Sitagliptin (Januvia) for type 2 diabetes mellitus Sitagliptin (Januvia) for type 2 diabetes mellitus

PBS listing | Reason for PBS listing | Place in therapy | Safety issues | Dosing issues | Information for patients | References

(SI-ta-GLIP-tin)

PBS listing

Authority required

Dual oral therapy with either metformin or a sulfonylurea in patients with type 2 diabetes whose HbA_1c is > 7% despite treatment with metformin or a sulfonylurea, and when a combination of metformin and a sulfonylurea is contraindicated or not tolerated.

Sitagliptin is not listed on the Pharmaceutical Benefits Scheme for use in combination with metformin and a sulfonylurea (triple oral therapy), as monotherapy or in combination with a thiazolidinedione (glitazone).

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee recommended the listing of sitagliptin as dual oral therapy with metformin or a sulfonylurea on a cost-minimisation basis — that is, similar efficacy and cost — compared with rosiglitazone.¹ The equi-effective doses for this comparison were sitagliptin 100 mg daily and rosiglitazone 8 mg daily.¹

Place in therapy

Sitagliptin is the first member of a new class of oral drugs for type 2 diabetes called dipeptidyl peptidase 4 (DPP-4) inhibitors. Sitagliptin is a treatment option for dual oral therapy with either metformin or a sulfonylurea, when the combination of metformin and a sulfonylurea is contraindicated or not tolerated.

Insulin or a glitazone (rosiglitazone or pioglitazone) are alternatives to sitagliptin. The choice of drug should take into account the effect on diabetes-related clinical outcomes, the long-term safety profile and the patient's preference.

There is insufficient evidence to support the use of sitagliptin as monotherapy or triple oral therapy with metformin and a sulfonylurea. Sitagliptin may be used with a glitazone for some patients²; however, this combination has limited efficacy and safety data and is not PBS listed.

The pharmacological action of sitagliptin differs from that of other antidiabetic drugs

Incretin hormones (or 'incretins'), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine to control blood glucose levels after a meal.² Incretins are rapidly metabolised by the DPP-4 enzyme.² The activity and levels of incretins are reduced in people with type 2 diabetes.³

Sitagliptin is an 'incretin enhancer' that inhibits DPP-4 and thereby increases the levels of active incretins, prolonging their effect in stimulating insulin release and decreasing glucagon secretion.² This differs from the action of 'incretin mimetics' — such as the injectable drug exenatide — which are GLP-1 receptor agonists.³

DPP-4 inhibitors may also prolong the action of neuropeptides, including substance P, thereby increasing the risk of inflammatory and allergic reactions.^4–7 DPP-4 is found in T cells, raising theoretical concerns that this drug class may affect the immune system (see Safety issues).^5,6

The effect of sitagliptin on morbidity and mortality is unknown

There are no data on the effects of sitagliptin on diabetes-related complications and mortality. Clinical trials have been short-term (12–52 weeks) and measured HbA_1c levels as a surrogate for clinical outcomes.⁴ Sitagliptin has little to no effect on lipids or on reducing blood pressure, and its impact on cardiovascular events is not known.^2,8–15

In contrast there is evidence that metformin improves glycaemic control and reduces the incidence of diabetes-related complications and mortality.¹⁶ Sulfonylureas also improve glycaemic control and reduce the incidence of microvascular complications.¹⁷

In light of their proven clinical benefits, metformin is combined with a sulfonylurea (glibenclamide, gliclazide, glimepiride or glipizide) when metformin alone does not adequately control blood glucose (HbA_1c > 7%).¹⁸

Sitagliptin is an option for people who require combination therapy but are unable to use either metformin or a sulfonylurea

Sitagliptin improves glycaemic control in combination with either metformin or a sulfonylurea (dual oral therapy) in patients who are inadequately controlled on metformin or sulfonylurea monotherapy. Consider sitagliptin when the combination of metformin and a sulfonylurea is contraindicated or not tolerated.

