Though glycaemic regulation is an important and effective method of preventing and limiting the progression of complications associated with diabetes, type 2 diabetes is a disease that is often difficult to manage. It is estimated that 20.8 million people are diagnosed with diabetes in United States alone and a worldwide prevalence of approximately 180 million that is expected to double by 2030 (Neumiller et al., 2008).
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Introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors offered an alternative to the conventional medicines for intensifying glucose-reducing treatment after metformin monotherapy failing to do so and thus flagged a major possible progression in type 2 diabetes management. DPP-4 inhibitors trigger insulin secretion and decrease glucagon release in a glucose-dependent manner by prolonging the activity of incretin hormones. Compared to insulin secretagogues sulphonylureas and glinides, this results in a more glycaemic control. Ultimately, DPP-4 inhibitors have a good safety profile which can be used in elderly people and patients with minor renal impairment without having to need to adjust the dosage; they have a neutral effect on body weight and do not induce hypoglycaemia on their own. Health concerns, reported predominantly in after-market surveillance programmes, including cardiovascular complications and the risk of developing acute pancreatitis, are being studied extensively (Sesti et al., 2019).
Many affected patients would potentially require multi-drug therapy to achieve appropriate glycaemic goals. Dipeptidyl peptidase-4 (DPP-4) inhibitors have constructed a new class of oral drugs for the treatment of type 2 diabetes symptoms, these inhibitors have become extensively integrated into clinical practice.
Diabetes is an increasing problem in the world especially Type 2 which accounts for more than 90% of all diabetes cases in the world (Healthline, n.d.). Although it is a preventable disease, most people will not know they are diagnosed until it is too late therefore, they must undergo necessary treatment. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recently approved new class of drugs that are used for the treatment of type 2 diabetes, they are known as gliptins and are prescribed to people when they do not respond well to drugs like metformin and sulphonylureas. DPP-4 inhibitors work by preventing the action of the DPP-4 enzyme which breaks down incretin hormones that are produced by the endocrine cells in the epithelium of the small intestine (Watson and Dokken, 2015). There are two types of incretin hormones in humans, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). These hormones induce the release of insulin after a meal or when needed therefore people with Type 2 diabetes who cannot produce enough insulin require them the most. The three main DPP-4 inhibitors are Sitagliptin, Saxagliptin and Linagliptin. Their trade names are Januvia, Onglyza and Tradjenta respectively.
GLP-1 and GIP are degraded rapidly after their secretion by DPP-4 enzyme which results in their inactivation, this is done by cleaving a dipeptide from the N-terminus. DPP-4 can often be found attached to cell membranes as well as circulating in the blood stream (Bennett, 2018). After discovering that DPP-4 was associated in the degradation of the incretin hormones, it led to the production and use of DPP-4 inhibitors which aims to increase the half-life of endogenous GLP-1 and GIP.
Development of Sitagliptin: The idea of glucagon-like peptide 1 (GLP-1) as a well-validated solution to type 2 diabetes treatment and the preclinical evidence of inhibition of DPP-4 as an alternative oral route to GLP-1 therapy led Merck to launch a DPP-4 inhibitor programme in 1999. The DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were licensed to start the programme but the development was discontinued due to extreme toxicity that was observed in rats and dogs during trials. The discovery of both compounds inhibiting the associated proline peptidases DPP-8 and DPP-9 directed to the hypothesis that the inhibition of either or both enzymes could induce a series of harsh toxicities in the preclinical species that were used (Thornberry and Weber, 2007). In reality, the toxicities reported was recapitulated using a selective dual DPP8/9 inhibitor but not a selective DPP-4 inhibitor. As a result, studies in medicinal chemistry shifted its focus to discovering a selective DPP-4 inhibitor. Due to lack of selectivity, initial work on the sequence of amino acids linked to isoleucyl thiazolidide was discontinued. Nonetheless, two-screening SAR experiments have resulted in the discovery of a highly selective sequence of B-amino acid piperazine. A number of bicyclic variants were prepared in an attempt to stabilise the piperazine moiety, which was thoroughly metabolised in vivo, resulting in the discovery of a potent and selective sequence of triazolopiperazine. Such formulations usually exhibited great pharmacokinetic properties in preclinical species unlike their monocyclic counterparts. Optimisation of this sequence led to the development of JANUVIATM (sitagliptin), a selective DPP-4 inhibitor for treatment of type 2 diabetes (Kumar, Tripathi and Garg, 2013). Sitagliptin was first approved by the FDA for the treatment of type 2 diabetes in 2006 (Drugs.com, 2019). It is available in doses of 25, 50 and 100 mg tablets. It is used as a monotherapy or in conjunction with other diabetic drugs, including metformin, sulfonylureas and pioglitazone A (Sekar et al., 2016).
