Dipeptidyl Peptidase-IV Inhibitors: A New Drug in the Therapeutic Armamentarium for Treatment of Type 2 Diabetes Mellitus

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1 REVIEW ARTICLE JIACM 2009; 10(3): Dipeptidyl Peptidase-IV Inhibitors: A New Drug in the Therapeutic Armamentarium for Treatment of Type 2 Diabetes Mellitus Rajesh Rajput* Introduction The incidence of diabetes is escalating to epidemic proportions with the latest International Diabetic Federation (IDF) projections showing that 246 million adults are having diabetes worldwide and this figure is likely to increase to 380 million by India alone is home to 31.7 million diabetics, and this number is likely to increase to 79.4 million by Also, diabetes accounts for around 6% of total global mortality with 50% of the total deaths being attributed to cardiovascular diseases. As the global burden of diabetes is increasing, there is a need for novel treatments to slow the disease progression and achieve good metabolic control. Two decades ago we had sulphonylureas (SUR) as the only orally available drugs for control of hyperglycaemia, but the last decade has witnessed the availability of a newer class of oral anti-diabetic drugs. Despite the availability of a large number of drugs to control hyperglycaemia, only 37% of adults achieve the HbA1c level of < 7%, the current standard of care as per the American Diabetes Association (ADA) recommendations 3. This highlights the fact that the treating physicians should know in-depth about each newly available class of anti-diabetic drug so as to use them judiciously for treatment of diabetic patients. Dipeptidyl peptidase-iv (DPP-IV) is a new class of antidiabetic medication that augments the actions of the endogenous glucagon-like peptide-1 4. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion and slowing of gastric emptying, which result in improvements in glycaemic control in patients with type 2 diabetes. Incretin concept The incretin concept is based on the fact that enteral administration of a nutrient load evoked a 26% greater insulin secretory response than an isoglycemic challenge administered by the intravenous route 5. Subsequent research identified that normal glucose homoeostasis is controlled by multiple pancreatic and gut hormones including insulin, glucagon, amylin, glucagon-like peptide- 1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) 6. The two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, are secreted by enteroendocrine cells of the intestines within minutes of food ingestion and augment nutrient-stimulated insulin secretion in a glucose-dependent manner 5-6. People with type 2 diabetes have reduced circulating levels of GLP-1 but retain their ability to respond to this hormone. In response to intraluminal glucose, GLP-1 is released from the L cells of the gastrointestinal tract. GLP- 1 causes glucose-dependent increase in insulin secretion; thus, there is minimal risk of hypoglycaemia, making this molecule and its congeners likely candidates for use as antihyperglycaemic agents. GLP-1 also contributes to glucose homoeostasis through its effects on insulin biosynthesis, β-cell apoptosis, and its inhibition of glucagon release. GLP-1 is also associated with increased satiety, possibly because it reduces the rate of gastric emptying 5-6. Under normal physiological conditions, GLP-1 is rapidly degraded by the enzyme system DPP-IV and therefore is not itself viable as a pharmacological agent. Therapeutic agents that are agonists of the GLP-1 receptor, thereby mimicking the functions of GLP-1 ( incretin mimetics ), or that enhance the action of endogenous GLP-1 by inhibiting the DPP- IV are currently commercially available and in various stages of clinical development 6. The action of endogenous GLP-1 with that of DPP-IV inhibitors are compared in Table I. * Associate Professor, Department of Medicine, Postgraduate Institute of Medical Sciences, Rohtak , Haryana.

