Management of type 2 diabetes: summary of updated NICE guidance
BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39560.442095.AD (Published 05 June 2008) Cite this as: BMJ 2008;336:1306All rapid responses
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In the summary of the recently published NICE guidelines for the treatment of type 2 diabetes mellitus (1), the use of fibrates was recommended in the following situations:
• serum triglycerides >4.5mmol/L, after assessment of possible
secondary causes.
• serum triglycerides 2.3-4.5mmol/L despite statin therapy in which case
statin-fibrate combination therapy should be considered.
Unfortunately, this position is wholly unsupported by the available evidence in those with or without diabetes. Although the evidence to support a reduction in non-fatal myocardial infarction (MI) with fibrates is generally sound with a 22% reduction confirmed in a recent meta- analysis of 10 relevant randomised control trials (2), effects on other important outcomes are far from reassuring. Indeed, coronary heart disease (CHD) mortality is not reduced by fibrates and non-CHD mortality appears to be significantly raised with the consequence that overall mortality is borderline elevated (HR1.07 [0.99 to 1.15] versus placebo).
Whilst the guideline quotes changes in lipid parameters at length, the only outcome data provided for fibrate therapy is that from the Veterans Affairs High-Density Lipoprotein Intervention Trial (3) which used gemfibrozil, a drug which certainly must not be prescribed with a statin. Furthermore, the apparently beneficial effects of fenofibrate on lipid parameters in the FIELD study are listed but without discussion of the all important (and disappointing) outcome data (4). The guideline quotes apparently arbitrary triglyceride threshold values above which fibrate therapy is advised or should be considered; a serum triglyceride level of 4.5mmol/L is clearly far lower than that at which pancreatitis is a risk and these two indications for therapy, namely risk reduction for cardiovascular events and pancreatitis, must be considered separately. Clinicians must also consider the increased risk of important side-effects on statin-fibrate combination therapy, in particular rhabdomyolysis, which appears to be far more common with this combination amongst older patients with diabetes (5). Moreover, there is no evidence whatsoever that fibrates reduce CHD risk in patients who are already on statin therapy.
We conclude that there is little compelling evidence to support the widespread use of fibrate therapy for cardiovascular risk reduction in type 2 diabetes. Statin therapy must remain first choice therapy more or less regardless of serum triglyceride concentration unless there is a clear risk of pancreatitis.
References
1. Home P, Mant J, Diaz J, Turner C, Guideline Development Group. Management of type 2 diabetes: summary of updated NICE guidance. BMJ 2008;336:1306-8.
2. Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease-a pooled meta- analysis of long-term randomized placebo-controlled clinical trials. Am Heart J. 2007;154:943-53.
3. Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ et al. Diabetes, plasma insulin, and cardiovascular disease - Subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med 2002;162:2597-604.
4. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
5. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;292:2585-90.
Competing interests: NS has given lectures and participated on advisory boards for all drug companies producing both statins and fibrates
Competing interests: No competing interests
The advice on control of blood lipids contains a few potentially misleading erroneous statements.
The statement "if serum cholesterol is still below the target on further review" should read "is still above the target" as the target cholesterol is defined as a total cholesterol of less than four (< 4.0 mmol/L) (see full version of guidance, recommendations 80 and 81).
The stated high-density lipoprotein cholesterol target of equal to or less than 1.4 mmol/L is misleading as this may be read as an aim to achieve low values whereas in general higher values are of greater benefit as this lipoprotein is cardioprotective.
When triglyceride levels are in the range 2.3 to 4.5 mmol/L despite statin treatment, fibrate therapy should be considered in addition to statin therapy rather than as monotherapy. The statin and fibrate combination should be used with caution because of the increased risk of serious muscle toxicity (see British National Formulary under Fibrates and under Lipid-regulating drugs for Committee on Safety of Medicines advice on muscle effects). Gemfibrozil with statins must be avoided because of the high risk of rhabdomyolysis with this combination.
Competing interests: None declared
Competing interests: No competing interests
Having read the article ‘Management of type 2 Diabetes: updated NICE guidelines1’ we feel it is important to highlight recent NICE guidelines of Diabetes in Pregnancy2.
As the article states the prevalence of Type 2 diabetes is rising rapidly1 which includes a proportion of women at child bearing age. The recent NICE guideline states that 0.1% of all pregnancies are complicated by Type 2 diabetes which equates to 6500 births a year2.
Women with Type 2 diabetes have the same pregnancy risks as women with type 1 diabetes3 which include stillbirth (five fold increase), neonatal death (three fold), major congenital anomaly (two fold), macrosomia (>4.5kg) and related birth trauma2,3.
All healthcare professional should advise women with type 2 diabetes the importance of avoiding unplanned pregnancies with a particular emphasis on need for proactive preconception glycaemic control and high dose folic acid supplementation (5mg/day).
We feel this article missed an ideal opportunity to inform the readers of this major part of a women’s care with type 2 diabetes.
1 National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes (update) (Clinical guideline 66.) London: NICE, May 2008. http://www.nice.org.uk/nicemedia/pdf/CG66NICEGuideline.pdf
2 National Institute for Health and Clinical Excellence. Diabetes in Pregnancy (clinical guideline (CG63) London: NICE: March 2008. http://www.nice.org.uk/nicemedia/pdf/CG063Guidance.pdf
3 Confidential Enquiry into Maternal and Child Health (CEMACH). Pregnancy in women with type 1 and type 2 diabetes in 2002-2003, England, Wales and Northern Ireland. London; RCOG Press; 2005. www.cemach.org.uk
Competing interests: None declared
Competing interests: No competing interests
The NICE team have missed an opportunity to rectify the dietary advice given to diabetics. The usual "healthy eating" advice is to be continued on the premise that what is considered good for non diabetics applies to diabetics too.