The usage of sitagliptin and metformin combination was approved by the FDA in April 2007 and is distributed in doses of 50/500 mg or 50/1000 mg under the trade name Janumet. In a monotherapy trial, 743 patients with diabetes were randomised to receive 5, 12, 25 or 50 mg twice daily of sitagliptin. All doses of sitagliptin resulted in a heavy reduction in HbA1c after 12 weeks of treatment (Sekar et al., 2016).
Mechanism of action of Sitagliptin: sitagliptin prolongs the life span and activity of the incretins; GLP-1 and GIP via inhibition of the DPP-4 enzyme. After a meal, the secretion of GLP-1 and GIP are triggered by the L-cells and K-cells respectively. Inhibition of DPP-4 allows for levels of active incretin hormones to be increased; essentially, sitagliptin augments the ability of glucose synthesis by pancreatic beta cells which in turn releases insulin as a response to glucose concentration increasing. The release of insulin contributes to the glucose reduction process in the liver (Pathak and Bridgeman, 2010). JANUVIATM (sitagliptin) enhances insulin release and reduces glucagon levels in the bloodstream in a glucose-dependent manner by increasing and prolonging active incretins concentration. Sitagliptin displays DPP-4 selectivity and does not inhibit in vitro DPP-8 or DPP-9 activity at concentrations resembling those from therapeutic doses (RxList, n.d.).
Adverse effects of Sitagliptin: the most frequent adverse reactions were upper respiratory tract infection, nasopharyngitis, and headaches in more than 5% of patients receiving the DPP-4 inhibitor sitagliptin. Seeing as renal and hepatic pathways are associated in eliminating oral doses of sitagliptin, patients with renal and hepatic insufficiency were also tested. Following the intake of carbon-14 labelled sitagliptin, roughly 13% was detected in stool and 87% in urine. Of the 87% that was found in urine, 24% was structurally unchanged, while 36% were active parental metabolites (Mrknewsroom.com, 2013).
Development of Saxaglipton: A longer duration of action was desirable during the development of DPP-4 inhibitors. Compounds that had a vinyl substitution at the β-position of α-cycloalkyl-substituted glycines and their oxygenated metabolites did not result in deterioration of potency but resulted in a desired increase in duration of action is what caused Bristol-Myers Squibb pharmaceutical company to develop saxagliptin. Consecutive exploration of molecules with a hydroxylated adamantyl group led to saxagliptin, this is distinguished by the potency in vitro and in vivo, good oral bioavailability (F = 75%), good period of activity (t 1/2 = 2.1 hours) as well as no inhibition of CYP3A4 (Gallwitz, 2010). A 24-week clinical study showed that saxagliptin as a monotherapy was effectively successful in lowering HbA1C by 0.4 to 0.9%. It showed to be well tolerated in the dose ranges of 2.5 to 40 mg (Dave, 2011). Saxagliptin was effective and well tolerated in type 2 diabetes patients with moderate to severe renal impairment with contraindicated metformin. In patients with end-stage renal disease or haemodialysis, saxagliptin was not effective (Nowicki et al., 2011). Saxagliptin was FDA approved in 2009
Mechanism of action of Saxagliptin: saxagliptin and its active metabolite M2 which are two times less effective than the parent drug and are also competitive DPP-4 inhibitors that enhance glycaemic control by preventing the inactivation of GLP-1 and GIP incretin hormones. It raises levels of GLP-1, promoting the release of insulin, and reduces levels of postprandial glucagon and glucose. Saxagliptin and M2 are much more selective for inhibiting DPP-4 than DPP-8 or DPP-9 enzymes or a large group of several other proteases (Dave, 2011).
