Prevention and early detection of vascular complications of diabetes
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38922.650521.80 (Published 31 August 2006) Cite this as: BMJ 2006;333:475
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Marshall and Flyvberg reinforce the importance of tight control of
blood glucose levels to minimise the devastating complications of
diabetes(1). Appropriate use of hypoglycaemic agents is a key factor in
achieving this objective. Yet the UK spends less on hypoglycaemic
medication per diabetic patient than many other European countries, even
though it is much more expensive to treat the complications of long-term
poor glycaemic control.(2)
We examined trends in the amount and cost of diabetic medications and
monitoring equipment prescribed in England between 1991-2004. Data on all
community dispensed prescriptions for diabetes was obtained from the
Prescription Cost Analysis system (PCA), which compiles data for the
Department of Health. The number of prescriptions (medicines and
monitoring) rose from 7,613,000 (1991) to 24,325,640 (2004), more than a
300% increase. Total expenditure increased by 650%, from £68.5 million to
£448.6 million. Insulins were the biggest contributor to costs (£196.8
million), followed by monitoring equipment (£131.5 million) and then oral
medications (£120.3 million). Insulins accounted for over 60% of the cost
of drugs but comprised only 23% of total prescriptions. Metformin,
currently the most widely used anti-diabetic medication accounted for 40%
of prescriptions but comprised only 7% of the total medications bill.
Since 1991, the proportion of total prescribing accounted for by metformin
has doubled, whilst that for sulphonylureas has almost halved. In 2004
spending on glitazones (£50.6 million) was higher than on metformin (£22.6
million) or sulphonylureas (£40.1) million).
We found a sharp increase in prescribing expenditure on diabetes over
the last 14 years. Nevertheless, we are probably still spending less on
drugs for diabetes then our European counterparts. In the US, the more
costly glitazones are used at least twice as much as they are in the
UK.(3) Unfortunately, there is insufficient evidence to determine whether
our lower spending is due to differential prescribing habits, prevalence
patterns or other reasons. Nonetheless, healthcare planners need to
proactively provide more funding for treating diabetes, otherwise costs
due to the burden of complications will increase still further.
References
1. Marshall S, Flyvberg A. Prevention and early detection of vascular
complications of diabetes. BMJ 2006;333:475-80.
2. Jonsson B. CODE-2 advisory board. Revealing the cost of type II
diabetes in Europe. Diabetologica 2002;45:S5-12.
3. Wysowski D, Armstrong G, Governale L. Rapid increase in the use of
oral anti-diabetic drugs in the United States, 1990-2001. Diabetes Care
2003;26:1852-1855
Competing interests:
Professor Azeem Majeed is an Associate Director (Primary Care) for the Diabetes Research Network.
Competing interests: No competing interests
Marshall and Flyvbjerg state (Box 6) that patients should be referred
to a nephrology department, if possible, when GFR <60 ml/min/1.73 m2.
If implemented across the UK, this would completely overwhelm nephrology
departments while adding little or no value to the care of the great
majority of patients referred. Around 4.3% of the adult population has a
GFR between 30 and 60 ml/min/1.73 m2 [1]; the great majority of these
people will never develop established renal failure [2], nor will they
have complications of kidney disease requiring specialist treatment. UK
guidelines for the identification, management and referral of chronic
kidney disease in adults have recently been developed by a
multiprofessional group including representatives from Diabetes UK [3],
and are available online at http://www.renal.org/eGFR/eguide.html. Their
use is endorsed by the National Service Framework for Renal Services [4].
These suggest that diabetic patients with stage 3 Chronic Kidney Disease
(estimated GFR 30-59 ml/min/1.73 m2) require referral only if additional
conditions apply, including renal osteodystrophy, renal anaemia, or
suspected atherosclerotic renal artery stenosis; haematuria; and worsening
clinical proteinuria in the absence of diabetic retinopathy.
