T2DM is a global epidemic with

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: a new option for the management of type 2 diabetes Marc Evans MRCP, MD, Consultant Diabetologist, Llandough Hospital, Cardiff Incretin-based therapies for the treatment of diabetes mellitus (T2DM) present a new approach to disease management. Over recent years, several new drugs have entered the marketplace, and NICE have recently issued guidance on how best to incorporate these new drugs into treatment regimens. In this article, Marc Evans reviews saxagliptin, a dipeptidyl peptidase- IV (DPP-IV) inhibitor, and considers its potential clinical use. T2DM is a global epidemic with an estimated prevalence of 6% (246 million people) worldwide in 2007, which is forecast to rise to 7.3% (380 million people) by 2025. 1 Progressive impairment of beta-cell function and increased insulin demand as tissue becomes insulin resistant are core pathophysiological defects in the development and progression of hyperglycaemia in T2DM. Other important factors are also known to further exacerbate this pathology, including excess alpha cell glucagon secretion, abnormal gastric emptying during hyperglycaemia, obesity and increased food intake. 2 The incretin pathway, in particular glucagon-like peptide (GLP-1) and, to a lesser extent, glucosedependent insulinotropic polypeptide (GIP), plays an important role in modulating islet cell function, gastric emptying and satiety. DPP-IV Islet of Langerhans cells. DPP-IV inhibitors like saxagliptin enhance glucose-stimulated insulin release (beta cells) and decrease glucagon release (alpha cells). is the enzyme responsible for the initial rapid degradation of both GLP-1 and GIP. 3 These peptides are incretin hormones that primarily enhance glucose-stimulated insulin secretion, upregulate all steps in insulin biosynthesis, and enhance glucose-mediated suppression in alpha cell glucagon release. 3 In T2DM, incretin actions are impaired, 3,4 but exogenously infused GLP-1 can normalise both fasting and postprandial glucose concentrations (FPG and PPG respectively). 4 When given by continuous subcutaneous infusion over six weeks, GLP-1 improved beta-cell function, resulting in lowered glucose profiles and reduced glycated haemoglobin (HbA 1c ) levels, and was associated with weight loss and minimal risk of hypoglycaemia. 5 However, because of its rapid degradation, native GLP-1 cannot be used therapeutically; consequently there has been much interest in the role of agents that utilise the potential therapeutic benefits of the incretin pathway. 6 Two classes of therapy have subsequently been developed. The first class are the GLP-1 receptor agonists (exenatide, liraglutide, taspoglutide), which are structurally similar to human GLP-1, exerting similar agonist effects at the GLP-1 receptor. These have sufficient structural differences to human GLP-1 to render them resistant to degradation by DPP-IV. The second class of incretin-based therapies to have been developed are a group of agents that selectively and reversibly inhibit the activity of DPP-IV. GLP-1 receptor agonists are injectable therapies that result in Skyline Imaging Ltd FUTURE PRESCRIBER VOL 10(3) 13

DPP-IV inhibitors GLP-1 and GIP enhanced Oral Increased levels of GLP-1 in physiological range Dependent upon endogenous GLP-1/GIP Comparable efficacy to thiazolidinediones and sulphonylureas Well tolerated Weight neutral around a 10-fold increase in plasma GLP-1 levels, while DPP-IV inhibitors are oral therapies that result in around a four-fold increase in plasma GLP-1 levels. 7 Due to the glucose-dependent effects of GLP-1, both GLP-1 agonists and DPP-IV inhibitors are associated with a low risk of hypoglycaemia, while due to the differing plasma GLP-1 levels, GLP-1 agonists are associated with modest weight reduction ( 2.2 to 3.1kg), while DPP-IV inhibitors are associated with weight neutrality ( 0.2 to +0.8kg). 7 The different plasma GLP-1 levels may also largely account for the different tolerability profiles of the incretin therapies, with gastrointestinal sideeffects, in particular nausea, being the most common adverse event associated with GLP-1 agonists, occurring at a frequency of up to 44%. However, in clinical trials, <5% of patients withdrew due to nausea. 