Adverse effects of Saxagliptin: In a clinical trial that lasted for 52 weeks, the test subjects were split into two groups; one group being given Onglyza (saxagliptin) and the other group taking a placebo. Urinary tract infection, fever, headache, nasopharyngitis and diarrhoea were the most frequent adverse effects at 52 weeks. In the 52 weeks of treatment, few patients experienced hypoglycaemia events; 1.3% of patients with saxagliptin and 2.5% of patients with the placebo. Also, rates were no different from those recorded at 24 weeks. During the study, no patient had a significant episode of hypoglycaemia. Small increases were detected at 52 weeks in systolic (0.8 mmHg) and diastolic (0.3 mmHg) blood pressure equivalent within both groups. Increases in serum lipids, total cholesterol, low- and high-density lipoprotein cholesterol, and triglycerides in each category of therapy were minimal (Matthaei et al., 2016).
Saxagliptin is readily absorbed orally with a bioavailability of approximately 67%. It is widely dispersed in extravascular tissues with the highest concentrations being located in the intestinal tissue and kidney. It is primarily hydrolysed by CYP3A4/5 to the main metabolite M2 and some other minor metabolites and therefore dosage should be lowered in patients with concurrently strong CYP3A4 inhibitors. Both renal and hepatic pathways excrete saxagliptin. 75% of saxagliptin is removed through urine and 22% through faeces (Dave, 2011).
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Development of Linagliptin: the research for the discovery of an optimal and more potent oral DPP-4 inhibitor began with the screening of over 500,000 different molecules by using high-performance screening (HTS), which detected many compounds that were members of different structural classes with a low micro molar inhibition of DPP-4. One of these candidates was a compound based on the xanthine scaffold, which is made up of four residues of varying structural features which showed characteristics that were deemed a very promising starting point for the search for an effective DPP-4 inhibitor (Eckhardt et al., 2015).
Tradjenta (linagliptin) is a small xanthin based molecule. The substantial structural heterogeneity that underlies the DDP-4 inhibitor class members demonstrates distinct pharmacological properties. Linagliptin is a novel chemical class for the therapy of type 2 diabetes in this regard, as no other xanthine-based DPP-4 inhibitor is currently licenced for this indication. Linagliptin is a competitive, reversible DPP-4 inhibitor with a slow dissociation rate from the enzyme. Linagliptin is extremely selective for DPP-4, being at least 10,000 times higher than DPP-8 and DPP-9 selectivity. The corresponding selectivity for sitagliptin and saxagliptin, on the other hand, is approximately 4-fold and 100-fold lower (Thomas et al., 2008). Linagliptin seems to be the DPP-4's most effective inhibitor in its class. Linagliptin inhibited in vitro DPP-4 activity with an IC50 of 1 nM compared to 19, 62, 50 and 24 nM respectively for sitagliptin, vildagliptin, saxagliptin, and alogliptin. After 24 hours of administration, DPP-4 inhibition in vivo was significantly higher than any other DPP-4 inhibitor and decreased in the order of linagliptin, sitagliptin, saxagliptin, and vildagliptin for the duration of action (Forst and Pfützner, 2013). Linagliptin was discovered and produced by Boehringer Ingelheim, a pharmaceutical company based in Ingelheim, Germany. It was approved by the FDA in May of 2011 (Eli Lilly and Company, 2011).
Mechanism of action of Linagliptin: just like the other two previous drugs; linagliptin is also a DPP-4 inhibitor which prevents the degradation of the GLP-1 and GIP by the enzyme therefore in turn increases the concentration of active incretin hormones circulating around the body which induces the release of insulin in a glucose-dependant manner while at the same time decreasing the levels of glucagon in the body also. GLP-1 and GIP have the sole purpose is to maintain a natural regulation of glucose homeostasis within the body (Freeman, 2011).