Late referral of patients requiring renal replacement therapy is
harmful, and around 1 in 5 of diabetic patients starting RRT in the UK is
referred with less than 4 months of the start of RRT [5]. It is critically
important that such patients are seen coming and referred in a timely
manner. However, referring all patients with reduced GFR is not the right
way to achieve this.
1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of
chronic kidney disease and decreased kidney function in the adult US
population: Third National Health and Nutrition Examination Survey. Am J
Kidney Dis 2003;41(1):1-12.
2. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal
follow-up and outcomes among a population with chronic kidney disease in a
large managed care organization. Arch Intern Med 2004;164(6):659-63.
3. Joint Specialty Committee for Renal disease of the Royal College of
Physicians of London and the Renal Association. Chronic kidney disease in
adults: UK guidelines for Identification, Management, and Referral: Royal
College of Physicians of London, 2006.
4. Department of Health. National Service Framework for Renal Services.
Part Two: Chronic Kidney Disease, Acute Renal Failure, and End of Life
Care. London: Department of Health, 2005:1-30.
5. Ansell D, Feest T, Rao R, Williams A, Winearls CG (eds). The Renal
Association UK Renal Registry: The Eighth Annual Report, 2005.
Competing interests:
None declared
Competing interests: No competing interests
In
Drs. Marshall and Flyvbjerg’s review of diabetes treatment1 one of
their major points was pharmaceutical lowering of
blood lipids. No doubt statin treatment may reduce the risk of
cardiovascular disease in diabetic patients, but the
absolute effect is small; in secondary prevention less than
6 % and in primary prevention less than 2 %.2 Crucial is also
that no significant effect has been seen on total mortality and the question is
therefore if the small reduction of
non-fatal events is sufficient to balance the risks of side effects. Of
particular interest for diabetic patients is peripheral neuropathy.
According to a large population study the odds ratio for that risk in
patients treated with statins for longer than two years was 26.4 (17.8-45.4).3
Other researchers found polyneuropathy in five of 50 cardiology clinic patients
after 28 months of statin treatment.4 Most likely the risk is larger
in diabetic patients and such symptoms may be seen as a complication to the
primary disease and not to the treatment preventing their alleviation by
discontinuation of the drug.
The authors also stressed the importance of reducing
total and LDL-cholesterol below a certain level. This advice is not supported by
scientific evidence. Several studies have shown that high cholesterol is not a
risk factor in diabetic patients,5-7 and no statin trial has shown
association between baseline total or LDL-cholesterol, or between individual
degree of cholesterol lowering, and outcome8 indicating that the
benefit from the statins has nothing to do with cholesterol lowering. To govern
statin treatment by its effect on the blood lipids is therefore meaningless.
Also
surprising is that the authors´ only dietary advice was to “eat healthily”
referring to a multifactorial trial that included a low-fat diet ignoring the
promising results from a steadily increasing number of succesful, controlled
low-carbohydrate trials. A general finding from these experiments is that a
low-carb diet is more effective for weight reduction than a low-fat diet,9-10
most of all in overweight patients with decreased insulin sensitivity.11
A reduction of dietary carbohydrates also leads to a substantial lowering of HbA1c and improvement of insulin sensitivity.9-12
As a consequence many patients with type 2 diabetes were able to stop or reduce
their antidiabetic treatment. Most interesting is that in spite of high intakes
of saturated fat no adverse effects on serum lipids were seen. On the contrary
HDL-cholesterol increased in some of the trials and in all of them triglycerides
went down substantially.
A common argument against the lowcarb diet is that we
have not yet tested its effect on hard end-points in long-term, unifactorial
trials. True, but the lowfat diets have been tested that way and have failed.13
Considering the many short-term benefits on important risk factors a lowcarb
diet appears at least as a promising alternative when other treatments have
failed.
- Marshall SM, Flyvbjerg A. Prevention
and early detection of vascular complications of diabetes. BMJ
2006;333:475-80. - Costa J, Borges M, David C, Vaz Carneiro A. Efficacy
of lipid lowering drug treatment for diabetic and non-diabetic patients:
meta-analysis of randomised controlled trials. BMJ
2006;332:1115-24. - Gaist
D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH.
