Dipeptidyl peptidase-4 inhibitors (‘gliptins’) for type 2 diabetes mellitus
Published in NPS RADAR
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Sitagliptin (Januvia) and vildagliptin (Galvus) are listed on the Pharmaceutical Benefits Scheme (PBS) for type 2 diabetes mellitus as dual oral therapy with either metformin or a sulfonylurea, when a combination of metformin and a sulfonylurea is contraindicated or not tolerated. Treatment is subsidised for patients whose HbA1c was > 7% before starting a dipeptidyl peptidase-4 (DPP-4) inhibitor (gliptin) or thiazolidinedione (glitazone) despite metformin or sulfonylurea monotherapy.
Sitagliptin with metformin fixed-dose combination tablets (Janumet) are listed on the PBS for patients whose HbA1c is > 7% before starting a gliptin or a glitazone despite metformin monotherapy, and when a combination of metformin and a sulfonylurea is contraindicated or not tolerated. Treatment is also subsidised for patients who have previously received and been stabilised on a PBS-subsidised regimen that includes sitagliptin and metformin.
The Pharmaceutical Benefits Advisory Committee (PBAC) recommended the listing of vildagliptin on a cost-minimisation basis — that is, similar efficacy and cost — compared with sitagliptin.1 Equi-effective doses compared with sitagliptin 100 mg daily were vildagliptin 50 mg twice daily (with metformin) and vildagliptin 50 mg once daily (with a sulfonylurea).1 Sitagliptin was listed on the PBS on a cost-minimisation basis compared with rosiglitazone (in August 2008).2 Sitagliptin with metformin combination tablets were listed on the PBS on a cost-minimisation basis compared with the individual components sitagliptin and metformin (in August 2009).3
The PBAC also revised the restriction for all gliptins and glitazones to permit patients to switch between drugs in these classes without the need for an HbA1c of > 7%. Although there is limited evidence to support switching from a gliptin to a glitazone and vice versa, the PBAC considered it unreasonable for patients to require a loss of diabetes control in order to qualify for an alternative treatment.
Dipeptidyl peptidase-4 (DPP-4) inhibitors (‘gliptins’) are a recently introduced class of oral drugs for type 2 diabetes. Sitagliptin and vildagliptin are currently available in Australia (saxagliptin is awaiting regulatory approval).
Gliptins block the DPP-4 enzyme metabolism of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are secreted by the intestine in response to food.4 This increases the levels of active incretins, prolonging their effect in stimulating insulin release and decreasing glucagon secretion.4
Sitagliptin or vildagliptin is a treatment option for dual oral therapy with either metformin, a sulfonylurea or a glitazone* when diet, exercise and the single drug alone inadequately controls blood glucose.5,6 Only the combination with metformin or a sulfonylurea is subsidised on the PBS (see PBS listing).
Insulin, a glitazone (rosiglitazone or pioglitazone) or exenatide are alternatives to a gliptin when initial drug monotherapy becomes inadequate for glycaemic control.7–9 The choice of drug should take into account the effect on diabetes-related clinical outcomes, safety profile and patient’s preference.
Gliptins are not TGA approved or PBS listed for use as monotherapy, triple oral therapy with metformin and a sulfonylurea, or in combination with other drugs for diabetes (including acarbose, exenatide, insulin and repaglinide).
* Vildagliptin is TGA approved for use in combination with pioglitazone, but not rosiglitazone.6
The effect of gliptins on morbidity and mortality is unknown
There are no long-term data on the effects of gliptins on diabetes-related complications and mortality. Clinical trials were generally short term (12–52 weeks) and measured HbA1c levels as a surrogate for clinical outcomes.10 Sitagliptin and vildagliptin have little to no effect on fasting lipids and their long-term impact on cardiovascular events is unknown at present.11–19
In contrast, there is evidence that metformin reduces the incidence of diabetes-related complications and mortality.20 Sulfonylureas and insulin also reduce the incidence of microvascular complications.21
Sitagliptin and vildagliptin have similar efficacy in improving glycaemic control
Consider sitagliptin or vildagliptin for people with type 2 diabetes who require dual oral therapy but for whom a combination of metformin and a sulfonylurea is contraindicated or not tolerated. Choice of drug is guided by specific precautions (see Safety issues) and the patient’s preference.
