T2D. In this review, we highlight the drugs in this class, describe their role in glucose homeostasis preservation and the specificities/differences among them, as well as clinical results, safety profiles, and off-label indications within different metabolic diseases. We also delve into the ongoing research along with future prospects of DPP-4 inhibitors, suggesting an increasing role for these agents in applications beyond the management of diabetes. With the increasing global burden of T2D, understanding and optimizing the use of DPP-4 inhibitors is important to address the progressive rise in the prevalence of this disease.

2. Structure and Function of DPP-4:

2.1. Molecular structure and enzymatic activity of DPP-4:

2.1.1. Molecular Structure: DPP-4 (766 amino acid residues and binds with proline and alanine at the N-terminal of the peptide) [8]. The protein DPP-4 is localized to a small pocket known as the catalytic pocket, which has serine at position 630. This protein harbors a stalk extending from the cells, with a stalk anchored to the cell membrane via a tethered rigid linker coupled to a transmembrane region. It contains a short arm at the other end as well, which is inside the cytoplasm. Two DPP-4 proteins come together to form one pair on the cell membrane. These pairs can then be cleaved at a particular bond to release a full-length DPP-4 that goes free into the circulation [5].

Figure 1. Tridimensional structural organization of Dipeptidyl Peptidase-4 (DPP-4) with its locations for extracellular, transmembrane, and intracytoplasmic regions, as well as the main functional domains.

2.1.2. Enzymatic Activity: DPP-4 is an enzyme that degrades proteins by first removing dipeptides. It works best on proteins where the second amino acid is proline or alanine. It can also cleave proteins where the second position is glycine, serine, valine, or leucine, but more slowly. It cannot cut proteins if proline is in the third position [5]. DPP-4 inhibitors degrade certain entero-hormones (e.g., glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1)), or incretins, which are primarily produced within minutes [9].

2.2. Tissue distribution and biological functions beyond glucose metabolism:

2.2.1. Tissue Distribution: DPP-4 is present in many organs and tissues of the human body (the intestinal and renal epithelium, blood vessel walls, pancreas, liver, gland cells, gut, as well as lymphocytes) [5]. Plasma contains the soluble form of DPP-4. This protein mainly comes from seminal plasma, kidneys, and endothelial cells—the cells lining blood vessels—as well as a couple of populations of white blood cells (lymphocytes) [9].

2.2.2. Biological Functions Beyond Glucose Metabolism: DPP-4 is a protein that not only digests other proteins, but also plays a crucial role in important body processes, such as how cells grow, move, and connect with their environment, known as the extracellular matrix [5]. DPP-4 also fulfills its non-proteolytic functions as a receptor or co-stimulatory protein in the field of immunology [10]. DPP-4 also cleaves cytokines and chemokines, contributing to inflammation [11].

2.3. DPP-4 involvement in immune regulation, cardiovascular function, and inflammation:

2.3.1. Immune Regulation: DPP-4, also known as CD26, is an immune protein that functions as a co-stimulatory molecule to amplify the functions of other immune system components [5].  B cells: DPP-4 is located in B cells and may help their development and function when the bones self-renew [10]. DPP-4 is indispensable for immune responses, T-cell activation, and maturation, and it often functions as a sole receptor of DPP-4 in isolation from its catalytic action [12].

2.3.2. Cardiovascular Function: DPP-4 is present on the endothelial cells [5], [9].

2.3.3. Inflammation: Inflammation is regulated by DPP-4 clearance of proteins that modulate immune responses. Additionally, its soluble form, sDPP-4, directly interacts with immune cells [12]. Experimental inhibition of DPP-4 could block inflammation. In human beings, it showed that soluble DPP-4 correlated with MCP-1 and up-regulation of interleukin-8 (IL-8) and interleukin-6 (IL-6), both mediators that initiate inflammation. These mediators are called pro-inflammatory cytokines and are the main culprits for launching and sustaining inflammation. Therefore, inhibiting the cytokines that induce inflammation could decrease inflammation and its associated effects in our bodies by targeting DPP-4. Better knowledge of how DPP-4 interacts with these cytokines may provide novel therapeutic strategies for inflammatory diseases [11].