The effect of sitagliptin 100 mg daily has been compared with that of placebo, a sulfonylurea or a glitazone in people with type 2 diabetes who are inadequately controlled on metformin or sulfonylurea monotherapy.^9–12,14 Patients in the trials had a mean baseline HbA_1c of 7.5–9.2%.^9–12,14

Adding sitagliptin to metformin for 18–24 weeks reduced mean HbA_1c by 0.5–1.0% compared with adding placebo.^9,12,14 One trial that added sitagliptin to glimepiride found a mean reduction in HbA_1c of 0.6% compared with adding placebo.¹⁰ More patients achieved a target HbA_1c < 7% when metformin was combined with sitagliptin (22–55%) than with placebo (3–38%).^9,12,14

Combining metformin with sitagliptin, glipizide or rosiglitazone provides similar improvements in glycaemic control.^11,14 The mean reduction in HbA_1c did not differ significantly between sitagliptin (0.51%) and glipizide (0.56%) in all patients treated in a 52-week trial.¹¹ Similar reductions in mean HbA_1c were found in another trial with sitagliptin 100 mg daily (0.73%) and rosiglitazone 8 mg daily (0.79%) after 18 weeks.¹⁴

Greater reductions in HbA_1c occurred in patients with higher baseline levels.^8,10–12,14 However, there are limited data for sitagliptin in patients with severe hyperglycaemia (HbA_1c > 11%), as they were excluded from most trials.* The efficacy of sitagliptin in the later stages of diabetes is as yet unknown. Most patients in trials had diabetes for 3–5 years, and generally for no longer than 10 years.^4,12,14

*An open-label cohort from one study included patients with HbA_1c > 11%.¹⁹

Insulin or a glitazone are other options

Starting insulin or dual oral therapy with a glitazone (rosiglitazone or pioglitazone) are alternatives to using sitagliptin when the combination of metformin and a sulfonylurea is contraindicated or not tolerated.

Insulin has been shown to reduce the risk of diabetes-related complications.¹⁷ Oral treatments such as sitagliptin or a glitazone may be preferred by patients who cannot use metformin and a sulfonylurea but are reluctant to start insulin. However, the effect of these oral drugs on diabetes-related clinical outcomes is not known, and neither is their long-term safety profile. Insulin should not be delayed when oral drug therapy no longer controls blood glucose (for more information, see NPS News 56: Managing hyperglycaemia in type 2 diabetes). The efficacy and safety of sitagliptin have not been compared with those of insulin.

Sitagliptin is not associated with changes in body weight or hypoglycaemia (see Safety issues). It may be a useful alternative to insulin or a glitazone for patients who are overweight. However, sitagliptin does not offset the weight gain or risk of hypoglycaemia caused by other drugs (e.g. sulfonylureas).

Sitagliptin may be preferred to the glitazones for some patients in light of recent safety concerns over the use of these drugs, including an increased risk of cardiovascular events, peripheral fractures and diabetic macular oedema (see the NPS RADAR reviews of Rosiglitazone (Avandia) and rosiglitazone with metformin (Avandamet) for type 2 diabetes mellitus and Pioglitazone (Actos) for type 2 diabetes mellitus). However, when choosing between treatment options consider that the long-term benefit–harm profile of sitagliptin is yet to be established (see Safety issues).

There are limited data on using sitagliptin with drugs other than metformin or a sulfonylurea

Do not use sitagliptin in combination with exenatide, insulin, acarbose or repaglinide. There are no data on the efficacy and safety of using sitagliptin with these drugs.^2,4 For patients who require the addition of insulin to improve glycaemic control, stop sitagliptin and maintain other oral drug therapy (for more information, see NPS News 56: Managing hyperglycaemia in type 2 diabetes).

There is some evidence for using sitagliptin with a glitazone. In one 24-week trial, adding sitagliptin 100 mg daily to pioglitazone reduced mean HbA_1c by 0.7% compared with adding placebo.¹³ The benefit of using this combination may be offset by the potential adverse effects associated with the glitazones (see Insulin or a glitazone are other options).

Do not use sitagliptin as monotherapy or triple oral therapy

Sitagliptin should not be used for type 2 diabetes inadequately controlled by diet and exercise alone. In the trials of initial drug therapy, sitagliptin reduced mean HbA_1c by 0.8% compared with placebo.⁴ However, there is no evidence comparing its effect on glycaemic control or diabetes-related outcomes with that of metformin or sulfonylurea monotherapy.^4,15,19

There is limited evidence for using sitagliptin as triple oral therapy with metformin and a sulfonylurea, and this is not approved by the Therapeutic Goods Administration. Consider initiating insulin or triple oral therapy with a glitazone when the combination of metformin and a sulfonylurea does not improve glycaemic control.