7 By contrast, DPP-IV inhibitors are associated with minimal gastrointestinal side-effects. 7 (Table 1 summarises the differing properties of GLP-1 agonists and DPP-IV inhibitors.) A number of DPP-IV inhibitors have entered clinical development. Of these, sitagliptin and vildagliptin have been approved and are now available for the treatment of T2DM. Alogliptin is awaiting GLP-1 agonists Pure GLP-1 effect Injectable Supraphysiological levels of GLP-1 Not limited by endogenous secretion Nausea Weight loss Table 1. Comparison of the therapeutic profiles of DPP-IV inhibitors and GLP-1 agonists regulatory approval, and others (eg BI1356) are in phase 3 clinical trials. is currently undergoing regulatory review by the Food and Drug Administration in the USA and the European Medicines Agency in Europe. The most recent NICE guidance 8 advocates DPP-IV inhibitors as an alternative second-line addon to metformin in place of a sulphonylurea (SU) in people in whom there is a significant concern regarding hypoglycaemia, when control of blood glucose remains inadequate despite maximal tolerated metformin monotherapy. PHARMACOLOGY is a selective, durable but reversible inhibitor of DPP-IV. 9 At 37 C, it has an inhibition constant (Ki) of 1.3±0.3nM for DPP-IV inhibition, which is 10-fold more potent than either vildagliptin (13±3nM) or sitagliptin (18±2nM). 9 demonstrates greater specificity for DPP-IV than for either the DPP-VIII or DPP-IX enzymes (400- and 75-fold, respectively). 9 The active metabolite of saxagliptin (BMS-510849) is two-fold less potent than the parent drug. Both saxagliptin and its metabolite are highly selective (>4000-fold) for the inhibition of DPP-IV compared with a range of other proteases (selectivity of sitagliptin and vildagliptin for DPP-IV is >2600 and 32 250-fold, respectively, compared with DPP-VIII/IX). shows a high sensitivity for DPP-IV (the half maximal inhibitory concentration [IC50] = 3.5, 18, and 26nM for vildagliptin, sitagliptin and saxagliptin, respectively). 10 Conversely, saxagliptin demonstrates a low affinity for DPP-VIII and DPP-IX (IC50 for DPP-VIII = IX and >50nM for vildagliptin and sitagliptin, respectively; IC50 for DPP-IX = >50nM for sitagliptin). 10 Age and gender do not appear to have a significant impact on the pharmacokinetic properties of saxagliptin, 11 while a less than two-fold difference was observed for the pharmacokinetics of saxagliptin, or its active metabolite, in patients with any category of hepatic impairment compared with healthy individuals, suggesting that no dose adjustment is required for saxagliptin in people with hepatic impairment. 11 Since saxagliptin is cleared by both metabolism and renal excretion, a recent study was conducted to evaluate the effects of renal impairment and haemodialysis on the pharamacokinetics of saxagliptin. 12 In this study the degree of renal impairment did not affect the C max of saxagliptin or its major metabolite. In mild renal impairment subjects, the overall mean systemic exposure (AUC ) values of saxagliptin and its major metabolite were 1.2- and 1.7-fold higher, respectively, than mean AUC values in subjects with normal renal function. The saxagliptin and metabolite AUC values in moderate renal impairment subjects were 1.4- and 2.9-fold higher, respectively, than subjects with normal renal function. The corresponding values in severe renal impairment subjects were 2.1- and 14 FUTURE PRESCRIBER VOL 10(3)

4.5-fold higher, respectively. A four-hour haemodialysis session removed 23% of the saxagliptin dose. Based on these data, saxagliptin may have potential clinical utility in people with renal impairment, and larger studies are ongoing to fully evaluate the effects of saxagliptin, its efficacy and its safety in people with varying degrees of renal impairment. EFFECTS ON GLYCAEMIC CONTROL There have been several phase 3 trials assessing the effectiveness of saxagliptin-based therapy in groups of patients with T2DM. Treatmentnaïve patients with T2DM (HbA 1c 7 10%; n=401) were treated with saxagliptin once daily (2.5, 5 and 10mg) for 24 weeks, with an additional open-label cohort (HbA 1c, >10% and 12%; n=66) being treated with saxagliptin 10mg once daily for 24 weeks. 