2.4. Pathophysiological role of DPP-4 in diabetes and metabolic disorders:

2.4.1. Diabetes and Metabolic Disorders: Changes in DPP-4 expression and/or activity are linked to metabolic disorders such as obesity and diabetes [5]. DPP-4 blood activity is several times higher in type 1 and type 2 diabetes than it is in healthy people. This increased activity is strongly associated with HbA1c, the level reflecting average blood sugar over weeks. Moreover, rapid degradation of GLP-1 occurs since DPP-4 inactivity is upregulated. The reason GLP-1 is important is that it stimulates the body to secrete a little bit of insulin. Faster degradation of GLP-1 means the body might not release enough insulin, especially for people who have type 2 diabetes [9].

2.4.2. DPP-4 inhibitors: DPP-4 inhibitors are drugs that prevent the degradation of incretin hormones, such as GLP-1 (an incretin hormone that actively contributes to blood sugar control) in the DPP-4 rich incretin pathway. These drugs help reduce blood sugar by protecting GLP-1 from degradation. They trigger a rise in insulin when blood sugar levels are high, lower glucagon (the hormone that can cause blood sugar levels to rise), and slow gastric emptying. Consequently, they help to control blood sugar levels better at the same time [9].

3. Mechanism of Action of DPP-4 Inhibitors:

Dipeptidyl peptidase-4 (DPP-4) is a medicine used to reduce blood sugar. DPP-4 is one of the most important classes of drugs in diabetes treatment. They work by inhibiting an enzyme (DPP-4) that increases the quantities of various hormones. The hormones tell the pancreas to secrete more and higher amounts of insulin (the hormone that reduces blood sugar). DPP-4 inhibitors decrease the production of liver glucose, which prevents blood sugar from going too high. Together, these functions enable DPP-4 inhibitors to help individuals with diabetes maintain better regulation of their blood sugar [13]. DPP-4 inhibitors increase glycemic control in patients with type 2 diabetes through multiple mechanisms.

Figure 2. DPP-4 inhibitors prevent enhancing insulin secretion, incretin degradation, and reducing glucagon release for better glucose control

3.1. Inhibition of incretin degradation and prolonged action of GLP-1 and GIP: As DPP-4 inhibitors, they work by elevating the amounts of incretin hormones in the body. DPP-4 inhibitors raise levels of these hormones, which include glucose-dependent insulinotropic polypeptides (GIP) and glucagon-like peptide-1 (GLP-1). These hormones regulate blood sugar levels. DPP-4 inhibitors help the body manage blood sugar levels better by elevating these hormones, especially in diabetic patients who have to deal with their blood sugar. A high level of GIP and GLP-1 binding causes increased insulin secretion, leading to stronger control over glucose in the body [6].  GLP-1 is rapidly degraded by DPP-4 under normal circumstances. Inhibiting DPP-4 enables the body to retain the active form of GLP-1 for a longer time [14].

3.2. Enhanced insulin secretion and reduced glucagon levels: DPP-4 inhibitors prevent the degradation of GLP-1 and GIP, which in turn enhances the response of the pancreas's β-cells to blood sugar. They reduce the hormone glucagon, lowering blood sugar levels and making it easier to manage blood sugar levels [6]. Raising unmodified GLP-1 levels improves pancreas functioning. It causes more insulin release and less glucagon, which helps keep blood sugar down [15].

3.3. β-cell preservation and insulin sensitivity improvement: The DPP-4 inhibitors help the pancreas by supporting insulin-producing β-cells in the body. Experimental studies confirm that these inhibitors improve the function of β-cells in general and help to prevent poor pancreatic health [16].