In a 24-week trial of patients who were inadequately controlled with metformin and glimepiride, adding sitagliptin 100 mg daily reduced mean HbA_1c by 0.9% compared with adding placebo.¹⁰ However, the triple combination was associated with a greater risk of hypoglycaemia than dual oral therapy with sitagliptin and glimepiride.¹⁰

Safety issues

Sitagliptin is associated with an increased risk of nasopharyngitis and upper respiratory tract infection, and it may cause headache and nausea.^{2,5,6,9,13,14} These adverse effects were usually reported by fewer than 10% of patients in trials.^2,5,9,13,14

The overall incidence of clinical adverse events in trials (30–60% of patients) was similar between sitagliptin and placebo when combined with metformin or pioglitazone.^9,12–14 More patients experienced adverse events with sitagliptin (56%) than with placebo (41%) when used in combination with glimepiride.¹⁰ This was mainly because of an increased risk of hypoglycaemia.¹⁰

The long-term benefit–harm profile of sitagliptin is not established. Postmarketing reports of serious hypersensitivity reactions have occurred.²

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Be vigilant for potential adverse effects

Long-term safety data for sitagliptin are currently not available. In clinical trials sitagliptin did not increase the risk of serious adverse effects compared with placebo⁴; however, most patients were only followed for less than a year.

Sitagliptin may cause adverse effects in various tissues including the skin, gastrointestinal tract, skeletal muscle and nervous system.^5,6 Those reported more frequently by patients in trials taking sitagliptin (compared with placebo) included abdominal pain, cough, arthralgia, myalgia, osteoarthritis, pain in the extremities or back, fatigue and dizziness.^{5,6,8,9,11,13}

Be vigilant for hypersensitivity reactions and infections during treatment with sitagliptin. Inhibition of DPP-4 in T cells is a potential safety concern, although the clinical and pre-clinical data for sitagliptin do not suggest a major effect on T cell immune responses.^5,6 The safety of using sitagliptin in people with underlying immune or allergic conditions is not known.

A meta-analysis of randomised controlled trials found a slightly higher incidence of all-cause infections among patients treated with sitagliptin, compared with placebo (relative risk 1.29, 95% confidence interval 1.09 to 1.52).⁴ The type of infections mostly reported were nasopharyngitis, pharyngitis, upper respiratory tract infection and urinary tract infection.^{2,4–6,8,9,11,13,14,20} Infections characteristic of impaired T cell function, such as herpes simplex virus, were not reported more frequently with sitagliptin, compared with placebo.⁶

There have been postmarketing reports of anaphylaxis, angioedema, rash, urticaria and exfoliative skin conditions, including Stevens–Johnson syndrome, with sitagliptin.² These reactions occurred within 3 months of starting treatment, with some reports after the first dose.² One patient receiving sitagliptin withdrew from a trial because of urticaria and angioedema.¹³ While a causal link has not been established, sitagliptin must be stopped if a hypersensitivity reaction is suspected, and other drug therapy initiated.²

Sitagliptin was associated with very small increases in serum creatinine concentrations in placebo-controlled trials.⁶ The changes were not clinically significant, but their magnitude was greater in patients with moderate to severe renal impairment.⁶ The long-term effects of sitagliptin on the kidney are unknown. Be aware that rapidly deteriorating renal function increases the risk of lactic acidosis with use of metformin, and renal impairment increases the risk of hypoglycaemia with use of sulfonylureas¹⁸ — either of which may be used with sitagliptin.

Sitagliptin has a neutral effect on weight

Sitagliptin does not appear to alter body weight. Combining sitagliptin with metformin, a sulfonylurea or a glitazone is unlikely to cause additional weight loss or weight gain. However, it is not known if sitagliptin treatment remains weight-neutral in the long term.

The mean change in body weight in trials of sitagliptin with metformin (–0.4 to –0.7 kg) was similar to that of placebo with metformin.^9,12,14 Sitagliptin did not affect weight loss with metformin, whereas glipizide or rosiglitazone led to weight gain with metformin.^11,14

Sitagliptin does not attenuate the weight gain associated with a sulfonylurea or glitazone. Patients who took sitagliptin or placebo with pioglitazone gained a mean weight of 1.8 kg and 1.5 kg, respectively.¹³ Sitagliptin combined with glimepiride increased mean weight in one trial by 1.2 kg, compared with placebo and glimepiride.¹⁰

Low hypoglycaemic risk unless combined with a sulfonylurea

Sitagliptin lowers blood glucose levels only if they are elevated, so it is not expected to cause hypoglycaemia.² Sitagliptin did not increase the rate of hypoglycaemia compared with placebo when used as monotherapy or in combination with metformin or pioglitazone.^{8,9,12–15,19} Severe episodes of hypoglycaemia were not reported with sitagliptin in trials.⁴

Adding sitagliptin to metformin poses a lower risk of hypoglycaemia than adding a sulfonylurea.^5,11 The proportion of patients in a trial who reported at least 1 episode of hypoglycaemia was 4.9% with sitagliptin and 32% with glipizide, when combined with metformin over 52 weeks.¹¹