Statins and risk of polyneuropathy: a case-control study. Neurology
2002;58:1333-7. - Langsjoen PH, Langsjoen JO, Langsjoen AM, Lucas LA.
Treatment of statin adverse effects with supplemental Coenzyme Q10 and
statin drug discontinuation. BioFactors 2005;25:147–52. - Fontbonne A, Eschwege E, Cambien F, Richard JL,
Ducimetiere P, Thibult N et al. Hypertriglyceridaemia as a risk factor of coronary heart disease
mortality in subjects with impaired glucose tolerance or diabetes. Results
from the 11-year follow-up of the Paris Prospective Study. Diabetologia
1989;32:300-4. - Laakso M, Lehto S, Penttila I, Pyorala K. Lipids
and lipoproteins predicting coronary heart disease mortality and morbidity
in patients with non-insulin-dependent diabetes. Circulation
1993;88:1421-30. - Liu J,
Sempos C, Donahue RP, Dorn J, Trevisan M, Grundy SM. Joint
distribution of non-HDL and LDL cholesterol and coronary heart disease risk
prediction among individuals with and without diabetes. Diabetes
Care
2005;28:1916-21. - Ravnskov U. Is atherosclerosis caused by high
cholesterol? QJM2002; 95: 397-403. - Arora SK,
McFarlane SI. The
case for low carbohydrate diets in diabetes management. Nutr
Metab 2005;2:16-24. - Yancy WS Jr, Foy M, Chalecki AM,
Vernon MC, Westman EC. A low-carbohydrate, ketogenic diet to treat type 2
diabetes. Nutr Metab 2005;2:34-40. - Cornier
MA, Donahoo WT, Pereira R, Gurevich I, Westergren R, Enerback S et al.
Insulin sensitivity determines the effectiveness of dietary macronutrient
composition on weight loss in obese women.
Obes Res 2005;13:703-9. - Gannon MC, Nuttall FQ. Control
of blood glucose in type 2 diabetes without weight loss by modification of
diet composition. Nutr
Metab 2006;3:16-23. - Ravnskov U. The questionable role of saturated and
polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998;51:443-60.
Competing interests:
None declared
Competing interests: No competing interests
Hypertension in a critical determinant of the development and
progression of both the macrovascular and microvascular complications of
diabetes. Importantly, hypertension is common in the setting of insulin
resistance; 70% of patients with type 2 diabetes have a blood pressure
greater than or equal to 140/90 mmHg. Multiple clinical trials have
demonstrated a close correlation between blood pressure and cardiovascular
events and mortality, development and progression of nephropathy, and
progression of retinopathy and development of blindness. For example, in
the United Kingdom Prospective Diabetes Study (UKPDS), every 10 mmHg
decrease in mean systolic pressure was associated with reduced risk by 12%
for any diabetic complication, 15% for diabetes-related deaths, 11% for
myocardial infarction, 13% for macrovascular complications, and a no risk
threshold was found for any end-point studies [1]. In addition,
hypertension exacerbates diabetic cardiomyopathy, enhancing the
progression to heart failure, which occurs commonly in patients with
diabetes. Because of these pathophysiological relationships to renal and
cardiovascular disease, hypertension increases mortality in diabetes by 4
–5 fold.
1. Adler, A.I., et al., Association of systolic blood pressure with
macrovascular and microvascular complications of type 2 diabetes (UKPDS
36): prospective observational study. Bmj, 2000. 321(7258): p. 412-9.
Competing interests:
None declared
Competing interests: No competing interests
With regard to the outstanding clinical review by Marshall and
Flyvbjerg1, we would like to highlight an option to consider in the
management of patients with diabetes with Peripheral Artery Disease. Some
indications exist on the potential effectiveness of iloprost, a synthetic
prostacyclin analog with potent anti-aggregating and vasodilatory
properties, and able to modulate damage from ischemia-reperfusion 2.