The efficacy and safety of sitagliptin and vildagliptin have not been directly compared in head-to-head trials. Indirect comparisons suggest that these drugs provide similar improvements in HbA1c levels when combined with metformin, a sulfonylurea (glimepiride) or a glitazone (pioglitazone). Patients in clinical trials had diabetes for 3–7 years on average, a mean baseline HbA1c of about 7–9% and a mean age of 50–60 years.10–19,22–26In people inadequately controlled with metformin alone, adding sitagliptin (100 mg once daily) or vildagliptin (50 mg twice daily) to metformin reduced mean HbA1c by 0.5–1.1% compared with adding placebo.12–14,17,19 Combining metformin with a gliptin provides comparable improvements in glycaemic control to those achieved by a combination of metformin with a sulfonylurea16,22,24 or a glitazone.11,19
In people inadequately controlled on a sulfonylurea alone, adding sitagliptin (100 mg once daily) or vildagliptin (50 mg once daily) to glimepiride reduced mean HbA1c by 0.6% compared with adding placebo.15,25 Trials found similar improvements in glycaemic control when pioglitazone was combined with a gliptin in people inadequately controlled on glitazone monotherapy (note that this is a TGA-approved but not PBS-listed indication).18,26
Gliptins may be preferred for some patients but their long-term benefit–harm profile is yet to be established
Sitagliptin or vildagliptin may be a useful alternative to a sulfonylurea, a glitazone or insulin for people who are overweight or at high risk of hypoglycaemia (see Safety issues). They are also an option for people in whom a glitazone may be unsuitable (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 for safety issues with the glitazones). However, when choosing between treatments consider that the long-term benefit–harm profile of the gliptins has not been established.
Gliptins have not been proven to reduce the risk of diabetes-related complications. They also have specific safety concerns that might make them an unsuitable choice for certain patients (see Safety issues).
Combining metformin with a gliptin provides the most favourable balance of benefits and harms compared with other possible gliptin combinations (see Safety issues).
Adverse effects with the gliptins are usually mild and transient and may include nasopharyngitis, headache, dizziness, arthralgia, nausea and constipation.5,6,10,27–31
Combining a gliptin with metformin resulted in a similar incidence of adverse effects to that for metformin alone.12–14,17,19 Patients receiving a sulfonylurea are more likely to experience weight gain or hypoglycaemia if a gliptin is added to therapy.15,25
The long-term safety profile of the gliptins is yet to be established. Some adverse effects have emerged post marketing, including hypersensitivity reactions and pancreatitis.5,6
Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.
Weight gain may occur in combination with a sulfonylurea
Gliptins have a neutral effect on body weight. They do not appear to alter the weight-reducing effects of metformin or the weight gain caused by a sulfonylurea.
There are no significant changes in body weight when sitagliptin or vildagliptin is added to metformin.11–14,17,19,22–24 In contrast, combining metformin with a sulfonylurea or a glitazone leads to weight gain (mean increase of 1.3–2.5 kg was reported in trials when compared with a combination of metformin with a gliptin).11,16,19,22–24
However, weight gain occurred when sitagliptin 100 mg once daily was added to glimepiride (mean increase 1.1 kg).15 A similar but dose-dependent effect was found in a trial with vildagliptin: weight gain occurred when glimepiride was combined with vildagliptin 50 mg twice daily (mean 1.3 kg), compared with weight loss when glimepiride was combined with vildagliptin 50 mg once daily (mean 0.1 kg) or placebo (mean 0.4 kg).25
Low risk of hypoglycaemia unless combined with a sulfonylurea
Trials have found no significant increase in the rate of hypoglycaemia when a gliptin is combined with metformin.12–14,16,17,19,22,24 However, the risk of hypoglycaemia is greater when a gliptin is combined with a sulfonylurea than for a sulfonylurea alone.
More patients reported hypoglycaemia when glimepiride 4–8 mg daily was combined with sitagliptin (12%) than with placebo (2%).15 The incidence of hypoglycaemia was also higher when glimepiride 4 mg daily was combined with vildagliptin 50 mg twice daily (3.6%) rather than placebo (0.6%), although the risk was lower when the 50 mg once-daily dose was used (1.2%).25
If starting a gliptin with a sulfonylurea, reducing the dose of either drug may be required to minimise the risk of hypoglycaemia (see Dosing issues).