By contrast, combining sitagliptin with a sulfonylurea appears to increase the risk of hypoglycaemia compared with a sulfonylurea alone (see Dosing issues). More patients reported hypoglycaemia in one trial with sitagliptin (12%) than with placebo (2%) when added to glimepiride, either alone or with metformin.¹⁰

The risk of hypoglycaemia with sitagliptin in combination with insulin or exenatide has not been studied. There are also no data on the use of sitagliptin with sulfonylureas other than glimepiride. Hypoglycaemia is a greater risk with glibenclamide or glimepiride, compared with glipizide or gliclazide, especially in the elderly and those with renal or hepatic impairment.¹⁸

Dosing issues

The recommended dose of sitagliptin is 100 mg once daily, taken with or without food.² When combining sitagliptin with a sulfonylurea, the dose of the sulfonylurea may need to be decreased to reduce the risk of hypoglycaemia.²

Reduce dose in moderate to severe renal impairment

Sitagliptin is primarily cleared by the kidney, and dosage reduction is required in patients with moderate to severe renal impairment.² For patients with creatinine clearance of 30 to < 50 mL/min, the recommended dose of sitagliptin is 50 mg once daily.² For patients with creatinine clearance < 30 mL/min or end-stage renal failure requiring haemodialysis or peritoneal dialysis, the recommended dose is 25 mg once daily.²

Information for patients

Inform patients that sitagliptin is a new drug for type 2 diabetes that improves glycaemic control when added to existing therapy. However, the long-term benefits and adverse effects of sitagliptin are unknown.

Weight gain and hypoglycaemia are not associated with sitagliptin in combination with metformin. However, advise patients using sitagliptin with a sulfonylurea that these adverse effects may still occur.

Alert patients to the potential for adverse effects with sitagliptin, particularly:

• infections of the nasopharyngeal and upper respiratory tract
• skin reactions
• swelling of the face, lips, mouth, tongue or throat.

Reinforce to patients that lifestyle changes including a healthy diet and exercise remain important for controlling blood glucose in conjunction with drug therapy.

Discuss the Januvia consumer medicine information (CMI) leaflet with the patient.

Medicine Update

An NPS Medicine Update leaflet on sitagliptin is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with those of other medicines.

References

1. Australian Government Department of Health and Ageing. March 2008 PBAC Outcomes — Positive Recommendations. http://www.health.gov.au/internet/main/publishing.nsf/Content/72BFC3A986C01665CA25742D0010F20B/$File/03-08%20Positive%20decisions%20website%20ver%202.pdf (accessed 5 May 2008).
2. Merck Sharp & Dohme (Aust.) Pty Ltd. Januvia Product Information. 21 December 2007.
3. Deacon CF. Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2007;9(Suppl.1):23–31. [PubMed]
4. Richter B, Bandeira-Echtler E, Bergerhoff K, et al. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2008; Art. No: CD006739. DOI: 10.1002/14651858.CD006739.pub2. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006739/pdf_fs.html (accessed 22 April 2008).
5. European Medicines Agency (EMEA). European Public Assessment Report (Januvia): Scientific Discussion 2007. http://www.emea.europa.eu/humandocs/PDFs/EPAR/januvia/H-722-en6.pdf (accessed 5 May 2008).
6. Food and Drug Administration (FDA). Center for Drug Evaluation and Research: Medical Review of Januvia (sitagliptin phosphate) 2006; Application Number: 21-995: 1–214. http://www.fda.gov/cder/foi/nda/2006/021995s000_MedR.pdf (accessed 28 May 2008).
7. Grouzmann E, Monod M, Landis BN, et al. Adverse effects of incretin therapy for type 2 diabetes [comment]. JAMA 2007;298:1759–60. [PubMed]
8. Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29:2632–7. [PubMed]
9. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638–43. [PubMed]
10. Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:733–45. [PubMed]
11. Nauck MA, Meininger G, Sheng D, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194–205. [PubMed]
12. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Current Med Res Opin 2008;24:537–50. [PubMed]
13. Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006;28:1556–68. [PubMed]
14. Scott R, Loeys T, Davies M, et al. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2008; DOI:10.1111/j.1463-1326.2007.00839.x. [PubMed]
15. Scott R, Wu M, Sanchez M, et al. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract 2007;61:171–80. [PubMed]
16. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65. [PubMed]
17. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [PubMed]
18. Rossi S, ed. eAMH [online]. Adelaide: Australian Medicines Handbook (AMH), 2008.
19. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979–87. [PubMed]
20. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007;298:194–206. [PubMed]