Iloprost reduced rest pain, improved claudication and ulcer healing in 40-
60% of Peripheral Artery Disease, including Diabetic patients, and delayed
amputation in the majority of responding individuals3. Dubois and
colleagues 4 reported that in responders group, at 6 months, 96.5%
patients were alive without amputation compared to only 37% among non
responders. At one year, 79.3% of the responders and 31.4% of the non
responders were alive without amputation. The effects of iloprost on to
prevent vascular damage has been reported by Shindo et al5 that
demonstrated as iloprost reduced the urinary albumin excretion rate, the
urinary albumin-creatinine ratio and N-acetyl-beta-D-glucosaminidase
without decreasing creatinine clearance during the treatment period until
two weeks after.
Though not conclusive, these data seem to us of interest and iloprost an
additional, safe and effective therapeutic in Diabetic patients with
peripheral artery disease that merits to be systematically studied in this
setting.
Antonino Mazzone, M.D.
Department of Internal Medicine,
Hospital of Legnano, Italy
medicina2legnano@ao-legnano.it
1. Marshall SM,Flyvbjerg A. Prevention and early detection of
vascular complications of diabetes.BMJ 2006;333:475-480.
2. de Donato G, Gussoni G, de Donato G. Mazzone A et al. The ILAILL study:
iloprost as adjuvant to surgery for acute ischemia of lower limbs. A
randomized, placebo-controlled double-blind study by the Italian Society
for Vascular and Endovascular Surgery. Ann Surg 2006; 244: 185-93
3. Grant SM, Goa KL Iloprost. A review of its pharmacodynamic properties,
and therapeutics potential in peripheral vascular disease myocardial
ischaemia and extraxorporeal circulation procedures. Drugs 2002;889-924.
4. Dubois S, Cailleux N, Benosman B, Levesque H. Tolerance of
iloprost and results of treatment of chronic severe lower limb ischaemia
in diabetic patients.A retrospective study of 64 consecutive cases.
Diabetes Metab 2003 29;36-43.
5. Shindo H, Tawata M, Yokomori N, Hosaka Y, Ohtaka M, Onaya T. Iloprost
decreases urinary albumin excretion rate in patients with diabetic
nephropathy. Diabetes Res Clin Pract 1993:21;115-22.
Competing interests:
None declared
Competing interests: No competing interests
Glucotoxicity and lipotoxicity result in endothelial dysfunction
(microangiopathy) manifested as Retinopathy Nephropathy and Neuropathy.
Retinopathy is detected by fundoscopy.
Nephropathy is detected by checking for microalbuminuria if dipstick for
protein is negative. As it can be episodic, 2 out of 3 tests have to be
positive.
Neuropathy is detected by checking with monofilament and tuning fork.Feet
pulses if present, we can assume that there is no significant
macrovascular disease.
If glycaemic control is satisfactory, lipid profile is
satisfactory(TChol/HDL ratio <_4 then="then" no="no" statin="statin" is="is" necessary.="necessary." p="p"/>If there is microangiopathy then an Ace-inhibitor or Angiotensin receptor
blocker should be given +/-Aspirin.
Target BP for uncomplicated diabetes is 140/80. In presence of
nephropathy, it should be 130/70.
Exercise is very important as it helps to take insulin to all parts of the
body. Disabled patients can perform upper body exercise. Where adequate
glycaemic control cannot be achieved, then other factors like BP lipids
etc are treated.
Early diagnosis is essential and impaired glucose tolerance should also be
corrected by lifestyle changes.
Competing interests:
None declared
Competing interests: No competing interests
Editor
Marshall & Flyvbjerg's clinical review (reference 1) completely
overlooks the fallacy and gives some contradictory information about
measuring the ankle-brachial pressure ratio (ABPR) in diabetics. It also
portrays an over-simplistic and unrealistic picture of a vexed issue of
dealing with peripheral arterial disease assessment in diabetics.
