A fixed-dose combination medicine for treating two different conditions
Since this article was published Juvicor has been removed from the PBS and marketing of Juvicor has been voluntarily discontinued by the sponsor in Australia. The individual components sitagliptin and simvastatin will remain on the PBS and will continue to be commercially available in Australia
- There are no clinical data comparing fixed-dose combination sitagliptin and simvastatin with each taken separately
In patients with type 2 diabetes and hyperlipidaemia there is no evidence of additional clinical benefit using the fixed-dose combination formulation over concomitant use of sitagliptin and simvastatin taken separately.
- Fixed-dose combination products have benefits but may cause confusion for some
Benefits include reducing pill burden and out-of-pocket cost to the patient. Advise patients starting Juvicor to return their previous supply of sitagliptin and simvastatin to their pharmacy.
- Statins treat hyperlipidaemia and reduce overall cardiovascular risk
Statin monotherapy is effective as first-line therapy for reducing the risk of cardiovascular events in people with type 2 diabetes and hyperlipidaemia.
- Sitagliptin improves glycaemic control in type 2 diabetes
There are no data for an effect of sitagliptin on macrovascular disease or diabetes-related complications or mortality.
What is known about this drug
Sitagliptin improves haemoglobin A1c (HbA1c) levels when combined with metformin, a sulfonylurea or a glitazone.1–5
Sitagliptin acts via a glucose-dependent mechanism and therefore causes minimal hypoglycaemia.6–8 Trials have found no significant increase in the rate of hypoglycaemia in dual therapy with metformin.2–5
As with other 'gliptins', the risk of sulfonylurea-induced hypoglycaemia is increased when sitagliptin is combined with a sulfonylurea.9
Sitagliptin does not contribute to weight loss or gain.6
Simvastatin reduces plasma levels of total cholesterol, low-density lipoprotein–cholesterol (LDL-c) and very-low-density lipoprotein–cholesterol concentrations.10
In addition, simvastatin increases the plasma level of high-density lipoprotein–cholesterol (HDL-c) and reduces that of plasma triglycerides.10
Areas of uncertainty
There are no data to support a beneficial effect of sitagliptin on microvascular or macrovascular complications or mortality in type 2 diabetes.
Although sitagliptin has been in use in Australia for 4 years and in the US for 6 years, its long-term safety profile is yet to be established.
Cases of acute pancreatitis have been reported in people taking sitagliptin. This has not been observed in clinical trials;13,14 however, a recent population-based case–control study15 supports the U.S. Food and Drug Administration warning that there may be an association between sitagliptin treatment and acute pancreatitis. 8,16
The potential for adverse immune effects, which may be reflected in higher infection rates, has been raised in one meta-analysis;17 however, in a more recent meta-analysis this effect was not observed.13
What does NPS say?
Lowering cholesterol24 and blood pressure25,26 is more effective than tight glycaemic control26–31 to reduce overall cardiovascular risk24–26,28 in the short term (3–5 years) in people with type 2 diabetes. (See Diagram showing modelled effects of cholesterol, blood pressure and HbA1c lowering on major cardiovascular events (NPS News August 2012: Type 2 diabetes).
People at greatest absolute cardiovascular risk derive the most benefit from lipid-lowering treatment.32
The efficacy of statins in reducing cardiovascular risk depends on the extent of LDL-c lowering;33 all statins have a similar effect in reducing the relative risk of major coronary events in primary prevention.12,34–37
Weigh up the benefits and risks of adding sitagliptin as antihyperglycaemic therapy. Consider sitagliptin or an alternative add-on therapy only when a combination of metformin and a sulfonylurea is contraindicated or not tolerated.
There is no evidence of additional clinical benefit using the FDC formulation over concomitant use of sitagliptin and simvastatin taken separately.
Be alert to unintended double dosing at the time of switching and discuss this with the patient.
If an FDC product is appropriate for a patient requiring sitagliptin and simvastatin, consider all available combinations before deciding which is most suitable, see Table 1 in Dosing issues.
Authority required (Streamlined)
For use in patients with type 2 diabetes who satisfy the criteria for prescribing dipeptidyl peptidase-4 (DPP-4) inhibitors and who meet the criteria set out in the General Statement for Lipid-Lowering Drugs38 on the PBS website.
May be prescribed by nurse practitioners
Authorised nurse practitioners may prescribe this medicine. See the PBS website for more information on nurse practitioner PBS prescribing.