13 Figure 1 demonstrates the reductions in HbA 1c achieved with saxagliptin over a dose range 2.5 40mg. Significant (p<0.0075) reductions in FPG compared with placebo were observed in all saxagliptin treatment arms (15 23mg/dL), with reductions observed as early as week two. also reduced PPG AUC and resulted in significantly greater numbers of patients achieving an HbA 1c target <7%. 13 The efficacy and safety of saxagliptin has also been studied in patients with T2DM inadequately controlled by treatment with metformin, a thiazolidinedione (TZD) or an SU alone. 14 16 At week 24, once-daily saxagliptin (2.5 10mg) as an add-on treatment to stable metformin provided significant (p<0.0001) reductions in HbA 1c (0.71 0.83%) compared with placebo. 14 In the TZD study, 565 patients with inadequate glycaemic control (HbA 1c 7 10.5%) were randomised to receive add-on therapy with saxagliptin (2.5 or 5mg) or placebo once daily, in addition to either pioglitazone (30 or 45mg) or rosiglitazone (4 or 8mg) for 24 weeks. 16 At week 24, saxagliptin (2.5 and 5mg) add-on treatment provided significant adjusted-mean reductions in HbA 1c from baseline ( 0.66% and 0.94%, respectively) compared with placebo ( 0.30%; both p<0.001). In the SU study, 768 patients with T2DM inadequately controlled (HbA 1c 7.5 10%) with glyburide 7.5mg alone were randomised to receive saxagliptin 2.5 or 5mg, or glyburide 2.5mg in addition to open-label glyburide for 24 weeks. 15 Blinded uptitration of glyburide to a maximum of 15mg daily was permitted in the glyburide treatment arm only. At week 24, saxagliptin 2.5 and 5mg add-on treatment provided significant (p<0.0001) adjusted-mean reductions in HbA 1c ( 0.54% and 0.64%, respectively), compared with an increase for uptitrated glyburide (0.08%). In all of these studies, saxagliptin resulted Adjusted mean change in haemoglobin A 1c (% ±SEM) 0.0-0.2-0.4-0.6-0.8-1.0-0.27-0.72-0.90 in more patients achieving an HbA 1c target of <7%, along with significant reductions in both FPG and PPG levels. Initial combination therapy with saxagliptin plus metformin has also been investigated in drugnaïve patients with inadequate blood glucose control (HbA 1c 8 12%; n=1306). 17 Patients were treated with saxagliptin (5 or 10mg) plus metformin 500mg or placebo, in addition to either saxagliptin 10mg alone or metformin 500mg alone, for 24 weeks. (5 and 10mg) initial combination therapy with metformin provided significant (p<0.001) reductions in HbA 1c ( 2.53% and 2.49%, respectively), FPG ( 59.8 and 62.2mg/dL, respectively), PPG at 120 minutes during an oral glucose tolerance test (OGTT) ( 137.9 and 137.3mg/dL, respectively), and improved beta-cell function (homeostasis model [HOMA beta]; 33% and 38%, respectively), compared with saxagliptin 10mg alone (HbA 1c, 1.69%; FPG, 30.9mg/dL; Dose placebo 2.5mg 5mg 10mg 20mg 40mg -0.81-0.74-0.80 Figure 1. Significant reductions in HbA 1c are achieved with saxagliptin across a dose range from 2.5 to 40mg daily 13 FUTURE PRESCRIBER VOL 10(3) 15

PPG, 106.3mg/dL; HOMA beta, 18.2%) or metformin 500mg alone (HbA 1c 1.99%; FPG, 47.3mg/dL; PPG, 96.8mg/dL; HOMA beta, 22.6%). SAFETY AND TOLERABILITY as monotherapy and in combination with other antidiabetic drugs has demonstrated a good safety and tolerability profile in multiple randomised trials in patients with T2DM. 9,11 In doseranging studies, there were no apparent dose-related adverse events, and the frequency of adverse events was comparable between saxagliptin and placebo. 9 The most common adverse events reported have been headache, upper respiratory tract infection, urinary tract infection, and nasopharyngitis, seen during the 12-week study with doses up to 40mg and during the 24-week study with doses up to 10mg. 18 Small, reversible, dose-dependent reductions in absolute lymphocyte count were observed that were more apparent at doses 20mg, which did, however, remain within normal limits. 18 There was no effect on white blood cell or neutrophil count, and no evidence of altered immune function based on adverse event reporting. 