Firstly, 10-15% diabetics may have falsely elevated ABPR (reference
2)due to early calcification of the tunica media that renders the arteries
incompressible. One should not solely rely on this as an objective
assessment criteria. To overcome this problem pole-test (reference 3)is
more accurate. The arteries of the foot and toes are relatively spared in
diabetes. Therefore other tests like toe-pressure index, analysis of
doppler wave-form, pulse volume analysis and transcutaneous oxygen
measurements are far better but these can rarely be performed outside the
specilaist clinics.
Secondly, for practical reasons if one wants to measure ABPR in
diabetics to assess arterial insufficiency or ischaemia, it should be
measured at peroneal artery rather than posterior tibial or dorsalis pedis
as mentioned in the clinical review. Peroneal artery in the leg is also
relatively spared from calcification and thus offers the best available
option (reference 3).
Thirdly, the review very briefly mentions about identifying the four
"classic" risk factors for developing diabetic foot problem but it is
often not that straight forward. These so-called "classic" factors often
blur the picture rather than making it more obvious.Whereas symptoms like
pain in foot or leg while resting or during sleep indicate critical
ischaemia in non-diabetics, diabetics have a higher incidence of nocturnal
muscle cramping which is not due to arterial insufficiency at all.
Assessment of pulse in oedematous, ulcerated foot may not be possible and
infection of foot ulcers due to neuropathy often masks the sutle signs of
arterial insufficiency e.g. skin colour changes associated with elevation
or lowering of the foot.
I agree with the authors' very brief remark that early referral to a
specialist multidisciplinary team is essential in order to reduce
complications like amputation. We need to look at the interplay of all
contributing factors carefully rather than simply relying on just one
magic test or pressure-readings in diabetics.
1.Marshall SM, Flyvbjerg A. Prevention and early detection of
vascular complications of diabetes (clinical review).BMJ 2006;333:475-
80.(2 September.)
2.Weitz JI,Byrne J, Clagett GP, et al. Diagnosis and treatment of
chronic arterial insufficiency of lower extremities: a critical review.
Circulation 1996;94:3026-49.
3. Boulton AJM, Connor H,Cavanagh PR (Editors). The foot in diabetes
(3rd edition, 219). John Wiley & Sons Ltd.
4. Raines JK, Darling RG, Buth J, et al. Vascular laboratory criteria
for the management of peripheral vascular disease of the lower
extremities. Surgery 1976;79:21.
Competing interests:
None declared
Competing interests: No competing interests
This review of the prevention of vascular complications of diabetes
contributes to the volume of slightly differing guidelines around best
management of diabetes. Aside from whether it added anything to the range
of international guidance available, it was most notable in its
uncompromisingly didactic recommendations; challenging targets for blood
pressure and blood glucose control were suggested and bold statements were
made about the use of statins in every patient with diabetes who is over
40. No doubt as diabetic specialists this makes sense; as a GP who treats
patients who have diabetes, perhaps amongst many conditions, it left me no
further forward.
What should a patient with diabetes chose to do, especially if they
are more concerned about their low mood or painful knee? What degree of
benefit would they expect (number needed to treat in other words)? How can
I, as their advisor, outline the benefits and harms when they complain
about polypharmacy ("not another pill doctor")?
A better use of the authors time might have been to translate current
recommendations into useable advice to counsel patients so that they can
actively participate in shared decisions; this is especially so with a
long term condition such as diabetes where we only pay such a fleeting
part in the patients life and only they can decide on a gloomy Saturday
evening whether to take that cholesterol tablet or not.
Competing interests:
None declared
Competing interests: No competing interests
People suffering from diabetes are commonly instructed to consume a
diet high in carbohydrates, particularly starches, and to reduce fat
intake.
All carbohydrates are converted to blood glucose although some at a
slower rate than others.
It follows that, for insulin users a high carbohydrate diet will
necessitate a higher insulin dose.
Absorption of subcutaneous insulin shows considerable intra -
individual variation.1
Larger insulin doses may therefore result in more unstable control in
terms of hypo and hyperglycaemia.
Reducing dietary carbohydrate may therefore be a feasible means of
improving control without the disadvantage of more frequent or severe
hypoglycaemia. Blood glucose levels may become more predictable with less
postprandial hyperglycaemia.