What is it?
Juvicor is the first fixed-dose combination (FDC) medicine approved by the Therapeutic Goods Administration (TGA) for treating conditions affecting two different body systems, in this case cardiovascular and endocrine.
Sitagliptin is a DPP-4 inhibitor. DPP-4 inhibitors ('gliptins') are a recently introduced class of oral drugs for type 2 diabetes. They act to block metabolism by the DPP-4 enzyme of incretin hormones, including glucagon-like peptide and glucose-dependent insulinotropic polypeptide, which are secreted by the intestine in response to food. 6 This increases the levels of active incretins, prolonging their effect in stimulating insulin release and decreasing glucagon secretion.6
Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyses an early and rate-limiting step in the biosynthesis of cholesterol. This results in reduced levels of total plasma cholesterol, LDL-c and very-low-density lipoprotein–cholesterol. In addition, simvastatin increases HDL-c and reduces plasma triglyceride levels. 10
Who is it for?
Juvicor is for patients with type 2 diabetes who satisfy the criteria for prescription of dipeptidyl peptidase-4 (DPP-4) inhibitors and who meet the criteria set out in the PBS General Statement for Lipid-Lowering Drugs.
While Juvicor has the potential to reduce a patient's pill burden and overall medicine costs, there is no clinical reason to switch patients to Juvicor if they are responding well to other type 2 diabetes and lipid-modifying medicines.21
Choose type 2 diabetes and lipid-modifying therapy according to the clinical needs of the individual
Do not choose therapy solely based on the possibility of improved adherence, convenience or cost advantages of the FDC preparation. While FDC medicines are associated with a significant improvement in adherence,18–20 there is no evidence that improved adherence alone translates to improved health outcomes.21–23 Use of once-daily formulations and combination products does not by itself ensure improved adherence. A large number of factors can contribute to non-adherence, such as the lack of a support network, a language barrier limiting communication or a fear of adverse effects. 21–23
Where does it fit?
Primary prevention of cardiovascular disease in people with type 2 diabetes
Having type 2 diabetes more than doubles the risk of mortality due to cardiovascular causes.39,40 In the short term (3–5 years) tight glycaemic control has a limited effect on cardiovascular outcomes26–31 compared with lowering lipids24 or blood pressure.25,26 (For more information see NPS News August 2012: Type 2 diabetes.)
Lifestyle changes such as smoking cessation, consuming a diet rich in vegetables and fruit and doing at least 30 minutes of physical activity on most, preferably every, day of the week is recommended in all people to reduce cardiovascular risk.32
People at greatest absolute cardiovascular risk derive the most benefit from lipid-lowering treatment.32
Dual therapy for glycaemic control
Glycaemic control with monotherapy tends to deteriorate with time, as diabetes is a progressive disease.41,42 Metformin (or, when this is contraindicated, a sulfonylurea) is the drug of first choice for people with type 2 diabetes who have inadequate glycaemic control after 3 months of making lifestyle changes.43,44 Adding a sulfonylurea to metformin is the preferred dual therapy for glycaemic control when monotherapy is no longer effective.45–47
Sitagliptin with metformin or a sulfonylurea is an option for people who require dual therapy but who are intolerant of, or have a contraindication to the combination of, metformin and a sulfonylurea.44,48
How does it compare?
There are no other PBS-listed FDC products currently available for treating type 2 diabetes and hyperlipidaemia.
Juvicor compared with sitagliptin and simvastatin taken concomitantly
There is no evidence of additional clinical benefit using the FDC formulation over concomitant use of sitagliptin and simvastatin taken separately.
Bioequivalence studies established that the Juvicor 100 mg/10 mg, 100 mg/20 mg or 100 mg/40 mg taken once daily are bioequivalent with the corresponding strengths of sitagliptin and simvastatin taken concomitantly once daily.38
Reducing microvascular complications and safety profile
There are no long-term data on the effects of gliptins on microvascular complications and mortality in people with type 2 diabetes.3–5,7,9,49 In comparison there is evidence that metformin, sulfonylureas and insulin reduce the incidence of microvascular complications41,42 and, although they each have a range of possible adverse effects, their long-term safety profile is better understood than that of sitagliptin.50 A systematic assessment of cardiovascular adverse events reported in 19 clinical trials of sitagliptin,13 25 clinical trials of vildagliptin51 and eight clinical trials of saxagliptin52 found no increased rate of cardiovascular events in people treated for type 2 diabetes, although these were post-hoc analyses of adverse effects in trials with different comparators, and patients were only followed for up to 104 weeks.
