Dipeptidyl peptidase-4 inhibitors (‘gliptins’) for type 2 diabetes mellitus

• Sitagliptin and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors ('gliptins'). They provide similar improvements in glycaemic control for people with type 2 diabetes mellitus.
• The effect of gliptins on diabetes-related complications and mortality is unknown.
• Gliptins are listed on the PBS as dual oral therapy with metformin or a sulfonylurea, when a combination of metformin and a sulfonylurea is contraindicated or not tolerated.
• Insulin, a glitazone or exenatide are alternatives to a gliptin.
• Gliptins are not approved for use as monotherapy, triple oral therapy or in combination with other drugs for diabetes (acarbose, exenatide, insulin or repaglinide).
• Gliptins are not associated with weight gain or an increased risk of hypoglycaemia. However, when choosing between treatment options consider that:
• • insulin and sulfonylureas have been shown to reduce the risk of diabetes-related
    complications
  • weight gain or hypoglycaemia can still occur when a gliptin is used with a sulfonylurea
  • the long-term benefit–harm profile of gliptins is yet to be established.
• Adverse effects with gliptins include nasopharyngitis, headache, nausea, hypersensitivity and skin reactions.
• Postmarketing reports of acute pancreatitis have occurred with gliptins. A causal link has not been established.
• Reduce the dose of sitagliptin for people with moderate to severe renal impairment (creatinine clearance < 50 mL/min). Because of limited data, use of vildagliptin is not recommended in moderate to severe chronic kidney disease or end-stage renal disease.
• Vildagliptin is not recommended in people with any degree of hepatic impairment. Use sitagliptin cautiously in severe hepatic impairment, as there is no clinical experience.

Authority required (streamlined)

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 HbA_1c 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 HbA_1c 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 HbA_1c 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).

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 HbA_1c 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

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 HbA_1c 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 HbA_1c of about 7–9% and a mean age of 50–60 years.^{10–19,22–26}

Gliptins may be preferred for some patients but their long-term benefit–harm profile is yet to be established

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}

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

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

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

Limited data in people with hepatic impairment

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

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

The recommended dose of sitagliptin is 100 mg once daily.⁵ When combining sitagliptin with a sulfonylurea, the dose of the sulfonylurea may need to be decreased to reduce the risk of hypoglycaemia.⁵

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

Due to limited data, vildagliptin is not recommended for patients with moderate or severe kidney disease (eGFR < 60 mL/min/1.73 m²) or end-stage renal disease on haemodialysis (see Safety issues).⁶

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.

Medicine Update