Fears that lipid profile may deteriorate as additional fat is
substituted to maintain caloric intake, may be unfounded as the relatively
minor contribution of fats to blood lipids may be offset by the benefits
of improved glycaemic control on the lipid profile. If lipids are a
concern then the intake of saturated fat could be kept low and mono-
unsaturated fat consumed in its place.
A small study of a low carbohydrate diet( 70 to 90 g per day) in type
1 patients, demonstrated a reduction in HbA1c of 1.1 percent, reduction in
frequency of hypos, no increase in total cholesterol or deleterious effect
on HDLc, and a reduction in triglycerides.2
An American Physician with type 1 diabetes himself, of longstanding
duration, treats himself and his patients with a very low carbohydrate
diet, and attains normoglycaemia around the clock together with a healthy
lipid profile and absence of severe hypoglycaemia.3
His approach takes self denial to new extremes and flouts all the
conventional wisdom about diet, but it works for him and his patients.
A mor realistic approach for those who enjoy fruit and a few grains
would be perhaps to reduce carbs to around 30 to 40 percent of caloric
intake as opposed to 45 to 60 percent.
I have reduced my HbA1c from 7.6 percent to 6.5 percent by such an
approach.Total cholesterol has reduced from 4.1 to 3.6 mmol/L with a total
cholesterol: HDLc of 2.5 and triglycerides < 1mmol/L
When will we begin to tailor dietary advice to the individual in
order to truly optimize health rather than try to enforce a rather rigid
set of guidelines which in some cases may not benefit the patient and may
in fact worsen their health and quality of life. The reasons given for not
following a lower carbohydrate diet are usually side effects of poor
glycaemic control ( lack of energy, keto acidosis, kidney disease and poor
lipids) or high insulin doses ( severe hypoglycaemia) rather than results
of following such a diet.
1.Heineman.L. Diabetes Technol.Ther. 2002 4(5) 673-82
2. Nielssen JV. Jonsson E. Ivansson A. Low Carbohydrate Diet in Type
1 Diabetes. Clinical Experiment. A Brief Report. Ups.J.Med Sci. 2005 110
(3) 267-73
3.Richard K Bernstein, M.D. Dr Bernstein's Diabetes Solution. The
Complete Guide to Achieving Normal Blood Sugars. 2003
Competing interests:
Person with type 1 diabetes
Competing interests: No competing interests
Personalized Portions are the Key to Vascular Damage Prevention
It should be of interest that I am a Type 2 diabetic, who is in his
9th year of controlling his diabetes by diet alone, while staying free
from any evident complications. This dieting is done principally by
limiting my intake of all food, and food combinations, to the weight that
can be eaten without my postprandial blood glucose rising to levels where
macrovascular and microvascular body damage cause (or aggravate any
existing macrovascular) complications. Namely <10.0 mmol/l, and 9.0
mmol/l or below most of the time. At the same time I follow ADA and
Diabetes UK's nutrient guideline limits for carbohydrate, individual fats,
etc, so am not 'cheating' by low-carbing. The research has shown that
each individual has their own scale of such limiting food weights,
according to their diabetic severity and personal characteristics, and
that their scale can be readily determined. This OptimumCarbDiet is
available as a complete lifestyle change package on a CD called
DietControlDiabetes, which includes ‘body fitness’ plus highly
comprehensive supporting educational coverage of the subject. More
details on http://www.optimumcarbdiet.com/index.htm where there is an
interesting diagram comparing different diets.
Considerable effort is going into screening people for Type 2
diabetes, but there is no approach for significantly delaying their
progression once they are identified. DietControlDiabetes provides that
approach. The author, who is a scientist with a PhD, and whose wife is a
retired General Practitioner, believes the time is long overdue for the
medical profession to start taking seriously the findings of its better
qualified (albeit non-medical) patients.
Competing interests:
The DietControlDiabetes CD is sold for £29.50 (plus VAT for some), because there is no external source of funding.
Competing interests: No competing interests