3.4. Impact on gastric emptying and appetite regulation: The action of DPP-4 inhibitors does not affect the rate of gastric emptying. By contrast, GLP-1 receptor agonists delay gastric emptying, but DPP-4 inhibitors do not [6].

4. Classification and Pharmacokinetics of DPP-4 Inhibitors:

4.1. Classification of DPP-4 Inhibitors

As an oral antidiabetic drug, the Dipeptidyl peptidase-4 inhibitors (DPP-4) class plays an important role in treating type 2 diabetes mellitus (T2DM) [1]. They work by inhibiting the DPP-4 enzyme, which is responsible for degrading incretin hormones. This inhibition leads to increased insulin secretion and reduced glucagon levels by preventing the degradation of these hormones. DPP-4 inhibitors can be classified by chemical type, binding mode, and regulatory approvals.

4.1.1. Chemical Nature:

• Peptidomimetics: Medication that mimics a fragment of the enzyme DPP-4, includes saxagliptin and vildagliptin. The enzyme works on incretins, which are hormones that control the sugar levels in your blood. All these drugs bind to the same site of the incretin hormone that DPP-4 usually interacts with. Unfortunately, they are not very potent since they have a short half-life in vivo. Rapid degradation by peptidases prevents them from working effectively over time [17]. Recent research on improving the stability of DPP-4 inhibitors and peptidomimetics through structural modifications aims to prolong pharmacological activity [18].
• Non-peptidomimetics: Not unlike sitagliptin, linagliptin and alogliptin inhibitors do not replicate the dipeptidyl portion of the enzyme. This improvement enhances their bioavailability in the body, allowing them to circulate for longer. They ensure a more accurate and reliable management of specific conditions without mimicking important parts of enzymes [17]. Current advancements in this field have centered on improving selectivity to reduce on-target effects, which ultimately increases safety profiles [19].

4.1.2. Binding mechanisms:

DPP-4 inhibitors' binding modes can be grouped into three main classes that interact in different manners with specific sites on the DPP-4 enzyme:

• Class 1: Saxagliptin and vildagliptin bind to specific sites on the DPP-4 molecule, saxagliptin/S1 and saxagliptin/S2, and form a bond with Ser630. Saxagliptin is much more potent, with a 5-fold greater inhibition of DPP-4 compared to vildagliptin [7], [17], [20]. Studies using recent computational docking have revealed structural reasons for the improved binding affinity of saxagliptin and may facilitate the design of next-generation inhibitors [21].
• Class 2: Alogliptin and linagliptin are targeted at specific areas: S1, S2, and sometimes S1` and S2<sup>`</sup> , Comparatively, linagliptin is almost eight times stronger than alogliptin [7], [8], [17], [20]. Recent research has focused on the unique pharmacokinetics of linagliptin, specifically the high plasma protein binding and long half-life, which may be exploited for tailored dosing in various clinical conditions, including specific patient populations [22].
• Class 3: Sitagliptin, anagliptin, gemigliptin, and teneligliptin bind at the S2-extensive site and show the strongest inhibition potentials [17], [20]. Teneligliptin demonstrates 5 times greater activity compared to sitagliptin [8]. Recent studies have recognized the dual anti-inflammatory and glycemic control properties of teneligliptin, which imply that it may have additional benefits aside from glucose control [23].

4.1.3. FDA-Approved DPP-4 Inhibitors: DPP-4 inhibitors are used to treat blood sugar levels in people with diabetes. Modulation of DPP-4 enzymes includes teneligliptin, vildagliptin, saxagliptin, linagliptin, sitagliptin, anagliptin, alogliptin, gemigliptin, etc. They block the DPP-4 enzyme, which increases postprandial insulin secretion from these medications. This process assists in the reduction and maintenance of blood sugar levels. If you are diabetic, your doctor may recommend one of the following inhibitors to manage your blood sugar [7], [20]. Sitagliptin (the first of the DPP-4 inhibitors) was launched on the market in 2006 [7]. Since then, newer agents have been developed with enhanced pharmacokinetic properties while considering safety issues. A very good example is linagliptin, which is predominantly excreted through the bile rather than through the kidneys; hence, its dose should not be changed in renal impaired patients [24]. Some recent clinical trials have also examined combination therapies with other antidiabetic agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, or metformin for potential additive outcomes [25].