9,11,18 has been well tolerated when used in combination treatment. There was no difference in the occurrence of adverse events when used in combination with metformin compared with metformin alone, and saxagliptin was well tolerated when added to an SU, with the adverse event profile being similar to that of uptitrated glyburide alone. The combination of saxagliptin with a TZD was also well tolerated, with no clinically meaningful differences in adverse events between the treatment groups. 14 16 is metabolised to its active metabolite by cytochrome P450 CYP3A4/5, but does not inhibit or induce CYP3A4. In numerous studies, saxagliptin has not been shown to influence the pharmacokinetic profile of a variety of drugs including statins, ketoconizole, digoxin and diltiazem. 9 Drugs that inhibit CYP3A4/5, such as ketoconizole and diltiazem, when co-administered with saxagliptin, have been shown to increase the AUC and C max for saxagliptin. 9 Therefore, dosage adjustment of saxagliptin may be required when it is co-administered with such agents. HYPOGLYCAEMIA AND WEIGHT GAIN In all clinical studies, either as monotherapy or in combination, saxagliptin therapy appears to have minimal effects on body weight. 9,11 In monotherapy, hypoglycaemic symptoms were experienced by 6.3% of saxagliptin-exposed subjects in the low-dose (2.5 40mg) cohort (versus 1.5% on placebo) and by 13.6% of subjects in the high-dose (100mg) cohort (versus 0% with placebo). 13 However, at doses of up to 10mg, it has not been associated with any increased incidence of hypoglycaemia relative to placebo. When added to an SU, 15 hypoglycaemic events were reported by 14% of patients receiving combination therapy with saxagliptin (2.5 or 5mg), which was similar to that reported by the glyburide arm (10%), with the occurrence of confirmed hypoglycaemia (fingerstick glucose 50mg/dL) being similar in all three arms (2.4%, 0.8% and 0.7% for saxagliptin 2.5 and 5mg, and glyburide uptitration, respectively). A low incidence of hypoglycaemia was reported by those patients taking saxagliptin together with a TZD (4.1% and 2.7% for the 2.5 and 5mg doses), compared with 3.8% for TZD monotherapy, and only a single case of confirmed hypoglycaemia (fingerstick glucose 50mg/dL) occurred (2.5mg saxagliptin arm). THERAPEUTIC APPLICATIONS Traditional treatment strategies for patients with T2DM have generally used a stepwise, failure-based approach to medication selection. Simply stated, this approach features the sequential addition of therapies only when glycaemic control deteriorates significantly. Early aggressive intervention is now known to exert a legacy effect, even years after patients have opted out of intensive therapy protocols, fostering a sustained reduction in the risk of both micro- and macrovascular complications. 19 Consequently, the most recent NICE guidance on the management of blood glucose in people with T2DM advocates a stepwise approach to glucose-lowering therapy, aiming to produce optimal individualised HbA 1c targets. 8 Metformin, due to its long-term safety, efficacy and low cost, is recommended as the initial drug of choice for the majority of people once HbA 1c levels are 6.5%. Hypoglycaemia is the major consideration in the management of blood glucose. Severe hypoglycaemia is associated with increased mortality rates, 8 while the fear of hypoglycaemia is a recognised barrier to the achievement of glucose control and has a markedly negative impact on quality of life. 20 Hypoglycaemia avoidance is thus a key feature in the management of blood glucose and is of particular relevance when treatment is intensified to achieve lower HbA 1c targets. The most recent NICE 16 FUTURE PRESCRIBER VOL 10(3)

