Sitagliptin Phase III trials results announced at ADA

Newly released Phase III studies presented on 10th June 2006 at the American Diabetes Association (ADA) 66th Annual Scientific Sessions demonstrated that JANUVIA (sitagliptin phosphate), Merck and Co., Inc.'s investigational oral, once-daily medicine for type 2 diabetes, significantly reduced blood glucose levels when used as monotherapy or as an add-on treatment to two commonly used therapies (metformin or pioglitazone). Additionally, treatment with JANUVIA improved some measures of beta cell function.

Sitagliptin is DPP-4 inhibitor.

Side effects were low with coryzal symptoms, diarrhoea, headach and joint pain being reported slightly more than placebo.

It's effect on HbA1c is greater for higher starting levels of HbA1c. In three monotherapy studies in patients with mildly to moderately elevated A1C levels (mean baseline A1C levels ranged from 7.5% to 8.1%), JANUVIA 100 mg once daily (the proposed registration dose) showed significant mean placebo-subtracted reductions in A1C ranging from 0.60% to 1.05% (1.20% to 1.50% in patients with higher baseline A1C >9%; patients were to be enrolled in the studies with a baseline A1C <6.5% and >10%). In patients in the lowest pre-defined stratum (baseline A1C <8%), the mean placebo-subtracted A1C reductions ranged from 0.44% to 0.57%.

"The data for JANUVIA presented today showed significant glucose-lowering effects across a range of patients with type 2 diabetes, especially in those with more elevated baseline A1C levels. In these studies, a low rate of hypoglycemia was observed and JANUVIA was generally weight neutral," said Edward S. Horton, M.D., vice president of the Joslin Diabetes Center in Boston and head of its clinical research division.

3 days of amoxycillin as good as 8 in community acquired pneumonia

Discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.

BMJ 2006;332:1355

Researchers from the Netherlands sought to compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.

A randomised, double blind, placebo controlled non-inferiority trial was set up in nine secondary and tertiary care hospitals in the Netherlands. Adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score ≤ 110) who had substantially improved after three days' treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days.

Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval - 9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%, - 9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%, - 10% to 16%) and 86% compared with 79% at day 28 (difference 6%, - 7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1).

NICE approves herceptin

NICE has published draft guidance on Herceptin, just two weeks after the drug was licensed by the regulatory authorities for use in early breast cancer. The draft guidance recommends the drug for women with early stage HER2- positive breast cancer, except where there are concerns about the woman's cardiac function. Final guidance is expected to be issued at the beginning of July 2006, assuming there are no appeals.

NICE draft guidance on trastuzumab (Herceptin) for early breast cancer (June 9th 2006)

NICE Chief Executive Andrew Dillon said: "These proposals are very good news for women with HER2 positive breast cancer. Herceptin, for these women is clinically and cost effective in the early stage of the disease and we look forward to being able to issue final guidance, subject to any appeal against our recommendations, in a few weeks time."

The draft recommendations are as follows:

Trastuzumab, given at 3-week intervals for 1 year or until disease recurrence (whichever is the shorter period), is recommended as a treatment option for women with early-stage HER2-positive breast cancer following surgery,
chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable).

Cardiac function should be assessed prior to the commencement of therapy and trastuzumab treatment should not be offered to women who have a left ventricular ejection fraction (LVEF) of 55% or less, or who have any of the following:

• a history of documented congestive heart failure
• high-risk uncontrolled arrhythmias
• angina pectoris requiring medication
• clinically significant valvular disease
• evidence of transmural infarction on electrocardiograph (ECG)
• poorly controlled hypertension.

Cardiac functional assessments should be repeated every 3 months during trastuzumab treatment. If the LVEF drops by 10% from baseline and to below 50% then trastuzumab treatment should be suspended. A decision to resume trastuzumab therapy should be based on a further cardiac assessment and a fully informed discussion of the risks and benefits between the individual patient and their clinician.

ETHRISK - a British ethnic cardiovascular risk calculator

Ethnic groups within Britain have differing risk of coronary heart disease (CHD) and cardiovascular disease (CVD) at the same level of risk factors. The ETHRISK calculator developed by researchers from Bristol University adjusts for ethnic group and is based on a re-calibration of the Framingham risk equations. It also provides the standard Framingham estimates. The method uses the prevalence ratios for CHD and CVD for each ethnic group compared to the general population, and adjusts for differences in mean risk factor levels and prevalence of smoking between each ethnic group.

The calculator has been published in Heart (online first) today.