4.1.4. Recent Advances in DPP-4 Inhibitor Research

Finally, there has been a shift in the therapeutic landscape of DPP-4 inhibitors toward glycemic control in recent years in research. So far, they have also been studied for their anti-inflammatory and cardioprotective properties in subjects with T2DM who are at high risk for cardiovascular diseases [26], [27]. Recent improvements in molecular modeling have enabled the design of new inhibitors with higher selectivity for DPP-4 than for other dipeptidyl peptidases, thus minimizing side effects [28]. Investigations on fixed-dose combinations (FDCs) containing DPP-4 inhibitors as monotherapy are also underway to improve treatment simplification and medication adherence. Patients with cardiovascular (CV) risk, for instance, FDCs planned with sitagliptin and metformin or empagliflozin have shown superiority versus monotherapy on the grounds of treatment efficacy in clinical trials [29].

4.1.5. Comparison of Binding Affinities, Potency, and Selectivity: Saxagliptin displays efficacy at around a 50 nM concentration. Vildagliptin and sitagliptin have IC50 values of 62 nM and 19 nM, respectively. Linagliptin is the most powerful DPP-4 inhibitor with an IC50 of 1 nM, making it the most efficacious of these drugs [30]. Linagliptin is a drug that specifically acts upon the DPP-4 enzyme. It is approximately 44,000 times more selective for DPP-8 dpp-4 than DPP-8 and about 10,000 times more selective than DPP-9, which results in Linagliptin primarily targeting DPP-4 with very little effect on DPP-8 or DPP-9 [30].

4.2. Pharmacokinetics

• Absorption and Bioavailability: Oral administration of sitagliptin is rapidly absorbed, with peak plasma concentrations (Tmax) reached after 1 to 4 hours. The absolute bioavailability of sitagliptin (fed: fasting: >87%, meaning a substantial amount of the drug is absorbed into systemic circulation in its active form) indicates that food intake has no clinically relevant effect on the absorption, so it can be taken with or without meals [31].
• Metabolism: We have highlighted the minimal hepatic metabolism of sitagliptin, with essentially all of the compound remaining unmetabolized in circulation. This drug is mostly metabolized by the liver through the cytochrome P450 (CYP) enzyme system, primarily by CYP3A4 and, to a lesser extent, CYP2C8. While less than 16% of the administered dose becomes metabolized, hepatic impairment is of less concern when doses need to be adjusted [31]. Linagliptin, on the other hand, metabolizes through a different pathway, and the majority of the drug is excreted in a non-renal way compared to the others. In contrast to sitagliptin, which is largely metabolized by CYP enzymes, linagliptin shows a minimal metabolic role and is mainly eliminated unchanged in feces [32].
• Half-life: SITAGLIPTIN Elimination Half-Life (t½) in healthy subjects (60 mg single dose): Once administered at 100 mg, the elimination half-life (t½) of sitagliptin in healthy subjects is approximately 12.4 hours. This permits once-daily dosing, which maintains adequate plasma concentrations over a 24-hour period [31]. In contrast, Linagliptin is a long-acting drug because of its high degree of binding to dipeptidyl peptidase-4 (DPP-4). The considerable enzyme affinity implies a longer pharmacodynamic effect of this compound, with its short plasma half-lives that may not require dose adjustments in patients with renal dysfunction [32].
• Excretion: The major route of sitagliptin elimination is renal, with 79% of the administered dose excreted unchanged in the urine. Other mechanisms presumably involve active tubular secretion via renal transporters (Organic Anion Transporter-3 (OAT3) or P-glycoprotein (P-gp)). Fecal elimination represents approximately 13% of the dose; less than a minor fraction undergoes metabolic activation. Because of its principal renal excretion and clearance, dose modification is needed in patients with moderate-to-severe renal impairment to avoid drug accumulation and, likely, toxicity. Linagliptin, however, uses a distinct elimination route, as the majority of the drug is eliminated through the hepatobiliary system and, thus, is more favorable in cases of renal dysfunction [31].