guidance 8 advocates DPP-IV inhibitors (because of their low risk of hypoglycaemia) as an alternative second-line add-on to metformin in place of a sulphonylurea in people in whom there is a significant concern regarding hypoglycaemia, when control of blood glucose remains inadequate (HbA 1c 6.5%) despite maximal tolerated metformin monotherapy. Such treatment should only be continued if the person has had a beneficial metabolic response (a reduction of at least 0.5% in HbA 1c in six months). DPP-IV inhibitors, due to their general weight neutrality, are considered to be preferable to a TZD in people in whom further weight gain would cause or exacerbate problems associated with high body weight. All available data suggest that saxagliptin can be used as monotherapy or in combination with other antidiabetic agents, while once-daily administration might also increase patient compliance. The lack of an increased risk of hypoglycaemia and the neutral effect on weight thus makes saxagliptin a viable therapy option according to the current guidelines. CONCLUSIONS is a novel and highly selective DPP-IV inhibitor that has recently completed phase 3 clinical trials. It is an oral antidiabetic agent that is administered once daily and produces significant reductions in HbA 1c, fasting and postprandial glucose levels when used as monotherapy or in combination with metformin, SUs or TZDs. Treatment with saxagliptin is well tolerated, does not result in a significant increase in hypoglycaemia and appears generally weight neutral. appears to be a useful additional therapeutic option, particularly in patients where hypoglycaemia and further weight gain may have detrimental effects on quality of life. REFERENCES 1. International Diabetes Federation. The Diabetes Atlas, 3rd edition. Brussels: International Diabetes Federation, 2006. 2. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005;365:1333 46. 3. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409 39. 4. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 2009;297:127 36. 5. Vilsboll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357 66. 6. Deacon CF, Holst JJ. Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes. Int J Biochem 2006;38:831 44. 7. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med 2009;122(Suppl):S37 50. 8. National Institute of Health and Clinical Excellence. Clinical guideline 87: Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. May 2009. 9. Tahrani AA, Piya MK, Barnett AH. : a new DPP-IV inhibitor for the treatment of type 2 diabetes. Adv Ther 2009;26:249 62. 10. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract 2006;60:1454 70. 11. Deacon CF, Holst JJ. : a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Adv Ther 2009; 26:488 99. 12. Boulton D, Tang A, Patel C, et al. Pharmacokinetics of the dipeptidyl peptidase- 4 inhibitor saxagliptin in subjects with renal impairment. Endocrine Abstracts 2009;20:P35. 13. Rosenstock J, Aguilar-Salinas CA, Klein E, et al. Once-daily saxagliptin monotherapy improves glycemic control in drug-naïve patients with type 2 diabetes. Presented at: 68th Scientific Session of the American Diabetes Association; June 6 19, 2008; San Francisco, USA. Abstract 517-P. 14. Defronzo RA, Hissa M, Blauwet MB, et al. added to metformin improves glycemic control in patients with type 2 diabetes. Presented at: 67th Scientific Session of the American Diabetes Association; June 22 26, 2007; Chicago, USA. Abstract 0285-OR. 15. Ravichandran S, Chacra AR, Tan GH, et al. added to a sulfonylurea is safe and more efficacious than up-titrating a sulfonylurea in patients with type 2 diabetes. Presented at: 44th annual meeting of the European Society for the Study of Diabetes; September 7 11, 2008; Rome, Italy. Abstract. 16. Allen E, Hollander P, Li L, et al. added to a thiazolidinedione improves glycemic control in patients with inadequately controlled type 2 diabetes. Presented at: 44th annual meeting of the European Society for the Study of Diabetes; September 7 11, 2008; Rome, Italy. Abstract. 17. Chen R, Pfützner A, Jadzinsky M, et al. Initial combination therapy with saxagliptin and metformin improves glycemic control compared with either monotherapy alone in drugnaïve patients with type 2 diabetes. Presented at: 44th annual meeting of the European Society for the Study of Diabetes; September 7 11, 2008; Rome, Italy. Abstract. 18. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008;10:376 86. 19. Hollman RR, Paul SK, Bethel A, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577 89. 20. Amiel SA, Dixon T, Mann R, et al. Hypoglycaemia in type 2 diabetes. Diabet Med 2008;25:245 54. FUTURE PRESCRIBER VOL 10(3) 17