New data analyses presented at the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD) showed initial combination therapy with the dipeptidyl peptidase–4 (DPP–4) inhibitor, sitagliptin, and metformin provided substantial improvements in blood sugar levels (as measured by HbA1c1) over two years of treatment and was generally well tolerated. Also presented at the meeting was a separate, new pooled analysis of 6,139 patients that shows that sitagliptin 100 mg a day was generally well tolerated in clinical trials of up to two years in duration.
More than six million total prescriptions for sitagliptin have been dispensed worldwide since launch.+ Sitagliptin has received authorisation in 80 countries and is available in every region around the world. The European Medicines Agency (EMEA) licensed sitagliptin in Europe in April 2007 and recently licensed JANUMET++ (sitagliptin/metformin) in July 2008. Sitagliptin is indicated for the treatment of type 2 diabetes to improve glycaemic control in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control; in combination with a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance; and to improve glycaemic control in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. For patients with type 2 diabetes mellitus in whom use of a PPAR? agonist (i.e. a thiazolidinedione) is appropriate, sitagliptin is indicated in combination with a PPAR? agonist when diet and exercise plus the PPAR? agonist alone do not provide adequate glycaemic control. Sitagliptin# should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Sitagliptin is contraindicated in patients with hypersensitivity to the active substance or to any of the exicipients. The use of sitagliptin in combination with insulin has not been adequately studied.
Initial combination of sitagliptin and metformin provided powerful glycaemic improvements out to two years1
In a study of initial combination therapy with sitagliptin and metformin, glucose–lowering was assessed by measuring the mean change from baseline HbA1c levels at one year and two years. The mean HbA1c reductions from baseline in this study were 1.8 percent at one year (n=153) in patients treated with sitagliptin 50 mg/metformin 1000 mg twice–daily. In the extension study at two years, the mean HbA1c reduction was 1.7 percent (n=105; baseline HbA1c of 8.6 percent) for this group. Additionally, mean HbA1c reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with sitagliptin 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134 and two years, n=87) in patients treated with metformin 1000 mg twice daily, 1.0 percent (at one year, n=117) and 1.1 percent (at two years, n=64) in patients treated with metformin 500 mg twice daily. For patients treated with sitagliptin 100 mg once daily, there was a 0.8 percent reduction in HbA1c levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).1
In a subgroup analysis of patients grouped by severity of starting baseline HbA1c, treatment with JANUVIA 50 mg/metformin 1000 mg twice daily demonstrated greater mean HbA1c reductions from baseline in subgroups with higher baseline HbA1c. At one year a mean reduction of 3.1 percent was seen in patients with baseline HbA1c of 10 percent or more (n=17), while reductions of 2.2 percent, 1.7 percent, and 1.0 percent were seen with baseline HbA1c values of nine to 10 percent (n=43), eight to nine percent (n=60), and less than eight percent (n=33), respectively. At two years a mean reduction of 2.5 percent was seen in patients with baseline HbA1c of 9 percent or more (n=38), while reductions of 1.6 percent and 0.9 percent were seen with baseline HbA1c values of greater than or equal to eight to less than nine percent (n=38), and less than eight percent (n=29), respectively.
Three additional studies further demonstrate the safety and efficacy profile of sitagliptin as an add–on to other oral diabetes treatments
In one 52–week study, addition of sitagliptin to the combination of metformin and rosiglitazone* substantially improved glycaemic (blood sugar) control in patients with type 2 diabetes.3 In a separate 52–week study of Japanese patients, treatment with sitagliptin added to ongoing pioglitazone therapy provided effective glycaemic control and was generally well tolerated with a comparable occurrence of hypoglycaemia in the placebo and sitagliptin (50 mg, once daily) groups, and without clinically meaningful change in body weight. A sustained mean reduction in HbA1c from baseline of 0.7 percent was observed; 62 percent of patients achieved HbA1c <7 percent in the sitagliptin population at the end of the 52–week period.4
"These data are interesting for physicians treating type 2 diabetes as they show significant lowering of blood sugar with sitagliptin both as initial combination therapy with metformin and also as add on therapy to other commonly used oral diabetes medications," said Professor Bernard Charbonnel, Professor of Endocrinology and Metabolic Diseases, University of Nantes and Head of the Internal Medicine, Endocrinology and Diabetes Department, Hôtel Dieu (University Hospital of Nantes). "This is important for patients and physicians because type 2 diabetes is characterised by a progressive deterioration in beta cell function over time, resulting in the disease worsening. This progression of disease leads to decreased effectiveness of all known treatments over time, with patients often requiring multiple therapies in order to achieve their glycaemic goals."
