| USAN: | Sitagliptin Phosphate |
| Brand Name: | Januvia (Merck) |
| Molecular Weight: | 523.32 (Parent, 407.31) |
| FDA Approval: | 2006 |
| Drug Class: | Dipeptidyl peptidase-4 (DPP-4) inhibitor |
| Indications: | Type II Diabetes |
| Mechanism of Action: | Competitive and Reversible Dipeptidyl Peptidase IV (DPP-4) Inhibitor |
■ 1 History of Diabetes and Diabetic Drugs
Diabetes has been known since antiquity. In fact, the term “diabetes mellitus” comes from the Greek meaning “siphon and honey” due to the excess excretion (siphon or faucet) of hyperglycemic (sweetened, or honeyed) urine associated with diabetes. In ancient times, diabetes was mostly type I, which usually manifests acutely in the young, secondary to certain underlying insults (possibly infections) to the islet cells of the pancreas resulting in an absolute lack of insulin. Insulin was discovered by Banting and Best in 1921,1,2 and insulin injection has literally saved millions of lives since then. With the wondrous efficacy that insulin bestows, type I diabetes is largely controlled because type I diabetes is insulin-dependent. However, type II diabetes, a more prevalent form of diabetes, is not insulin-dependent.
In ancient times, when nutrition was scarce and obesity was not prevalent, type II diabetes mellitus (T2DM) was extremely rare. Indeed, type II diabetes is a disease more frequently associated with maturity, obesity, and gradually increasing blood glucose concentrations, and it may be asymptomatic for some time, only discovered on routine glucose screening. In fact, with the increasing body weight of the general population of the developed world, type II diabetes is becoming an epidemic. Serious complications of diabetes include nephropathy (kidney diseases), neuropathy (nerve damage), and retinopathy (blindness). Diabetes is the most common cause of blindness and amputation in the elderly in the United States. Oral diabetes drugs are required for most type II diabetic patients.
Diabetes drugs may be classified into four categories: (a) agents that augment the supply of insulin such as sulfonylureas; (b) agents that enhance the effectiveness of insulin such as biguanides and thiazolidinediones; (c) GLP agonists; and (d) DPP4 Inhibitors. The efficacy of all the antidiabetic drugs can be monitored by measuring glycosylated hemoglobin (HaA1c) as a long term marker of elevated blood glucose. The amount of HaA1c reflects the average level over the last 120 days, the life span of a red blood cell, and should remain below 7%.
1.1 Sulfonylureas
More than 20 million T2DM patients worldwide are treated with hypoglycemic sulfonylureas. Their introduction as a treatment during the 1950s represented the first reliable oral treatment of diabetes.
Janbon discovered sulfonylureas’ antidiabetic effects of in 1942 by chance when he observed hypoglycemia as a side effect after giving a sulfa antibiotic to soldiers to alleviate typhoid fever.3 That particular sulfonamide antibiotic drug was isopropylthia-diazole (IPTD, 2). Tolbutamide (Orinase, 3) and chlorpropamide (Diabinese, 4, see Table 6.1) emerged in the 1950s. Tolbutamide (3), with a toluene moiety, is readily metabolized and thus required a twice-daily treatment. Chlorpropamide (4), on the other hand, has a chlorine substituent in place of the methyl group in tolbutamide (3)—therefore, chlorpropamide (4) is less prone to metabolization and can be taken once daily. The advantage of tolbutamide (3) was that it did not possess antibacterial properties, thus avoiding build-up of bacterial resistance. Unfortunately tolbutamide (3), marketed since 1957, was found to be associated with increased cardiac mortality and was withdrawn from the market in 1997.
Table 6.1. Important Sulfonylureas4
| Name | R | R1 |
|---|---|---|
| tolbutamide (Orinase, 3) | –CH3 | –CH2CH2CH2CH3 |
| chlorpropamide (Diabinese, 4) | –Cl | –CH2CH2CH3 |
| tolazamide (Tolinase, 5) | –CH3 |  |
| acetohexamide (Dymelor, 6) | –C(O)CH3 |  |
| glibenclamide (Glynase, 7) |  |  |
| glipizide (Glucotrol, 8) |  |  |
| glimepiride (Amaryl, 9) |  |  |
Over time, sulfonylurea use increased dramatically. Many additional sulfonylureas, including tolazamide (Tolinase, 5) and acetohexamide (Dymelor, 6) emerged, as depicted in Table 6.2. Compounds 2–6 are the first generation sulfonylureas, whereas sulfonylureas 7–9 are the second-generation drugs.4 They are longer-acting and highly potent. The second-generation sulfonylureas are effective at 10–100 times lower concentrations and this difference in potency is a major distinction between the two generations of drugs. Today, the second-generation sulfonylureas are the most commonly used.