Adverse effects of Linagliptin: nasopharyngitis, hypertension, back pain and headache were the most commonly reported adverse effects during the clinical trials. There were rare side effects involving gastrointestinal system. It has been established that linagliptin is well tolerated either when administered alone or in combination in all the studies. In a dose ranging research, the frequency of adverse effects and the tolerability profile throughout all active dose groups have been similar and comparable to that of the placebo. Although linagliptin's activity is driven by ingestion of oral glucose, it has a low tendency to induce hypoglycaemia, which is expressed in clinical trials. In all the studies, it was frequently reported that hypoglycaemic occurrences with linagliptin treatment were mild and rare. Furthermore, linagliptin had no effects on body weight and adjustment to dosage is not required for people with renal or hepatic impairment (Htike and Lawrence, 2012).
This is due to linagliptin being mostly excreted non-renally. Less than 10% of the linagliptin dose in people with normal hepatic function undergoes renal clearance. In comparison, 80–90% of sitagliptin and vildagliptin are excreted through the renal route, meanwhile saxagliptin is excreted via both renal and hepatic pathways. Since linagliptin is excreted only to a small extent by the renal system, the main route of removal is through the entero-hepatic system. Linagliptin's hepatic metabolism is low and its metabolites are pharmacologically dormant, including its main metabolite CD1790 (Graefe-Mody et al., 2012).
Type 2 diabetes treatment is intricate; many patients are required to take multiple drugs to achieve the optimal glycaemic targets. Even though the DPP-4 class of inhibitors is not yet fully studied, clinical studies and trials suggest that the mechanisms of action of these drugs complement those of commonly used diabetic drugs. This attribute make these class of drugs suitable for the use of the elderly, for those with numerous co-morbidities that restrict the use of other medications, and for those with complicated insulin therapy (Green, 2010).
NICE recommends the usage DPP-4 inhibitors in the UK as a second- or third-line choice in type 2 diabetes management (Htike and Lawrence, 2012). DPP-4 inhibitors are an important alternative to the anti-hyperglycaemic drugs available today for type 2 diabetes. DPP-4 inhibitors provide the benefits of an enhanced tolerability profile, defined by a minimal risk of hypoglycaemia and no weight gain, with comparable efficacy to existing agents. Moreover, there is growing evidence that DPP-4 inhibitors have additional effects that are beneficial on β-cell function and improve cardiovascular risk through mechanisms that have not yet been fully developed. A number of DPP-4 inhibitors for the treatment of type 2 diabetes have been approved. In the coming years, clinical use and understanding of DPP-4 inhibitors, will increase substantially. This is due to a significantly improved safety profile compared to sulfonylureas, DPP-4 inhibitors could become the ideal oral drugs for combination therapy in type 2 diabetes, especially in patients who are not appropriately controlled on metformin monotherapy alone. (Forst and Pfützner, 2013).
To summarise the drugs, sitagliptin was developed after the discontinuation of the original DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide due to the fact that they caused severe toxicity in the animals during the clinical trials. After a successful attempt of developing sitagliptin to treat type 2 diabetes, it paved the way for other pharmaceutical companies to develop better and more potent DPP-4 inhibitors. The development of saxagliptin was primarily to produce a drug that shares the same molecular target as sitagliptin while having better pharmacokinetic properties such as higher bioavailability and a longer mode of action which saxagliptin does exactly that.
Linagliptin displayed the best pharmacological properties in its class out performing both sitagliptin and saxagliptin inside the body. It showed the highest selectivity for the DDP-4 enzyme without interfering with other molecular sites as much as the previous two in addition, linagliptin had a much lower IC50 than any other gliptins in the same class making it the most potent DPP-4 inhibitor.
Galvus (vildagliptin) is also another DPP-4 inhibitor developed in Switzerland with a recommendation of oral ingestion once a day has been approved by many European regulators. Novartis Pharmaceuticals Corporation revealed in February 2007 that they had received an approval letter from the United States. Food and Drug Administration (FDA) seeking additional data, such as a clinical trial to demonstrating the safety and efficacy of vildagliptin in specific groups of patients with renal impairment. Although vildagliptin is available in many countries, in the United States it is still commercially undeveloped and not FDA approved (Drugs.com, n.d.).
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