REVIEW ARTICLE: Medical Progress: Assessing Kidney Function -- Measured and Estimated Glomerular Filtration Rate

REVIEW ARTICLE: Medical Progress: Assessing Kidney Function -- Measured and Estimated Glomerular Filtration Rate: "In the coming years, estimates of the glomerular filtration rate (GFR) may replace the measurement of serum creatinine as the primary tool for the assessment of kidney function. Indeed, many clinical laboratories already report estimated GFR values whenever serum creatinine is measured. This review considers current methods of measuring GFR and GFR-estimating equations and their strengths and weaknesses as applied to chronic kidney disease."

GMC pushes ahead with revalidation

The GMC is pressing ahead with revalidation ahead of the Chief Medical Officer for England's (CMO) delayed review.

Proposals to start introducing licences to practise met with general approval at last week's GMC council meeting.

The GMC had initially agreed that licensing should wait until the CMO's report was published at the end of last year, but as the report is not now expected before the summer, council members agreed to the action because of the long delays.

Hospital Doctor understands some GMC members expect licences to be introduced as early as next year.

The news comes as a survey finds that support among doctors for revalidation has plunged from 52 per cent in 2005 to 42 per cent in 2006.

Hospital Doctor

Statins improve renal function?

"To define the effect of short-term rosuvastatin treatment on the estimated glomerular filtration rate (eGFR), the database of controlled clinical trials in the Rosuvastatin Clinical Development Program was reviewed. Thirteen studies comprising 3,956 rosuvastatin-treated patients were selected based on a serum creatinine measurement at 6 or 8 weeks after initiation of rosuvastatin treatment, randomization to approved and marketed rosuvastatin doses (5 to 40 mg), and unchanged rosuvastatin dose from treatment initiation (baseline) through 6 to 8 weeks of treatment. eGFR was determined with the Modification of Diet in Renal Disease formula. eGFR significantly increased for each dose of rosuvastatin individually and for all doses combined compared with baseline (range +0.9 to +3.2 ml/min/1.73 m(2)). Further analysis of 5 blinded, placebo-controlled trials comprising 525 patients showed an increase in eGFR of +0.8 ml/min/1.73 m(2) (95% confidence interval +0.1 to +1.5) for all rosuvastatin-treated patients, which was significantly different from baseline (p <0.04) and from a change of -1.5 ml/min/1.73 m(2) in the placebo-treated patients (95% confidence interval -2.5 to -0.5, p <0.001). The increase in eGFR for rosuvastatin-treated patients was consistent across all major demographic and clinical subgroups of interest, including patients with baseline proteinuria, baseline eGFR <60 ml/min/1.73 m(2), and in patients with hypertension and/or diabetes. In conclusion, these results are consistent with previous rosuvastatin studies that showed an upward trend in eGFR with long-term treatment (>/=96 weeks) and with the hypothesis that statins may have pleiotropic mechanisms of action that include beneficial renal effects."

Am J Cardiol. 2006 Jun 1;97(11):1602-6. Epub 2006 Apr 7

Risk factors for renal dysfunction in type 2 diabetes: UKPDS 74

"Not all patients with type 2 diabetes develop renal dysfunction. Identifying those at risk is problematic because even microalbuminuria, often used clinically as an indicator of future renal dysfunction, does not always precede worsening renal function. We sought to identify clinical risk factors at diagnosis of type 2 diabetes associated with later development of renal dysfunction. Of 5,102 U.K. Prospective Diabetes Study (UKPDS) participants, prospective analyses were undertaken in those without albuminuria (n = 4,031) or with normal plasma creatinine (n = 5,032) at diagnosis. Stepwise proportional hazards multivariate regression was used to assess association of putative baseline risk factors with subsequent development of albuminuria (microalbuminuria or macroalbuminuria) or renal impairment (Cockcroft-Gault estimated creatinine clearance <60 ml/min or doubling of plasma creatinine). Over a median of 15 years of follow-up 1,544 (38%) of 4,031 patients developed albuminuria and 1,449 (29%) of 5,032 developed renal impairment. Of 4,006 patients with the requisite data for both outcomes, 1,534 (38%) developed albuminuria and 1,132 (28%) developed renal impairment. Of the latter, 575 (51%) did not have preceding albuminuria. Development of albuminuria or renal impairment was independently associated with increased baseline systolic blood pressure, urinary albumin, plasma creatinine, and Indian-Asian ethnicity. Additional independent risk factors for albuminuria were male sex, increased waist circumference, plasma triglycerides, LDL cholesterol, HbA(1c) (A1C), increased white cell count, ever having smoked, and previous retinopathy. Additional independent risk factors for renal impairment were female sex, decreased waist circumference, age, increased insulin sensitivity, and previous sensory neuropathy. Over a median of 15 years from diagnosis of type 2 diabetes, nearly 40% of UKPDS patients developed albuminuria and nearly 30% developed renal impairment. Distinct sets of risk factors are associated with the development of these two outcomes, consistent with the concept that they are not linked inexorably in type 2 diabetes."

