A new analysis presented at the American Diabetes Association (ADA) 68th Annual Scientific Sessions showed treatment with 'Januvia'™ (sitagliptin), Merck & Co., Inc's diabetes medicine, was associated with a 93 percent lower risk of having a confirmed symptomatic hypoglycaemic event on a given day (p=0.001) compared to treatment with glipizide, a sulphonylurea (SU). This 52-week intent to treat analysis was based on 37 events in the sitagliptin group (n=588) and 492 events in the glipizide group (n=584). Both agents were added to ongoing metformin therapy in patients with type 2 diabetes and were associated with similar reductions in HbA1c [1] (-0.67% in both groups at week 52 confirming non-inferiority in the prespecified per-protocol analysis).

Sitagliptin is indicated, as an adjunct to diet and exercise, to improve glycaemic control in adult patients with type 2 diabetes. It should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. The product has not been studied in combination with insulin and is contraindicated in patients with a history of a serious hypersensitivity reaction to agent, such as anaphylaxis and angioedema.

Hypoglycaemia is a common side effect of some oral diabetes medications. The risk of hypoglycaemia observed in this study was lower in older patients (≥ 65 years), sitagliptin versus glipizide and with younger patients (< 65 years), sitagliptin versus glipizide. In the older age group (sitagliptin, n=120; glipizide, n=123), patients treated with sitagliptin had a 97 percent (29-fold) lower risk of confirmed hypoglycaemia compared to patients treated with glipizide and, in the younger age group (sitagliptin n=468; glipizide, n=461), non-SU patients had a 91 percent (11-fold) lower risk of confirmed hypoglycaemia compared to patients treated with glipizide (p<0.001 for both analyses). Risk was assessed using a model which took into consideration treatment, most recent HbA1c prior to the event, time from randomization to the event, gender, age group and interaction terms.

As is typical with other anti-hyperglycaemic agents 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 when combined with other agents.

Sitagliptin is a highly selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin axis, which helps to regulate glucose blood levels by affecting the beta-cells in the pancreas. Through DPP-4 inhibition, the product works only when blood sugar is elevated to address diminished insulin due to beta-cell dysfunction in type 2 diabetes mellitus. Glipizide is a sulphonylurea that lowers blood sugar by stimulating the pancreatic beta cells to release insulin independent of glucose levels.

Hypoglycaemia, or low blood sugar, occurs when the level of glucose in the blood drops too low for the body's needs. Symptoms may include shakiness, dizziness, sweating, hunger, headache, pale skin color, sudden behavioral changes, clumsy or jerky movements, seizure, confusion and unconsciousness.

"When treating patients with type 2 diabetes, it is important for physicians to balance lowering blood glucose levels with avoiding hypoglycaemia," said Nir Barzilai, M.D., professor of Medicine and Molecular Genetics and director of the Institute for Aging Research at Albert Einstein College of Medicine, New York.

In controlled clinical studies with metformin or pioglitazone, the overall incidences 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 were (greater than or equal to 5 percent and higher than placebo) stuffy or runny nose and sore throat, upper respiratory infection and headache. 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, in part related to a higher incidence of hypoglycaemia.

Lower risk of hypoglycaemia with sitagliptin compared to glipizide

This analysis showed that treatment with sitagliptin was associated with a significantly lower risk of hypoglycaemia compared to glipizide in patients with type 2 diabetes. Among patients with physician-confirmed symptomatic hypoglycaemic events, those taking the DPP-4 inhibitor had a 93 percent lower risk of experiencing a hypoglycemic event compared to those taking glipizide (random effects hazard ratio [HR]=0.07, 95% CI 0.04-0.11, p=0.001) according to the model used in this study.

The association between a lower risk of hypoglycaemia with sitagliptin compared to glipizide was stronger in older patients. In the older age group (>65 years) vs younger patients (< 65 years), patients treated with sitagliptin had a 29-fold or 97 percent lower risk of experiencing a hypoglycemic event compared to patients treated with glipizide (HR=0.03, 95% CI 0.01-0.11, p<0.001). In the younger age group (<65 years), patients treated with the DPP-4 inhibitor had an 11-fold or 91 percent lower risk of experiencing a hypoglycemic event compared to patients treated with the SU (HR=0.09, 95% CI 0.06-0.15, p<0.001).

The purpose of this pre-specified analysis was to evaluate the HbA1c-adjusted risk of a hypoglycaemic event on a given day. In this analysis, recent HbA1c, time from randomization to event and gender were also significant covariates in the model (p<0.001), impacting risk of hypoglycaemia similarly in both treatment groups. The endpoint was patient reported and physician confirmed symptomatic hypoglycaemic events with documented fingerstick glucose measurements (≤70 mg/dL or 3.9 mmol/L).

This analysis was based on a 52-week, randomised, double-blind, active-controlled study in which sitagliptin (100 mg once daily) or glipizide (up to 20 mg daily; mean daily dose 10 mg daily) was added to ongoing metformin therapy (> 1500 mg daily). This study showed that sitagliptin achieved the pre-specified bounds for non-inferiority vs. a sulphonylurea (glipizide). After one year, the mean HbA1c reduction from baseline was 0.67 percent for both groups in the prespecified per-protocol patient population and 0.5 percent for sitagliptin and 0.6 percent for glipizide in the intention-to-treat analysis [between-group difference in LS mean change from baseline (95% CI) = 0.04% (��"0.04, 0.13)], confirming the similar efficacy of sitagliptin compared to glipizide. The non-inferiority of sitagliptin to glipizide may be limited to patients with HbA1c levels comparable to those included in this study (over 70 percent of patients had a baseline HbA1c <8 percent and over 90 percent had a baseline HbA1c <9 percent).

In the study consisting of all reported cases, patients treated with glipizide experienced a significantly higher rate of hypoglycaemia vs. sitagliptin (32 percent vs. 5 percent, respectively; p<0.001). Additionally, patients in the group treated with sitagliptin experienced significant weight loss (mean -1.5 kg) from baseline, while patients treated with glipizide experienced significant weight gain (mean +1.1 kg) from baseline. The between-treatment difference was statistically significant (p<0.001, sitagliptin vs. glipizide).

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. Sitagliptin has not been studied in patients with severe hepatic insufficiency.

Selected cautionary information for sitagliptin

Tolerability and effectiveness in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. Sitagliptin and should not be used during pregnancy. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, it should therefore not be administered to a nursing woman. There have been post-marketing reports of hypersensitivity reactions in patients treated with the product. 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 the product, assess for other potential causes for the event and institute alternative treatment for diabetes. All adverse events should be reported to the regulatory agency or the manufacturer.

Expanding clinical development programme for sitagliptin family

Merck's clinical development programme for sitagliptin is robust and continues to expand with 55 studies completed or underway. It is estimated that approximately 12,000 patients have participated in the Company's clinical studies, with about 7,400 of these patients being treated with sitagliptin. Additionally, in clinical studies, approximately 2,300 patients have been treated with the product for more than one year and, of these, approximately 500 patients have been treated for at least two years.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programmes that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit http://www.merck.com.

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.

[1] HbA1c is a measure of a person's blood average blood glucose over a two- to three-month period.

Merck & Co., Inc.