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MeReC Monthly No.1
April 2008

MeReC Monthly is a new publication from the NPC. It will be published on the NPC website at www.npc.co.uk/merec.htm on the second to last Thursday of each month. A print-friendly version will also be available. To ensure that you are notified when a new MeReC resource is added to the website, please register to receive an email alert (www.npc.co.uk/mynpc/). The articles in MeReC Monthly are based upon blogs from the recently launched NPCi website (www.npci.org.uk). Further details of the studies outlined in this publication can be found on the blog pages (www.npci.org.uk/blog/). You can also try out our educational materials in the unique NPCi eLearning environment, which provides summarised evidence and information in 'bite-sized' chunks. Please feel free to discuss prescribing and therapeutic issues in our NPCi discussion rooms (www.npci.org.uk/discuss/) or give us feedback (www.npci.org.uk/feedback.php).

Newer antidepressants beneficial only in the severely depressed

A recent meta-analysis has found that the effect of newer antidepressants was statistically significantly different from placebo. However this effect was, on average, not clinically significant for all but the most severely depressed people.^1,2

What is the background to this?
Antidepressants have undoubtedly helped many people with depression. However, they are not recommended in NICE guidance on the management of depression for the initial treatment of mild depression, because the risk-benefit ratio is poor.³ The authors of this meta-analysis aimed to analyse information from all published and unpublished studies on six antidepressants (fluoxetine, venlafaxine, nefazodone, paroxetine, sertraline and citalopram).

What did the study find?
In line with earlier research, fluoxetine, nefazadone, paroxetine and venlafaxine were found to produce statistically significant improvements over placebo of, on average, 1.8 points in the Hamilton Rating Scale for Depression (HRSD).¹ However, this difference did not reach the 3-point difference adopted by NICE as the criterion for clinical significance.³ Also, the placebo response was large, duplicating more than 80% of the improvement seen with antidepressants. The difference between drug and placebo only exceeded NICE's criterion for clinical significance in trials which included severely depressed patients (mean baseline score 28 or more on the HRSD). Full datasets were not available for sertraline and citalopram.¹

So what?
These data have some limitations. For example, the results refer to averages, and we do not know the proportions of people who showed a clinically significant improvement, no improvement or worsened depression during antidepressant treatment. Also, mean improvement scores were not available, despite exhaustive searching, for one citalopram and four sertraline trials – instead these were reported as not showing a statistically significant drug effect. Inclusion in the meta-analysis of only those sertraline and citalopram trials for which mean improvement scores were reported to the US drug regulators, the Food and Drug Administration (FDA), would have constituted a form of reporting bias similar to publication bias and would have led to overestimation of drug-placebo differences for these drugs.¹ Several studies have found publication bias in trials of antidepressants.^4,5 Selective reporting biases the evidence base in favour of antidepressant drugs and, as a result of these perceived benefits, inappropriate prescribing decisions may be made.

Prescribers need to be aware of the limitations in the evidence for the effectiveness of anti-depressants, and be mindful that published evidence may be biased in favour of their effectiveness. They should follow NICE guidance for the management of depression (see also MeReC Briefing No.31 and the depression floor of NPCi). For mild depression, watchful-waiting, active monitoring and non-drug interventions, such as brief psychological therapy or exercise, may be all that is needed, and drug treatment is not recommended initially. Antidepressants are recommended by NICE for people with moderate to severe depression (see Panel 1, MeReC Briefing No.31). However, they may not be suitable for, or preferred by everyone.

References

1. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008 5(2): 45. doi:10.1371/ journal.pmed.0050045. Accessed from http://medicine.plosjournals.org/perlserv/?request=get-document& doi=10.1371/journal.pmed.005004 on 04/03/08
2. NPC. Newer antidepressants produce clinically significant benefits over placebo only in the severely depressed. NPCi blog. March 11th 2008. Accessed from http://www.npci.org.uk/blog/?p=78 on 14/03/08
3. National Institute for Health and Clinical Excellence. Depression: management of depression in primary and secondary care. Clinical Guideline No.23. December 2004. Accessed from http://www.nice.org.uk/ guidance/index.jsp?action=byID&o=10958 on 04/03/08
4. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. New Engl J Med 2008;358:252-60. Accessed from http://content.nejm.org/ cgi/reprint/358/3/252.pdf on 04/03/08
5. NPC. Publication bias in studies of antidepressants? NPCi blog. February 21st 2008. Accessed from http://www.npci.org.uk/blog/?p=71 on 04/03/08

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Is intensive control of blood glucose beneficial?