Sulfonylureas are also known as insulin secretagogues because they stimulate insulin secretion by inhibiting (closing) ATP-sensitive K+ (KATP) channels in pancreatic β-cells by binding to the sulfonylurea receptor SUR1.4,5 Sulfonylureas promote depolarization of the β-cell membrane by closing off ATP-gated potassium channels Kir6.2 (see Fig. 6.1). However, sulfonylureas are ineffective in completely insulin-deficient patients and successful therapy likely requires at least 30% of normal β-cell function. Sulfonylureas are commonly used as an add-on to metformin (19) in treating T2DM in patients who are insufficiently controlled by metformin (19) alone; they have good efficacy and have been shown to prevent microvascular complications. However, treatment with sulfonylureas is also associated with a high frequency of hypoglycemia, increased body weight, and a high risk of secondary failure.6
Repaglinide (Prandin, 10), nateglinide (Starlix, 11), and mitiglinide (Glufast, 12) are non-sulfonylurea secretagogues.7–9 They are a group of rapid-acting insulin secretion–stimulating agents also known as short-acting insulinotropic agents that can be regarded as better “sulfonylureas.” For instance, nateglinide (11) is highly tissue selective with low affinity for heart and skeletal muscle. Non-sulfonylurea secretagogues 10–12 interact with the ATP-sensitive potassium channel on pancreatic β-cells. The subsequent depolarization of the β-cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels.
1.2. Biguanides
Among the pharmacological interventions to preserve the β-cells, those that lead to short-term improvement of β-cell secretion include insulin, sulfonylureas, and metformin (19). Sulfonylureas serve to increase insulin production by the pancreas. But there is limited insulin production in the pancreas of a T2DM patient. In time, the pancreas will not be able to generate insulin any longer, so there is a need for drugs to increase the insulin sensitivity of the pancreas. Biguanides and thiazolidinediones belong to this category.
A century ago, guanidine (13) was tested to determine whether it reduced blood sugar level in rabbits, but was found to be too toxic for use in humans. The same was found to be true for galegine (14), isolated from Galega officinalis, and also known as French lilac, goat’s rue, or professor-weed. Synthalin A (15) was the first biguanide on the market in 1926, but was plagued by adverse effects. Synthalin B (16) was made in an effort to lower the toxicities associated with Synthalin A (15). However, it was also withdrawn in the 1940s due to liver and kidney toxicities.10
Phenformin (17), an early biguanide, was for some time one of the few available oral agents. However, it had limited utility due to serious side effects and was withdrawn from the US and most other markets in 1977 due to high risk of lactic acidosis. Buformin (18), an analog of phenformin (17), had a somewhat better safety profile. The safest biguanide to date is metformin (Glucophage, 19), which has 10–15 times fewer incidences of lactic acidosis and is thus safer than both phenformin (17) and buformin (18). Metformin (19) was first marketed in 1957 by Merck although it was first synthesized in 1922. It was reintroduced in the United States for the treatment of T2DM in 1994. Today, metformin (19) is one of the most commonly prescribed oral treatments for T2DM. It is preferred for obese patients unless contradicted.
The MOA of metformin (19) has been the subject of intense investigation. Metformin has been widely thought to act as an insulin sensitizer in people with diabetes, improving the ability of insulin to stimulate glucose uptake in muscle and suppress hepatic glucose production. Like sulfonylureas, metformin (19) is only active in the presence of insulin. More recently, however, a new study in mice shows that inhibitory phosphorylation of acetyl-CoA carboxylases Acc1 and Acc2 by the AMP-activated protein kinase (AMPK) is essential to the ability of metformin (19) to improve insulin sensitivity and lower blood glucose in patients who are obese.11
Unlike most other antidiabetes drugs, metformin (19) is not bound to serum proteins and thus is not displaced by competitive binding of other drugs. The highest concentrations of metformin (19) are found in the gut and liver. It is not metabolized but is rapidly cleared from plasma by the kidneys. Because of its rapid clearance, metformin is usually taken 2–3 times daily. The most frequent side effect associated with metformin (19) is diarrhea. This kind of gastrointestinal (GI) irritation can be a sign of early lactic acidosis. Unlike sulfonylureas, hypoglycemia is not a complication for the use of biguanides.
1.3 PPARγ Agonists
Similar to biguanides, thiazolidinediones (TZDs) are insulin sensitizers. Thiazolidinediones are often used with other oral antidiabetic drugs, preferably with metformin or sulfonylureas.
In 1997 Sankyo and Parke-Davis began to market the first thiazolidinedione, troglitazone (Rezulin, 20), in the United States for the treatment of T2DM. But it was voluntarily withdrawn in 2000 due to severe idiosyncratic hepatotoxicity. In 1999, the FDA approved two additional thiazolidinediones, rosiglitazone (Avandia, 21) by GSK and pioglitazone (Actos, 22) by Takeda and Lilly. Although they all possess the same TZD functional group as troglitazone (20), they are expected to be less toxic because they are more potent, thus requiring smaller doses. In 2011, the FDA severely restricted the prescription of rosiglitazone (Avandia, 21) due to its “purported” cardiovascular side effects after a long and very controversial public debate. The FDA lifted those restrictions in 2013 after more positive data surfaced from beta analysis.