Reducing cardiovascular events
The efficacy of statins in reducing cardiovascular risk depends on the extent of LDL-c lowering.33,53 More than 80% of the LDL-c-lowering effect of any statin is achieved with 50% of its maximum dose.44 All statins have a similar effect in reducing the relative risk of major coronary events in primary prevention.12,34–37
Trials designed to assess clinical outcomes are needed to confirm the impact of sitagliptin either alone or in combination with statin therapy on cardiovascular events. Currently, no clinical studies have established conclusive evidence of macrovascular risk reduction with sitagliptin or any other antihyperglycaemic medicine.29–31
Simvastatin has a high risk of interactions with grapefruit juice.54,55 Regular consumption of grapefruit juice (200 mL/day) can lead to significant increases in simvastatin blood concentrations,56 with larger juice volumes increasing the magnitude of this effect.57 This may increase the risk of statin-induced myopathy/rhabdomyolysis.56,57
See Table 2 under 'Dosing issues' for more CYP3A4 inhibitor drug interactions.
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis, in people taking sitagliptin.8 A recent population-based case–control study found an association between acute pancreatitis and sitagliptin within 30 days of use (adjusted odds ratio [OR] 2.24, 95% confidence interval [CI], 1.36 to 3.68, p = 0.01) and withrecent use (after 30 days, before 2 years) (OR 2.01, 95% CI 1.37 to 3.18, p = 0.01).15 Adjustments were made for confounding causes of pancreatitis such as diabetes, but residual confounding from unreported tobacco or alcohol use may have impacted on the results.
In clinical trials there was no increased incidence of pancreatitis-related adverse events with sitagliptin compared with non-exposed groups,14 and use of sitagliptin was not associated with increased risk for pancreatitis beyond that incurred from diabetes itself.16,58 For more information, see the NPS RADAR In-Brief item Postmarketing reports of acute pancreatitis with sitagliptin products (Janumet, Januvia).
Be vigilant for hypersensitivity reactions and infection
There have been postmarketing reports of serious but rare allergic and hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens–Johnson syndrome, in people taking sitagliptin.8,59 These reactions occurred within 3 months of starting treatment, with some reports after the first dose.8
The association of sitagliptin with higher infection rates is unclear. One meta-analysis found risk of all-cause infection was significantly elevated in patients treated with sitagliptin (relative risk 1.29, 95% CI 1.09 to 1.52, p = 0.0032).17 Another meta-analysis found no notable differences (between sitagliptin or placebo or an active comparator) in incidence rates for any infection-related adverse events and for specific adverse events of infection.13
Interstitial lung disease
Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long-term therapy. Symptoms include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever).38
Myopathy and rhabdomyolysis
There have been postmarketing reports of arthralgia and myalgia in people taking sitagliptin, but a causal association has not been established.8
Risk of myopathy due to the simvastatin component of Juvicor is increased in people with multiple diseases as well as people aged > 80 years, especially if they are frail. Start Juvicor at a low dosage in these patients, as high doses of statins are associated with an increased risk of myopathy.44 Advise patients to report promptly any symptoms of muscle pain. Discontinue Juvicor if myopathy is diagnosed or suspected.60
Do not use Juvicor in people with moderate or severe renal insufficiency, as the sitagliptin component is not available in the lower strengths required to accommodate patients with creatinine clearance < 50 mL/min.8,38 Prescribe with caution in older people, as renal function declines with age.44
Assess renal function before starting Juvicor and periodically thereafter using the Cockcroft–Gault formula to estimate creatinine clearance.8,38 There is little evidence that estimated glomerular filtration rate is suitable for adjusting drug doses in people with renal impairment. 44
Liver enzyme abnormalities
Check liver enzyme levels before starting therapy and as clinically indicated thereafter, as persistent elevations in hepatic transaminase levels can occur with simvastatin.60 People with active liver disease or unexplained persistent elevations of serum transaminase levels should not take Juvicor.38
Sitagliptin is weight neutral.6 There are no significant changes in body weight when sitagliptin is added to metformin.3–5 Weight gain can occur when sitagliptin is added to a sulfonylurea9 or a glitazone.49 For example, in one study sitagliptin 100 mg once daily in combination with sulfonylurea (glimepiride) resulted in mean weight increase of 1.1 kg.9
If starting sitagliptin with a sulfonylurea, consider lower doses of the sulfonylurea to minimise the risk of hypoglycaemia. Sitagliptin carries a low risk of hypoglycaemia unless it is combined with a sulfonylurea, which increases the risk of sulfonylurea-induced hypoglycaemia.9 More patients reported hypoglycaemia when glimepiride 4–8 mg daily was combined with sitagliptin (12%) than with placebo (2%), although none of the reported hypoglycaemia episodes was severe or required medical attention, and 73% of the episodes had precipitating factors.9
Different treatment targets in older people
Balance HbA1c targets against the increased risk of severe hypoglycaemia in older people.61 Older patients with diabetes are a heterogeneous group with varying physical capabilities, cognitive functioning, comorbidities and life expectancies, therefore treatment must be individualised.62
Pregnancy and breastfeeding
Report suspected adverse reactions to the 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.