Since type two diabetics do not have a normal first phase insulin response and type ones have no worthwhile insulin response at all, how can it be correct to assume that a typical "healthy" high carbohydrate, low protein, low fat diet is what is needed for diabetics?
The current SIGN 55 diabetes guideline has the same recommendation. This was based on the paper "Technical Review:Recommendations for the nutritional management of patients with diabetes mellitus" by TKK Ha and MEJ Lean. Many people may be surprised to learn that in this paper there is no discussion on how a person with insulin resistance or a failing or absent insulin response can handle dietary carbohydrate effectively.
Instead, the sum of evidence presented for a high carbohydrate diet amounts to the assertions that some people don't feel satisfied unless a meal contains a substantial amount of carbohydrate (Tremblay); it has been shown in one study that you can eat more calories from carbohydrate than from fat/protein and not put on weight, ie there is a metabolic advantage from eating carbohydrate (Prewitt); and that a variable carbohydrate/monounsaturated fat diet gives good blood sugar control (Unreferenced).
In this very issue of the BMJ the question, "Should we use large scale healthcare interventions without clear evidence that benefits outweigh costs and harms?" is debated by Crump and Landefeld.
Landefeld says, " When a large scale intervention is implemented without compelling evidence, wishful thinking may replace careful evaluation, and an unproved innovation may become an enduring but possibly harmful standard of care."
It must be remembered that diabetes is a disease of carbohydrate intolerance and the earlier dietary regimes in place were restricted carbohydrate diets.
This is a quote from the first page of Dr Lawrence’s “The Diabetic ABC : A Practical Book for Patients and Nurses” published in 1929.
“Starchy foods such as flour, bread and potatoes become sugar when digested and behave exactly like sugar itself in the body. The diabetic unfortunately cannot use and burn sugar and starch properly, and his illness arises from this. When such foods are eaten, sugar is not burned normally but accumulates in the body. It overflows and is wasted in the urine, making the patient weak, poisoning him and producing symptoms of illness....therefore the first step in treatment is to restrict the sugar producing foods, the carbohydrates, and the amount and kind of protein and fat eaten must be considered.”
What is the compelling evidence that overturned this sensible advice?
Poor glycaemic and metabolic control remain the cause of most complications and premature death for diabetics and these are worsened by a higher carbohydrate diet. Normal blood sugars and elimination of metabolic syndrome markers can only be achieved by a return to older dietary methods coupled with newer monitoring and medication regimes.
References:
1. Management of Diabetes
SIGN Publication No. 55
ISBN 1899893 82 2
Published November 2001
http://www.sign.ac.uk/guidelines/fulltext/55/index.html
2. Technical Review
Recommendations for the nutritional management of patients
with diabetes mellitus
TKK Ha and MEJ Lean
European Journal of Clinical Nutrition (1998) 52, 467± 481
ß 1998 Stockton Press.
3. Should we use large scale healthcare interventions without clear
evidence that benefits outweigh costs and harms?
Bernard Crump, Seth Landefeld and colleagues.
BMJ 7th June 2008 volume 336 p 1276-1277
4. Dr Lawrence’s “The Diabetic ABC : A Practical Book for Patients and Nurses” published in 1929.
5. Review Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal Anthony Accurso et al Nutrition & Metabolism 2008, 5:9doi:10.1186/1743-7075-5-9
Competing interests: None declared
Competing interests: No competing interests
Re: Blood lipid control
The advice on control of blood lipids contains a few potentially misleading erroneous statements.
The statement "if serum cholesterol is still below the target on further review" should read "is still above the target" as the target cholesterol is defined as a total cholesterol of less than four (< 4.0 mmol/L) (see full version of guidance, recommendations 80 and 81).
The stated high-density lipoprotein cholesterol target of equal to or less than 1.4 mmol/L is misleading as this may be read as an aim to achieve low values whereas in general higher values are of greater benefit as this lipoprotein is cardioprotective.
When triglyceride levels are in the range 2.3 to 4.5 mmol/L despite statin treatment, fibrate therapy should be considered in addition to statin therapy rather than as monotherapy. The statin and fibrate combination should be used with caution because of the increased risk of serious muscle toxicity (see British National Formulary under Fibrates and under Lipid-regulating drugs for Committee on Safety of Medicines advice on muscle effects). Gemfibrozil with statins must be avoided because of the high risk of rhabdomyolysis with this combination."
We regret the error inserted into the manuscript by a sub-editor, and for which we take responsibility for not spotting. We think that in any case the context makes the correct meaning clear.
We set no target for HDL cholesterol. We do use HDL cholesterol to qualify the circumstances under which total cholesterol is still valid (ie when HDL cholesterol is not high). The GDG recognized the problem of using total cholesterol when HDL cholesterol is high, but, unlike in the USA where professionals and the general population have long used LDL cholesterol, total cholesterol has unfortunately remained the common currency of cholesterol estimation in the UK.
The GDG did consider adopting non-HDL cholesterol instead, but this was judged unfamiliar at present, and is anyway more problematic as a measure in people with diabetes than in the general population. The GDG were aware of increased risk of muscle toxicity (uncommon) with fibrates and statins in combination, and recommended the combination when indicated on assessment of benefit: risk. Gemfibrozil is little used in the UK, and the recommendations specifically suggest fenofibrate as choice. Guideline recommendations in general assume prescribers are familiar with prescribing recommendations in the BNF.
Competing interests: All authors were members of the Guideline Development Group for the NICE guideline (PH the clinical lead, JM the chair and CT the project manager). Institutions associated with PH have received funding from nearly all pharmaceutical and diagnostics companies in connection with his research, educational, consultation, and development activities.
Competing interests: No competing interests