Thiazolidinediones exert their antidiabetic effects through a mechanism that involves activation (agonist) of the γ isoform of the peroxisome proliferators-activated receptor (PPAR-γ), a nuclear receptor.12 As shown in Fig. 6.2, the process of transcription begins with the binding of ligands (endogenous or exogenous) to the PAAR-γ receptor. Ligand-bound PPAR heterodimerizes with retinoid X receptor (RXR) and this heterodimer binds to the promoter region of peroxisome proliferator response elements (PPREs) with the recruitment of co-activators. This results in the increase in transcription activities of various genes involved in diverse biological process. In addition, thiazolidinedione-induced activation of PPAR-γ alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase, and the GLUT4 glucose transporter.13 Thiazolidinediones reduce insulin resistance in adipose tissue, muscle, and the liver, however, PPAR-γ is predominantly expressed in adipose tissue. It is possible that the effect of thiazolidinediones on insulin resistance in muscle and liver is promoted via endocrine signaling from adipocytes. Potential signaling factors include free fatty acids (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumor necrosis factor-α (TNF-α), which is overexpressed in obesity and insulin resistance.
Although there are still many unknowns about the MOA of thiazolidinediones in T2DM, it is clear that these agents have the potential to benefit the full insulin resistance syndrome associated with the disease. Thiazolidinediones may also have potential benefits for the secondary complications of T2DM, such as cardiovascular diseases, despite the temporary lessening of side effects associated with rosiglitazone (Avandia, 21).
We have summarized three classes of insulin sensitizers thus far: sulfonylureas, biguanides, and PPARγ agonists. Three additional classes of antidiabetic drugs are in use today: GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP4 inhibitors. Both GLP-1 agonists and DPP4 inhibitors are incretin-based therapies.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone and GLP-1 analogs or agonists are incretin mimetics. Unlike older insulin secretagogues, GLP-1 analogs have a lower risk of causing hypoglycemia. The first GLP-1 agonist exenatide was approved by the FDA in 2005. Exenatide (Byetta) is a synthetic form of exendin-4, a protein expressed in the salivary glands of the Gila monster, and shares 53% homology with human GLP-1. Since then, many GLP-1 analogs have followed:14 Liraglutide (Victoza) was approved in 2010. Three additional GLP-1 agonists, taspoglutide, albiglutide, and lixisenatide, are now on the market as well.
Sodium-glucose–linked transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT1) and the proximal convoluted tubule (PCT) of the nephron (SGLT2). They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron (98% in PCT via SGLT2). In plasma glucose concentration that is too high (hyperglycemia), glucose is excreted in urine (glucosuria) because SGLT are saturated with the filtered monosaccharide. Inhibition of SGLT2 leads to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of T2DM. Two SGLT2 inhibitors are now on the market for the treatment of T2DM: One is Johnson & Johnson’s canagliflozin (Invokana, 23) and the other is BMS/AstraZeneca’s dapagliflozin (Farxiga, 24).
Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as alternatives to sulfonylureas. They show similar efficacy as sulfonylureas but with lower risk of hypoglycemia and reduction or no change in body weight, and if confirmed in humans, they may preserve islet function and thereby minimize the risk for secondary failure. Their limitation at present is the lack of long-term (>5 years) experience on durability and safety. Overall, therefore, the conclusion emerges that sulfonylureas are less desirable than DPP-4 inhibitors in management of hyperglycemia in T2DM.
The approval of sitagliptin (Januvia, 1) by the FDA in 2006 established DPP-4 inhibitors as an important new therapy for the treatment of T2DM. In addition to Januvia (1), four other DPP-4 inhibitors—vildagliptin (25), saxagliptin (26), linagliptin (27), and alogliptin (Nesina, 28)—are also marketed for the treatment of T2DM. Januvia (1), vildagliptin (25), and saxagliptin (26) all mimic the dipeptide structure of DPP-4 substrates; while Januvia (1) is β-amino acid based, vildagliptin (25) and saxagliptin (26) are nitrile-based. Linagliptin (27), and alogliptin (Nesina, 28) are non-peptidomimetic inhibitors.
This chapter will focus on DPP-4 inhibitors with special emphasis on Merck’s Januvia (1), the first, and so far the best, drug in this class. Januvia (1) and Janumet [Januvia (1) plus metformin (19)] had combined sales of $5.7 billion in 2012.
■ 2 Pharmacology
2.1 Mechanism of Action
Both GLP-1 and glucose-dependent insulinotropic polypeptide (DIP) are “incretin” hormones.15–19 They are so named because they powerfully stimulate insulin secretion and biosynthesis in response of enteric rather than the parental glucose. As shown in Fig. 6.3, GLP-1 is a peptic gut hormone with 31 amino acids. It is secreted from the intestinal L-cells. DDP-IV is an enzyme that cleaves GLP-1 at the penultimate position from the N-terminus and makes it inactive.
As shown in Fig. 6.4, DPP-4 inhibitors decrease glucose by blocking the DPP-4 enzyme, which inactivates GLP-1. As a consequence, they stimulate insulin secretion indirectly by enhancing the action of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Since both GLP-1 and GIP stimulate insulin secretion in a glucose-dependent manner, they pose little or no risk for hypoglycemia. In addition, GLP-1 stimulates insulin biosynthesis, inhibits glucagon secretion, slows gastric emptying, reduces appetite, and stimulates the regeneration and differentiation of islet β-cells.