Reason for PBS listing
Juvicor was recommended for listing by the Pharmaceutical Benefits Advisory Committee (PBAC) as dual oral therapy with metformin or a sulfonylurea on a cost-minimisation basis compared with sitagliptin and simvastatin taken concomitantly. The PBAC accepted that the FDC is non-inferior to concomitant sitagliptin and simvastatin based on the bioequivalence data.
Consider all available combinations before deciding which is most suitable (Table 1).
Sitagliptin and simvastatin
Juvicor 100/10, 100/20, 100/40
Sitagliptin and metformin
Janumet 50/1000, 50/500, 50/850
Simvastatin and ezetimibe
Vytorin 10/10, 10/20, 10/40, 10/80
Dose adjustment if taken with a sulfonylurea
Low blood glucose and weight gain may occur when Juvicor is taken with a sulfonylurea medicine. The dose of any sulfonylurea medicines may need to be lowered while taking Juvicor.8
Avoid use in patients with creatinine clearance < 50 mL/min
Patients with moderate to severe renal impairment require a lower dose of sitagliptin.8 While Juvicor offers a choice of simvastatin doses, there is no option for dose adjustment of the sitagliptin component.
Adherence with dosing schedule is most important
Juvicor should be taken once a day at about the same time, before or after food.38 While simvastatin may be slightly more effective taken in the evening compared with the morning, this benefit is rendered irrelevant if it compromises adherence.44
Is FDC treatment appropriate for this patient?
Take into account:
In patients with comorbidities, what are the potential drug–drug interactions?
Drug–drug interactions with the simvastatin component of Juvicor may lead to myopathy and rhabdomyolysis:38,60
Be aware that people of Chinese ethnicity are more likely than others to have an interaction between niacin and simvastatin and should avoid taking more than 1 g/day of niacin. The risk of this interaction is higher with Juvicor containing the 40 mg strength of simvastatin.60
People with cardiovascular disease and at high risk of coronary events should start on the Juvicor formulation containing 40 mg simvastatin unless taking amiodarone, verapamil or diltiazem38
An adverse effect with an FDC medicine cannot be attributed to a particular medication based on initiation time or dosage increase.44 Common side effects that can be attributed to individual medicines include:
Some adverse effects (e.g. constipation) are common to simvastatin and sitagliptin8,60 so it may be hard to identify which drug is responsible
Is the required dose combination available?
While Juvicor offers a choice of simvastatin doses, there is no option for dose adjustment of the sitagliptin component for people with creatinine clearance < 50 mL/min.8 See 'Patients with renal impairment'
Information for patients
Switching to the FDC from taking sitagliptin and/or simvastatin separately
Ensure that patients and carers know the name and dose of all the active ingredients contained in the combination product and which medicines are being replaced by the combination product (Table 1).
Make patients aware that if they develop side effects to the FDC (which requires them to stop the FDC) they will most likely need to restart one of its components. See 'Will it be possible to identify which drug in the combination is causing adverse effects?' in Table 2.
Advise patients to:
- return previous supplies of sitagliptin and simvastatin alone or in other combination products to their pharmacy
- avoid grapefruit juice
- seek medical advice if they experience unexplained muscle pain, tenderness, or weakness, especially with fever, or symptoms of a serious allergic reaction, such as rash, hives or swelling of the face, lips, mouth, tongue or throat while taking Juvicor
- report signs of pancreatitis such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back.
An NPS Medicine Update article on Juvicor 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.
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- 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]
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