An additional analysis presented at the meeting demonstrated that in patients with type 2 diabetes, sitagliptin provided effective and consistent glycaemic control regardless of baseline characteristics of age, gender, BMI, HOMA–?, and P/I ratio.7
In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycaemia, and discontinuation of therapy due to clinical adverse reactions with sitagliptin were similar to placebo. In these clinical studies, the most common adverse reactions reported with sitagliptin (greater than or equal to 5 percent and higher than placebo) were stuffy or runny nose and sore throat, and upper respiratory infection. In clinical trials in combination with a sulphonylurea (glimepiride), with or without metformin, sitagliptin demonstrated an overall incidence of adverse reactions higher than that seen with placebo, principally related to a higher incidence of hypoglycaemia.
As is typical with other anti–hyperglycaemic agents, when sitagliptin is used in combination with a sulphonylurea, (a class of medications known to cause hypoglycaemia) the incidence of hypoglycaemia increased over that of placebo. Therefore, a lower dose of sulphonylurea may be required to reduce the risk of hypoglycaemia.
Initial combination of sitagliptin and metformin: study design and results
Initial combination therapy with sitagliptin and metformin significantly improved blood sugar levels compared with either metformin or sitagliptin alone over two years of treatment. After completing the initial, double–blind 54–week base study, 412 patients who received active treatment throughout the study were included in the all–patients–treated analysis of efficacy at two years.1
The mean HbA1c reduction from baseline in the 1–year base study was 1.8 percent (n=153) in patients treated with sitagliptin 50 mg/metformin 1000 mg twice daily. In the extension study at two years, the mean HbA1c reduction from baseline was 1.7 percent (n=105) in this group of patients. Additionally, mean HbA1c reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with sitagliptin 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134 and two years, n=87) in patients treated with metformin 1000 mg twice daily, 1.0 percent (at one year, n=117) and 1.1 percent (at two years, n=64) in patients treated with metformin 500 mg twice daily. For patients treated with sitagliptin 100 mg once daily, there was a 0.8 percent reduction in HbA1c levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).1
Pooled analysis of safety and tolerability of sitagliptin: study design and results
In a pooled analysis of clinical studies of up to two years in duration, treatment with sitagliptin 100 mg a day was found to be generally well tolerated, with generally similar incidence of adverse experiences in patients treated with sitagliptin relative to those not exposed to sitagliptin.2
The safety and tolerability of sitagliptin were evaluated by pooling data from 12 large, double–blind, randomised, completed Phase IIb and III studies of 18 weeks to two years duration that included 6,139 patients receiving either sitagliptin once–daily (n=3,415) or placebo or an active comparator (n=2,724; non–exposed group). The studies assessed sitagliptin as monotherapy, initial combination therapy with metformin or add–on therapy to oral antihyperglycaemic agents (metformin, pioglitazone, a sulphonylurea, a sulphonylurea plus metformin or metformin plus rosiglitazone). Patients not receiving sitagliptin received a range of treatments, including placebo, pioglitazone, metformin, a sulphonylurea, a sulphonylurea plus metformin, or metformin plus rosiglitazone. This comparison group, patients not receiving sitagliptin, is referred to as the "non–exposed" group.2
For clinical adverse experiences (AEs), the incidence of AEs overall, serious AEs and discontinuations due to AEs were similar between the sitagliptin and non–exposed groups. The incidence of drug–related AEs and discontinuations due to drug–related AEs were higher in the non–exposed group primarily due to events of hypoglycaemia in sulphonylurea–treated patients.2
Clinical AEs that occurred at a higher incidence in the sitagliptin group and for which the 95 percent confidence intervals around the between–group difference excluded 0 were as follows: atrial fibrillation, asthenia, chest discomfort, tooth abscess, osteoarthritis, acne, and contact dermatitis. Eleven AEs occurred at a higher incidence in the non–exposed group for which the 95 percent confidence intervals around the between–group difference excluded 0 and were as follows: bradycardia, goiter, change in bowel habit, blood glucose decrease, blood glucose increase, weight increase, hyperglycaemia, sinus headache, prostatitis, balanitis, hyperkeratosis2.
Combination therapy with sitagliptin, metformin, and rosiglitazone: Study design and results
In this study, 262 patients (mean baseline HbA1c 8.8 percent) taking metformin (?1500 mg/day) and rosiglitazone (?4 mg/day) were randomised in a 2:1 ratio to the addition of once–daily sitagliptin 100 mg (n=170) or placebo (n=92). After 18 weeks, the addition of sitagliptin significantly (p<0.001) reduced mean HbA1c by 0.7 percent relative to placebo (mean change from baseline –1.0 percent with sitagliptin vs. –0.3 percent with placebo). From the mean baseline HbA1c of 8.8 percent, the proportion of patients with an HbA1c <7 at week 18 percent was significantly (p=0.005) greater with the addition of sitagliptin (22 percent) compared with placebo (9 percent). In addition, measures related to ?–cell function were significantly (p?0.05) improved with sitagliptin compared with placebo.3 After 18 weeks of treatment, nasopharyngitis and upper respiratory tract infection were reported more frequently in patients treated with sitagliptin (5% and 6%, respectively) than in patients treated with placebo (4% and 5%, respectively). In the continuation of this study out to 54 weeks, the addition of sitagliptin to the combination of metformin and rosiglitazone was generally well tolerated and continued to show significant (p<0.001) reductions in HbA1c of 0.8 percent relative to placebo. Clinical adverse events occurring at an incidence rate ?3 percent and higher in the sitagliptin group included in the 54 week study were: upper respiratory tract infection, nasopharyngitis, peripheral oedema, headache, urinary tract infection, back pain, dizziness and cough.