Be vigilant for hypersensitivity reactions and infection
Inhibiting the DPP-4 enzyme prolongs the action of neuropeptides, including substance P, which may increase the risk of inflammatory and allergic reactions.10 DPP-4 is also found in T cells, raising theoretical concerns that this drug class may affect the immune system.10
Meta-analyses of randomised controlled trials have found a slightly increased risk of infection in patients treated with sitagliptin or vildagliptin.10,31,32 In particular, there was higher incidence of nasopharyngitis (6.4% vs 6.1%) and urinary tract infection (3.2% vs 2.4%) with a gliptin compared with placebo, respectively.32 Upper respiratory tract infection and influenza were also reported in trials.10,32 Infections characteristic of impaired T-cell function, such as herpes simplex virus, were not reported more frequently with sitagliptin or vildagliptin, compared with placebo.28,30
There have been postmarketing reports of anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis and exfoliative skin conditions, including Stevens–Johnson syndrome, with sitagliptin.5 These reactions occurred within 3 months of starting treatment, with some reports after the first dose.5 Angioedema and urticaria have also been reported with vildagliptin.6,28
Postmarketing cases of pancreatitis have been reported with gliptins
Cases of acute pancreatitis have been reported in people taking sitagliptin and sitagliptin with metformin products, although a causal association has not been confirmed.5,33,34 There are also recent postmarketing reports of pancreatitis with vildagliptin.6 Clinical trials did not detect an increased incidence of pancreatitis-related adverse events with sitagliptin (0.1%) or vildagliptin (0.1%) compared with non-exposed groups (0% and 0.2%, respectively).31,35 However, this does not rule out a rare adverse effect.
For more information, see the NPS RADAR in-brief item Postmarketing reports of acute pancreatitis with sitagliptin products (Janumet, Januvia).
Precautions in people with renal dysfunction
Sitagliptin is primarily cleared by the kidney: use a reduced dose in people with moderate or severe renal impairment (creatinine clearance < 50 mL/min) or end-stage renal disease (see Dosing issues).5 Sitagliptin was also associated with small increases in serum creatinine concentrations in trials that, although not clinically significant, were greater in people with moderate to severe renal impairment.30
Vildagliptin is not recommended in people with moderate or severe chronic kidney disease (eGFR < 60 mL/min/1.73 m2) or those with end-stage renal disease who are on haemodialysis: safety data and clinical experience of use are limited in these patients.6 The overall incidence of adverse events in trials with vildagliptin was slightly greater in people with moderate or severe renal impairment, although few people were studied.27
Limited data in people with hepatic impairment
There is no clinical experience with sitagliptin in people with severe hepatic impairment.5 The safety of vildagliptin in people with liver disease has not been established and use is not recommended in people with any degree of hepatic impairment, including those with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of > 2.5 times the upper limit of normal.6
Monitor liver function with vildagliptin
Vildagliptin increased the frequency of liver transaminase elevations in trials.27,28 Elevations were usually asymptomatic and not progressive or associated with cholestasis or jaundice.6 Hepatic dysfunction (including hepatitis) has been reported rarely with vildagliptin.6
Although the incidence of hepatic clinical adverse events with vildagliptin did not differ significantly from placebo, people with liver disease were not included in trials.11–13,22–27 Some studies also excluded people who had abnormal liver function tests (e.g. ALT or AST levels > 2–3 times the upper limit of normal and direct bilirubin > 1.3 times the upper limit of normal).11,22–26
Liver function tests are required before starting vildagliptin and should be monitored every 3 months during the first year of treatment and periodically thereafter.6 Stop vildagliptin if an ALT or AST elevation persists to > 3 times the upper limit of normal or if jaundice or other signs of hepatic dysfunction develop.6
Adverse effects in combination with a glitazone
The risk of hypoglycaemia is low when a gliptin is used as dual therapy with a glitazone.18,26 However, adding a gliptin to a glitazone does not offset the weight gain associated with glitazones.18,26 Oedema was also reported more frequently in trials that combined sitagliptin or vildagliptin with pioglitazone, compared with pioglitazone alone.6,18,26–28
Similar to the effect with a sulfonylurea, the weight gain with vildagliptin is dose dependent in combination with pioglitazone: in one trial the 50 mg twice-daily dose led to a mean weight gain of 1.3 kg over that for placebo, while this was only 0.1 kg for the 50 mg once-daily dose.26
Sitagliptin with metformin fixed-dose combination tablets should be taken twice daily with meals.34 Individualise the starting or switching dose according to the patient's current regimen of metformin, level of glycaemic control and tolerability, while maintaining a daily dose of sitagliptin of 100 mg/day.34
The recommended dose of vildagliptin is 50 mg once daily (in the morning) or twice daily.6 Use a dose of 50 mg once daily with a sulfonylurea to reduce the risk of hypoglycaemia.6 This lower dose is also less likely to cause weight gain in combination with pioglitazone (see Safety issues).