4.3. CYP450 Metabolism vs. Renal Elimination: Sitagliptin is not extensively metabolized by the liver enzymes cytochrome P450 3A4 and 2C8. Therefore, it should ideally have minimal interactions with other drugs that are metabolized through these pathways or the p-glycoprotein transport system. If you are on other medications that are metabolized by these pathways, major drug interactions with sitagliptin are thought to be unlikely. Thus, in patients on many drug regimens, sitagliptin is the best choice to minimize unexpected adverse effects or problems. You may feel more confident that sitagliptin is safe to take with other drugs and doesn't interfere with its hepatic metabolism. This is particularly important for patients regularly dosed on medications who would like their treatment to be free from drug interactions [31]. Unlike other DPP-4 inhibitors, linagliptin is renally excreted very little and is not significantly eliminated by the kidneys. Hence, patients with kidney problems can take it without having to change the dose [32].

4.4. Drug-Drug Interactions and Contraindications: Clinical trials failed to identify any significant interactions, other than those affecting Sitagliptin pharmacokinetics, which could potentially impact the dose [31]. If you are going to start any GLP-1 receptor agonists, please stop the DPP-4 inhibitors [7].

5. Therapeutic Applications of DPP-4 Inhibitors:

5.1 Treatment of Type 2 Diabetes Mellitus (T2DM)

5.1.1. Effects on Glycemic Control: DPP-4 inhibitors prevent the inactivation of incretin hormones (glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP)). These hormones:

• Promote the release of insulin by pancreatic beta cells in response to hyperglycemia.
• Reduce glucagon secretion from pancreatic alpha cells and hepatic glucose output.
• Slow gastric emptying: Post large meals, glucose control is improved.

In addition, DPP-4 inhibitors help to reduce long-term HbA1c levels (approximately 0.5–1%) through significant reductions in fasting and postprandial glucose levels, which allows for better long-term glycemic control. Unlike sulfonylureas, they do not cause hypoglycemia, making them the preferred option for many patients [33].

5.1.2. Monotherapy vs. Combination Therapy: DPP-4 inhibitors may be used as monotherapy in individuals with mild to moderate diabetes who are non-compliant or intolerant of metformin and other first-line agents. However, because of their lesser magnitude of glucose lowering, they are prescribed more commonly as an addition to another type of medicine rather than as monotherapy:

• Metformin: First-line therapy that decreases hepatic glucose output. 
• Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors: Promote glucose excretion through urine. 
• Thiazolidinediones (TZDs): Enhance peripheral insulin sensitivity. 
• Sulfonylureas: Drugs that increase the secretion of insulin from pancreatic cells. 
• Pancreatic insulin: Used in extreme cases, but this is the most efficient way for a person to control their blood sugar. 

In patients with progressive β-cell dysfunction, combination therapy is particularly advantageous as it focuses on multiple pathways in glucose regulation and overall increases diabetes control [33].

5.2. Benefits in Specific Patient Groups:

5.2.1. Elderly Patients: Hypoglycemia and weight gain are common problems in elderly diabetics receiving insulin or sulfonylureas, especially when the class of medications powerfully affects glucose. The popular regimen of DPP-4 inhibitors is as follows for this population:

• Minimal Risk of Hypoglycemia: As they are triggered by the presence of glucose, if the blood glucose is not too low, these agents will not increase insulin release, therefore avoiding excessive low blood sugar (hypoglycemia) episodes. 
• Safe and Weight Neutral: DPP-4 inhibitors do not cause weight gain, which is an advantage for the elderly who may already be metabolically challenged compared to sulfonylureas and insulin. 
• Easier to Take: DPP-4 inhibitors are oral medications, as opposed to injectable options like GLP-1 receptor agonists [33].