Diabetes. 2006 Jun;55(6):1832-9

State-of-the-art review of Rimonabant

"Rimonabant is a first selective blocker of the cannabinoid receptor type 1 (CB1) being developed for the treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking. In four large trials, after one year of treatment, rimonabant 20 mg led to greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is also associated with favorable changes in serum lipid levels and an improvement in glycemic control in prediabetes patients and in type 2 diabetic patients. At the same dose, rimonabant significantly increased cigarette smoking quit rates as compared with placebo. Rimonabant seems to be well tolerated, with a primary side effect of mild nausea. As an agent with a novel mechanism of action, rimonabant has a potential to be a useful adjunct to lifestyle and behavior modification in treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking."

J Am Coll Cardiol. 2006 May 16;47(10):1919-26

REVIEW ARTICLE: Current Concepts: Ambulatory Blood-Pressure Monitoring

REVIEW ARTICLE: Current Concepts: Ambulatory Blood-Pressure Monitoring: "Blood pressure is inherently variable, and ambulatory measurements of blood pressure predict clinical outcomes better than do conventional, clinic-based measurements. Ambulatory monitoring can help identify 'white-coat' hypertension, as well as patients whose blood pressure does not decrease the normal amount during the night. Ambulatory blood-pressure monitoring is practical, can lead to a reduction in health care costs, and can provide improved estimates of true blood pressures to guide decisions about treatment."

Risk Factors for Foot Infections in Individuals With Diabetes

Foot infections occur relatively frequently in individuals with diabetes, almost always follow trauma, and dramatically increase the risk of hospitalization and amputation. Efforts to prevent infections should be targeted at people with traumatic foot wounds, especially those that are chronic, deep, recurrent, or associated with peripheral vascular disease.

An international group of researchers evaluated then followed 1,666 consecutive diabetic patients enrolled in a managed care–based outpatient clinic in a 2-year longitudinal outcomes study. At enrollment, patients underwent a standardized general medical examination and detailed foot assessment and were educated about proper foot care. They were then rescreened at scheduled intervals and also seen promptly if they developed any foot problem.

During the evaluation period, 151 (9.1%) patients developed 199 foot infections, all but one involving a wound or penetrating injury. Most patients had infections involving only the soft tissue, but 19.9% had bone culture–proven osteomyelitis. For those who developed a foot infection, compared with those who did not, the risk of hospitalization was 55.7 times greater (95% CI 30.3–102.2; P < 0.001) and the risk of amputation was 154.5 times greater (58.5–468.5; P < 0.001). Foot wounds preceded all but one infection. Significant (P < 0.05) independent risk factors for foot infection from a multivariate analysis included wounds that penetrated to bone (odds ratio 6.7), wounds with a duration >30 days (4.7), recurrent wounds (2.4), wounds with a traumatic etiology (2.4), and presence of peripheral vascular disease (1.9).

This suggests that strategies aimed primarily at educating patients to seek specialist advice following trauma may be better at preventing the complications associated with diabetic foot infections.

Diabetes Care 29:1288-1293, 2006

SHOs to be stranded

Thousands of SHOs who are currently in research or non-standard posts could find themselves stranded following the introduction of specialty training in 2007.

Modernising Medical Careers (MMC) and the DoH are expected to make a formal announcement on run-through training within the next two weeks. However, Carrie Goddard, MMC director of communications, has already discussed changes informally with a group of ophthalmology trainees.

Early indications from MMC were that the old-style higher specialist training, or Calman training, would continue until 2009. However, Hospital Doctor now understands that all three years of specialty training (ST1, ST2 and ST3) will start simultaneously in 2007. Junior SHOs will be permitted to enter at ST2 and doctors ready to start their first year of SpR training will move into ST3.

In 2008, there will be no ST2 entry for SHOs and only a limited number will be allowed to enter at ST3. This means that any SHOs who do not enter specialty training by 2007 could find themselves frozen out (see case study).

Dr Jo Hilborne, chairman of the BMA's Junior Doctors Committee, said: 'Our advice is for SHOs to do the best they can to move into a standard post as they are then more likely to be counted in the new specialty training. Even better would be to get an SpR post and national training number this year.'

Hospital Doctor