Sitagliptin and vildagliptin may be taken with or without food.5,6
Reduce the dose of sitagliptin in moderate to severe renal impairment
For patients with creatinine clearance of 30 to < 50 mL/min, the recommended dose is 50 mg once daily.5 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.5
Gliptins improve glycaemic control when added to existing therapy. The benefits and adverse effects of these medicines are not fully known.
Headache, nausea, a runny nose, sore throat or cough may occur while taking a gliptin. Seek urgent medical attention if there is a sudden onset of rash, hives, or swelling of the face, lips, mouth, tongue or throat during treatment.
Weight gain and hypoglycaemia may occur when a gliptin is used with a sulfonylurea. Oedema and weight gain may also occur in combination with a glitazone.
Emphasise that lifestyle changes including a healthy diet and exercise remain important for controlling blood glucose in conjunction with drug therapy.
NPS Medicine Update leaflets on sitagliptin and vildagliptin are 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 other medicines.
- Australian Government Department of Health and Ageing. March 2010 PBAC Outcomes — Positive Recommendations. 2010. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar10-positive (accessed 23 April 2010).
- Australian Government Department of Health and Ageing. March 2008 PBAC Outcomes — Positive Recommendations. 2008. http://www.health.gov.au/internet/main/publishing.nsf/Content/72BFC3A986C01665CA25742D0010F20B/$File/03-08%20Positive%20decisions%20website%20ver%202.pdf (accessed 28 April 2010).
- Australian Government Department of Health and Ageing. March 2009 PBAC Outcomes — Positive Recommendations. 2009. http://www.health.gov.au/internet/main/publishing.nsf/Content/EE62734C748A1C12CA25759E0014357F/$File/PBACOutcomesMarch2009-Positiverecommendations.pdf (accessed 28 April 2010).
- Prins JB. Incretin mimetics and enhancers: Mechanisms of action. Australian Prescriber 2008;31:102–4.
- Merck Sharp & Dohme (Aust.) Pty Ltd. Januvia product information. 21 April 2010.
- Novartis Pharmaceuticals Australia Pty Ltd. Galvus Product Information. 7 June 2010. http://www.novartis.com.au/PI_PDF/gal.pdf (accessed 22 June 2010).
- Colagiuri S, Dickinson S, Girgis S, et al. National Evidence Based Guideline for Blood Glucose Control in Type 2 Diabetes. Diabetes Australia and the NHMRC. Canberra, 2009. http://www.diabetesaustralia.com.au/PageFiles/763/BGC%20guideline%20FINAL%20-%20Sept%202009.pdf (accessed 30 April 2009).
- Diabetes Australia and The Royal Australian College of General Practitioners. Diabetes management in general practice. Guidelines for Type 2 Diabetes. 2009/10. 2009. http://www.diabetesaustralia.com.au/PageFiles/763/Diabetes%20Management%20in%20GP%2009.pdf (accessed 30 April 2010).
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- 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; CD006739. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006739/frame.html (accessed 10 May 2010).
- Bolli G, Dotta F, Rochotte E, et al. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes, Obesity & Metabolism 2008;10:82–90. [PubMed]
- Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007;30:890–5. [PubMed]
- Ahren B, Gomis R, Standl E, et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004;27:2874–80. [PubMed]
- 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]
- 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, Obesity & Metabolism 2007;9:733–45. [PubMed]
- 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, Obesity & Metabolism 2007;9:194–205. [PubMed]
- 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 Medical Research & Opinion 2008;24:537–50. [PubMed]
- 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. Clinical Therapeutics 2006;28:1556–68. [PubMed]
- Scott R, Loeys T, Davies MJ, et al. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes, Obesity & Metabolism 2008;10:959–69. [PubMed]
- UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65. [PubMed]
- 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). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–53. [PubMed]
- Ferrannini E, Fonseca V, Zinman B, et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity & Metabolism 2009;11:157–66. [PubMed]
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- Filozof C, Gautier J-F. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabetic Medicine 2010;27:318–26. [PubMed]
- Garber AJ, Foley JE, Banerji MA, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes, Obesity & Metabolism 2008;10:1047–56. [PubMed]
- Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes, Obesity & Metabolism 2007;9:166–74. [PubMed]
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Updated August 2010: This article replaces the review of sitagliptin (Published August 2008) and incorporates a review of vildagliptin. Minor corrections to references have been made to this article since print publication.
First published August 2010