2 Table I: Comparison of GLP-1 and DPP-IV inhibitors. Characteristics of T2DM Mechanism of action of GLP-1 analogues DPP-IV inhibitors incretin hormones Impaired glucose-dependent Glucose-dependent Yes Yes stimulation of insulin stimulation of insulin Hyperglucagonaemia Suppression of Yes Yes glucagon secretion Loss of biphasic insulin release Restoration of biphasic response Yes Not clear at this time Slow insulin secretory Restoration of insulin secretion Yes Yes response to meals in response to meal Reduced pancreatic β-cell mass Increased pancreatic β-cell mass Yes Yes and synthesis of proinsulin Accelerated β-cell apoptosis Inhibition of β-cell apoptosis Yes Probable Normal, decelerated or Deceleration of Yes Less significant accelerated gastric emptying gastric emptying Hypercaloric energy intake Suppression of appetite/ Yes No induction of satiety Obesity Weight loss Yes No Pharmacological characteristics Route of administration Intravenous Subcutaneous Oral Frequency of administration Continuous OD/BD OD/BD Side-effects Nausea and vomiting None Dosage adjustment in presence None According to GFR of impaired renal function DPP-IV inhibitors Dipeptidyl peptidase-iv (DPP-IV) inhibitors represent a new class of oral antihyperglycaemic agents to treat patients with type 2 diabetes 4. DPP-IV inhibitors improve fasting and postprandial glycaemic control without hypoglycaemia or weight gain. DPP-IV inhibitors enhance incretin action by blocking their degradation, and hence inactivation. Inhibition of DPP-IV extends the half-life and increases the concentrations of circulating intact (active) GLP-1. In patients with type 2 diabetes, DPP-IV inhibition leads to higher levels of active incretins fasting and postmeal, in turn leading to higher insulin release, lower glucagon levels, and improved fasting and post-meal glucose concentrations. Patients with type 2 diabetes have reduced post-meal GLP-1 concentrations, with normal GLP-1 action; thus, DPP-IV inhibition addresses one defect that may contribute to hyperglycaemia in this disease 7-8. Several orally active DPP-IV inhibitors have now been developed to treat type 2 diabetes, including sitagliptin, vildagliptin, saxagliptin, alogliptine, and denagliptine. Sitagliptin was approved in the United States in October 2006 for the treatment of patients with type 2 diabetes; and vildagliptin, a second agent in this class, is likely to join it on the US market soon 9. Sitagliptin: DPP-IV inhibitor Dipeptidyl peptidase encompasses a large family of enzymes. Full-scale inhibition of an enzyme system could cause myriad deleterious effects, and, because of this, the selectivity of an inhibitor is of prime importance. Sitagliptin exhibits a > 2,600-fold higher affnity for DPP- IV than for structurally related DPP-VIII and DPP-IX enzymes. Sitagliptin has not been associated with toxicity as a result of inhibition of these related enzyme systems 10. It is available as 100 mg, 50 mg, and 25 mg tablets. It is also available as a combination product with Journal, Indian Academy of Clinical Medicine Vol. 10, No. 3 July-September,

3 metformin in doses of 50 mg sitagliptin/500 mg metformin, and 50 mg sitagliptin/1,000 mg metformin. The usual recommended dose of sitagliptin is 100 mg per day 9. The sitagliptin-metformin combination should be taken twice daily with meals and titrated slowly to minimise potential gastrointestinal side-effects associated with metformin. Sitagliptin is relatively rapidly absorbed with median Tmax of 1-4 h. The absorption of sitagliptin is not influenced by food intake and has oral bioavailability of 87%. Following ingestion of a single oral 100 mg dose in healthy volunteers, sitagliptin exhibits an apparent terminal t 1/2 of 12.4 h. Sitagliptin exhibits low and reversible binding to plasma proteins (approximately 38%) and is widely distributed in tissues with a distribution volume of 198 l The majority of sitagliptin (79%) is excreted unchanged in urine with minority being metabolised in the liver 13. Because of its predominant renal clearance, increased exposure (i.e., AUC) is seen in patients with decreased renal function and it needs dosage adjustment in the presence of renal insufficiency. In a study of sitagliptin pharmacokinetics in patients with renal insufficiency, an approximately 2- fold increase in exposure was observed in patients with moderate renal insufûciency (CrCl ml/min), and an approximately 4-fold increase was observed in patients with severe renal insufûciency (CrCl 30 ml/min), or in patients on dialysis 14. On the basis of this, to obtain similar exposure as would occur in a patient with normal renal function, half the dose, i.e., 50 mg/day would be needed in patients with GFR < 50 ml/min, and a quarter the dose, i.e., 25 mg/day would be needed in