The National Heart Lung and Blood Institute (NHLBI) in the USA recently announced that it has stopped the intensive blood glucose lowering arm of a large type 2 diabetes trial. This is due to findings that intensively lowering blood glucose below current US recommended targets increased the risk of death compared with a less intensive standard treatment strategy.^1,2

What is the background to this?
People with type 2 diabetes are at increased risk of cardiovascular (CV) events compared to people without diabetes. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study was designed to look at the effects of intensive blood glucose, blood pressure (BP) and lipid lowering in people with type 2 diabetes who are at high risk of CV events. 10,251 participants were randomised to either an intensive therapeutic strategy that targeted an HbA_1c of <6.0% or a standard strategy that targeted an HbA_1c of 7.0% to 7.9%. This was to be achieved through diet and lifestyle measures, and drug therapy including all available diabetes medications.^1,2,3

What concerns have been raised?
After an average four years of follow-up, people in the intensive treatment arm had a 27% higher relative risk of dying than those in the standard treatment arm. For this group, this translated into a number needed to harm (NNH) of 95 and equates to 3 extra deaths per 1,000 participants per year, over an average of 4 years of treatment. The increased risk between the two groups outweighed potential benefits of the intensive treatment strategy on non-fatal events. Accordingly, the NHLBI made the decision to stop this intensive treatment approach of the trial.^1,2 We await the publication of the blood glucose lowering arm of ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), which was also designed to find out whether intensive treatment (HbA_1c <6.5%) improved patient outcomes.⁴

The currently available evidence suggests that interventions addressing CV risk reduction can reduce both microvascular and macrovascular complications in people with type 2 diabetes. However, the evidence for the benefits of tight blood glucose control alone is much less convincing. A recent randomised controlled trial in 160 Danish patients with type 2 diabetes and microalbuminuria has demonstrated that intensive multifactorial interventions can reduce the risk of dying from any cause or from CV disease.^5,6 A target driven, intensive multifactorial intervention, which included tight control of BP (<130/80mmHg), blood glucose (HbA_1c <6.5%) and lipids (fasting serum total cholesterol <4.5mmol/L and triglycerides <1.7mmol/L), use of renin-angiotensin system blockers for micro-albuminuria, low-dose aspirin and behaviour modification, was compared with conventional treatment consistent with Danish national guidelines. The study found that, during 13.3 years of follow-up, 30% of patients in the intensive therapy group died, compared with 50% in the conventional therapy group (absolute risk reduction [ARR] 20%; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.32 to 0.89; P=0.02). Death from CV causes was also lower in the intensive therapy group (ARR 13%; HR 0.43, 95%CI 0.25 to 0.67; P=0.04).⁶

The point estimates in this small study (but with a long period of follow up) have a wide margin for error. However, a 50% death rate over 13.3 years among patients receiving conventional treatment highlights the poor prognosis for patients with type 2 diabetes and microalbuminuria.⁶

So what?
Both of these studies support previous evidence suggesting that clinicians and patients should be aware of the importance of managing CV risk factors in those with type 2 diabetes. This may include encouraging smokers to stop smoking, controlling BP, adding a statin (ideally simvastatin 40 mg/day) and adding aspirin once their BP is controlled. Blood glucose should also be managed to control symptoms (probably using diet and lifestyle measures along with metformin) but the evidence indicates that the benefits of intensive control of blood glucose may be less than some patients and healthcare professionals perceive.^2,6,7,8 Further information on the manage-ment of type 2 diabetes is available on NPCi.

References

1. National Heart, Lung and Blood Institute. For safety, NHLBI changes intensive blood sugar treatment strategy in clinical trial of diabetes and cardiovascular disease. Press release. February 6th 2008. Accessed from http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2551 on 03/03/08
2. NPC. Increased death rate found in intensive blood glucose-lowering arm of trial in type 2 diabetes – study arm halted. NPCi Blog. February 7th 2008. Accessed from www.npci.org.uk/blog/?p=64 on 03/03/08
3. ACCORD study purpose. June 30th 2006. Accessed from www.accordtrial.org/web/public/index.cfm on 03/03/08
4. The George Institute for International Health. Major international diabetes study does not confirm increased risk of death reported by US trial. Media release. February 13th 2008. Accessed from www.advance-trial.com/static/html/virtual/contents.asp?P=39 on 17/03/08
5. Gaede P, Lund-Andersen H, Parving H-H, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Eng J Med 2008:358:580–91. Accessed from http://content.nejm.org/cgi/content/short
   /358/6/580?query=TOC on 03/03/08
6. NPC. Intensive interventions in type 2 diabetes reduce mortality. NPCi Blog. February 11th 2008. Accessed from www.npci.org.uk/blog/?p=69 on 03/03/08
7. NPC. Has reaction against "glucocentricity" in type 2 diabetes "gone too far"? NPCi Blog. January 21st 2008. Accessed from www.npci.org.uk/blog/?p=58 on 03/03/08
8. Bailey C, Barnett A, Petrie J. Value of glycaemic control in diabetes. Lancet 2008; 371:116. Accessed from www.thelancet.com/journals /lancet/article/PIIS0140673608601014/fulltext on 17/03/08

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