5.2.2. Renal-Impaired Individuals: Chronic kidney disease is a major risk factor for diabetes, and many antidiabetic drugs are either contraindicated or need dose modifications in patients with renal impairment. DPP-4 inhibitors:

• Linagliptin: hepatobiliary excretion (no dose adjustment required in patients with renal impairment, making it preferred)
• Other DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, and alogliptin) are predominantly eliminated by the kidneys, so dosage must be adjusted in cases of severe renal dysfunction.

Furthermore, some DPP-4 inhibitors have specific features that make them safe to use in patients with CKD without the need for dose adjustment and are therefore necessary in this subset [34].

5.2.3. Cardiovascular Risk Groups:T2DM patients commonly have a high burden of cardiovascular diseases (CVD), such as heart attacks and stroke. Studies on the anti-CVD cardiovascular effects of DPP-4 inhibitors are extensive. That is:

• • Neutral Cardiovascular Safety: Large clinical trials (e.g., TECOS; linagliptin, CARMELINA) show that DPP-4 inhibitors are not associated with any risk of major adverse cardiovascular events.
  • Beneficial Cardiometabolic Effects: They do not reduce CVD risk per se but are likely to contribute to favorable lipid profiles, lower blood pressure, and reduced inflammation, consequently potentially supporting heart health indirectly.
  • No Significant Increase in Heart Failure Risk: Concerns regarding an increase in heart failure with saxagliptin, and to a lesser extent alogliptin, resulted in no use or cautious use of these agents in patients with cardiac backgrounds. However, in subjects with or without pre-existing HF symptoms, linagliptin and sitagliptin had a neutral effect.

With this in mind, DPP-4 inhibitors represent a good choice for patients with high cardiovascular risk, but they are not a first-line consideration for cardiovascular protection compared to SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists, which showed greater CV benefits [35], [27].

5.3. Cardiovascular and Renal Benefits

Figure 3. Cardiovascular Protective Properties of DPP-4 inhibitors: protection of endothelial function, reduction of inflammation, and improvement in glucose metabolism.

Cardiovascular Outcome Trials:

• DPP-4 inhibitors and glycemic outcomes followed up: p. 46 | Several studies, including TECOS, SAVOR-TIMI 53, EXAMINE, and CARMELINA, have reported on heart-related endpoints of DPP-4 inhibitors. The trials were meant to determine if these diabetes drugs would pose significant heart risks. A hopeful finding is that there is no effect of DPP-4 inhibitors on major adverse cardiovascular events (MACE), the major outcome we care about. This provides some comfort that the use of DPP-4 inhibitors by patients is unlikely to confer additional heart risk from these drugs [35].
• SAVOR-TIMI 53 study stated that patients receiving saxagliptin were associated with a higher rate of hospitalizations for heart failure [35].
• In the CARMELINA trial, the scientists looked at how linagliptin performed versus a placebo (no drug) in the CAROLINA study: linagliptin vs. other studies, such as the one above, which compare linagliptin against another drug, glimepiride. In both trials, major cardiovascular (MACE) events occurred equally in linagliptin-treated patients compared to those receiving other medications. Furthermore, there were no significant differences in hospitalizations due to heart failure among any of the groups [35].

Impact on Cardiovascular Health: DPP-4 Inhibitors for a Healthy Heart: Controlling Cholesterol and Blood Pressure Issues. They fight inflammation, protect cells from damage, provide benefits to blood vessels, and reduce protein excretion in urine [27].

Figure 4. Schematic representation of the kidney-protective actions of DPP-4 inhibitors, including both GLP-1-dependent and independent effects on renoprotection