patients with GFR < 30 ml/min or on dialysis. Because of limited hepatic metabolism of sitagliptin by cytochrome P450 enzymes 3A4 and 2C8, it is unlikely to be involved in clinically meaningful drug interactions with cytochrome P450 isoenzymes or p-glycoprotein transport system 15. In phase I drug-drug interaction studies, sitagliptin did not meaningfully alter the pharmacokinetics of other oral antihyperglycemic agents, including metformin, rosiglitazone, or sulphonylureas; and metformin did not meaningfully affect the pharmacokinetics of sitagliptin 15. The drug can be used safely in moderate hepatic impairment (Child-Pugh score 7-9) 16. Patients treated with sitagliptin monotherapy or combination sitagliptinmetformin, or sitagliptin-pioglitazone therapy had an incidence of adverse events and rates of discontinuation of therapy similar to those of control subjects 17. Three side-effects that have been reported to occur with more frequency in sitagliptin group than in control subjects include nasopharyngitis (5.2% vs. 3.3%), upper respiratory tract infection (6.3% vs. 3.4%), and headache (5.1% vs. 3.9%) when used in combination with pioglitazone The incidence of hypoglycaemia in subjects receiving sitagliptin is similar to that in the control subjects (1.2 vs. 0.9%) and it is not enhanced by the addition of metformin or pioglitazone 18. It is classified as category B agent during pregnancy and should only be used during pregnancy if deemed necessary 18. Caution is also advised in women who are nursing, as presently it is not clear whether sitagliptin is secreted in human breast milk or not; and if excreted, then its effects on nursing babies are also unknown 18. Safety and efficacy in type 2 diabetic patients < 18 years of age have not been studied, but nothing thus far suggests that problems would result from using the agent in this age group 18. Since DPP-IV inhibitor augments the action of endogenous GLP-1 which acts by stimulating pancreatic insulin secretion, it is contraindicated in patients with type 1 diabetes and is not intended for use in the treatment of diabetic ketoacidosis. Efficacy studies in T2DM Clinical trials have demonstrated that sitagliptin is safe and efficacious for the management of hyperglycaemia in T2DM. In a phase III trial involving 741 of T2DM aged years with a mean baseline HbA1c of 8.0%, sitagliptin administered in 100 mg and 200 mg per day for 24 weeks reduced haemoglobin A 1C (HbA 1C ) levels by 0.79 and 0.94% respectively and causes improvement in both fasting and postprandial glucose levels and demonstrated improvement in markers of β-cell function. These differences were statistically significant when compared to placebo (P < 0.001). Patients with HbA 1C levels > 9.0% showed greater reductions in HbA 1C 19. Sitagliptin also has been evaluated in combination with metformin and pioglitazone. In one trial, 701 patients with a mean baseline HbA 1C of 8% (range: 7-10%) who were previously treated with metformin were randomised to receive either 100 mg sitagliptin or placebo daily for 24 weeks in addition to ongoing metformin therapy 20. Those treated with sitagliptin plus metformin realised additional 0.65% 130 Journal, Indian Academy of Clinical Medicine Vol. 10, No. 3 July-September, 2009

4 reduction in HbA 1C at 24 weeks with 47% of the patients acheiving HbA 1C levels < 7%, and 17% reached an HbA 1C of < 6.5%. Only 18% of patients in the placebo group reached an HbA 1C level < 7%, and only 5% reached an HbA 1C < 6.5%. Similar results have been published from other clinical trials evaluating the effcacy of combination metformin and sitagliptin therapy 21. In a trial evaluating efficacy of sitagliptin in combination with pioglitazone, 353 patients previously treated with pioglitazone with mean baseline HbA 1C values of 8% (range: 7-10%) received either 100 mg sitagliptin or placebo daily in addition to 30 or 45 mg/day pioglitazone for 24 weeks 22. A mean reduction in HbA 1C of 0.7% was reported in patients treated with combination therapy, compared to no signifcant change in HbA 1C in the placebo group. In another randomised, double-blind, placebo-controlled, parallel-group study involving 441 patients with mean HbA 1c, 8.3%, patients received sitagliptin 100 mg once daily or placebo in addition to glimepiride 4 mg once daily alone or in combination with metformin 1,500 mg/ d. The trial lasted for 24 weeks and examined the effect of adding sitagliptin to treatment with glimepiride alone or in combination with metformin. After 24 weeks, it was observed that the addition of sitagliptin decreased HbA 1c by 0.74% (P <.001) and FPG by 20.1 mg/dl (P <.001). But in this trial, the addition of sitagliptin resulted in a greater incidence of hypoglycaemia (P <.001) and significant weight gain (P <.001) versus placebo and than what is observed in trials done with combination therapy with metformin and glitazone 23. To summarise, current evidence suggests that sitagliptin is an efficacious antihyperglycaemic agent when used as monotherapy or in combination with metformin, glimepiride, or pioglitazone, for the treatment of type 2 diabetes. In addition to favourable changes in A 1C, clinical trials of sitagliptin have shown improvement in fasting and postprandial glucose levels. Other DPP inhibitors-iv on horizon Vildagliptin has been studied for treatment of hyperglycaemia in type 2 diabetes as monotherapy and in combination with metformin, pioglitazone, or insulin. It has been shown to improve glycaemic control in type 2 diabetes both as monotherapy and as combination therapy. Patients treated with 100 mg/day vildagliptin for 24 weeks showed mean reductions in A 1C of 1.1% from a mean baseline A 1C of 8.7% in 1,301 subjects (P < 0.01 vs baseline values) 24. The most common adverse events reported with vildagliptin were mild and included nasopharyngitis, headache, and dizziness. Vildagliptin has been associated with very few episodes of hypoglycaemia when used as monotherapy or in combination with other antihyperglycaemic medications. No signifcant laboratory abnormalities have been observed during or resulting from trials involving vildagliptin 25. One case of signifcant peripheral oedema was reported and attributed to the study drug in clinical trials of vildagliptin. The FDA has asked the manufacturer to provide additional safety data for review before approval. Saxagliptin is the third DPP-IV inhibitor undergoing trial for management of T2DM. In the recently concluded annual meeting of European Association for the Study of Diabetes held in Rome, Italy, results of an international trial involving 1,306 patients with type 2 diabetes, with baseline haemoglobin A 1C ranging from 8% to 12% revealed that approximately 60% of patients in the saxagliptin plus metformin arms achieved target haemoglobin A 1C levels compared with 32.2% of patients on saxagliptin plus placebo and 41.1% of patients on metformin plus placebo. The incidence of adverse effects was no higher when saxagliptin was added to metformin therapy than was seen with metformin alone. Available trial data for alogliptin are currently limited to abstract form. A total of 55 patients who were either newly diagnosed or who had not received diabetic therapy for the previous 3 months were randomised to receive alogliptin 25 mg (n = 15), 100 mg (n = 14), or 400 mg (n = 15) or placebo (n = 11) once daily for 14 days. On Day 14, mean 4-hour plasma glucose levels were decreased significantly from baseline in the alogliptin group versus the placebo group after each of 3 meals (P <.05). The study investigators observed that alogliptin was well tolerated, with no serious adverse events reported. The incidence of hypoglycaemia was similar among groups 26. To conclude, DPP-IV inhibitors enhance endogenous incretin levels and improve 24-h glycaemic control and β-cell function in patients with T2DM. Since the efficacy Journal, Indian Academy of Clinical Medicine Vol. 10, No. 3 July-September,

5 of these agents is entirely dependent on secretion of endogenous incretins, they may be best employed early in type 2 diabetes before substantial impairments in incretin secretion become apparent. Out of various DPP- IV inhibitors discussed, sitagliptin is now available in India. It may be administered with or without food (typically at a once-daily dose of 100 mg) either as monotherapy or in combination with metformin, glimepiride, metformin plus glimepiride, or a thiazolidinedione agent and has a low propensity for drug interactions. It is generally welltolerated with a safety profile similar to placebo, and is not associated with an increased risk of adverse events, particularly hypoglycaemia and weight gain, which can limit the clinical utility of other antihyperglycaemic agents. DPP-IV inhibitors show promise as a new therapeutic class for the treatment of patients with type 2 diabetes. References 1. 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6 24. Nathwani A. The use of vildagliptin for treatment of patients with type 2 diabetes mellitus. Diabetes 2006; 55 (Suppl. 1): Abstract 474-P. 25. Henness S, Keam SJ. Vildagliptin. Drugs 2006; 66: Christopher R, Covington P, Davenport M et al. Pharmacokinetics, pharmacodynamics, and tolerability of multiple doses of alogliptin benzoate (SYR-322), a dipeptidyl peptidase-iv inhibitor, patients with type 2 diabetes [abstract]. Presented at: American Diabetes Association 67th Annual Scientific Sessions; June 22-26, 2007; Chicago, IL. Abstract 0499-P. Diamicron XR 60 Journal, Indian Academy of Clinical Medicine Vol. 10, No. 3 July-September,