Treatment with an investigational dosing regimen of sitagliptin (50 mg once daily) added to ongoing pioglitazone therapy in Japanese patients with type 2 diabetes over 52 weeks: study design and results
A 12–week double–blind period where patients (n=134) on a stable dose of pioglitazone were randomised to the addition of once–daily sitagliptin 50 mg (n=66) or placebo (n=68) was followed by a 40–week open–label extension period where patients on placebo were reallocated to sitagliptin 50 mg and sitagliptin could be titrated from 50 mg to 100 mg. In the double–blind period, sitagliptin significantly reduced mean HbA1c from baseline relative to placebo at week 12 by 0.8 percent. In the open–label extension period of 66 patients allocated to sitagliptin treatment, 50 patients completed 52–week treatment. In this patient population, efficacy at week 52 was observed with a sustained change in HbA1c from baseline of 0.7 percent and with 62 percent of patients at an HbA1c goal of <7 percent. Treatment with sitagliptin was generally well tolerated compared to placebo with a low occurrence of hypoglycaemia (3.0% versus 2.9%) and oedema (1.5% versus 0%) and without clinically meaningful change in body weight.4
Dosing of Sitagliptin
The recommended dose of sitagliptin is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl ?50 mL/min). Clinical study experience with sitagliptin in patients with moderate or severe renal insufficiency is limited. Therefore, use of sitagliptin is not recommended in this patient population.
Selected cautionary information for sitagliptin
Sitagliptin is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy. There are no adequate data from the use of sitagliptin in pregnant women. Due to lack of data, sitagliptin should not be used in pregnancy. There have been post–marketing reports of hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens–Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first three months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event and institute alternative treatment for diabetes.
About Merck
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Forward Looking Statement
This press release contains "forward–looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management´s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward–looking statements may include statements regarding product development, product potential or financial performance. No forward–looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward–looking statement, whether as a result of new information, future events, or otherwise. Forward–looking statements in this press release should be evaluated together with the many uncertainties that affect Merck´s business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck´s Form 10–K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company´s periodic reports on Form 10–Q or current reports on Form 8–K, which the Company incorporates by reference.
JANUVIA TM and JANUMET TM are trademarks of Merck & Co., Inc.
JANUMET TM is still not authorised and commercialised in Italy.
* Such combination is not indicated in Italy
+ HbA1c is a measure of a person´s average blood glucose over a two–month to three–month period.
++ JANUMET is still not authorised and commercialised in Italy.
# In Italy sitagliptin is approved only for use in combination with metformin and in combination with a PPAR? agonist when diet and exercise plus the drug alone does not provide adequate glycaemic control.
1 Qi DS., et al. Two year treatment with sitagliptin and initial combination therapy of sitagliptin and metformin provides substantial and durable glycemic control in patients with type 2 diabetes. EASD Abstract August, 2008.
2 Williams–Herman D., et al. Safety and tolerability of sitagliptin, a selective DPP–4 inhibitor, in patients with type 2 diabetes: pooled analysis of 6139 patients in clinical trials for up to 2 years. EASD Poster August, 2008.
3 Arjona Ferreira, J., et al. Triple combination therapy with sitagliptin, metformin, and rosiglitazone improves glycemic control in patients with type 2 diabetes. EASD Poster August, 2008.
4 Maegawa H., et al. Sitagliptin added to ongoing treatment with pioglitazone study up–to 52 weeks in Japanese patients with T2DM. EASD Poster August, 2008.
5 Alba M., et al. In patients with type 2 diabetes, sitagliptin added to metformin effectively lowers HbA1c regardless of patient age, gender, body mass index, or baseline measure of ?–cell function. EASD Poster August, 2008.
6 IMS Health, NPA TM Weekly, TRxs, week–ending October 20, 2006 through week–ending July 25, 2008.
7 Alba M., et al. In patients with type 2 diabetes, sitagliptin added to metformin effectively lowers HbA1c regardless of patient age, gender, body mass index, or baseline measure of ?–cell function. EASD Poster August, 2008.
