Management of hyperglycaemia in type 2 diabetes: the end of recurrent failure?
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.39022.462546.80 (Published 07 December 2006) Cite this as: BMJ 2006;333:1200
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The type 2 diabetes T2DM review by Heine, Nathan et as has notable
omissions:
Prevention comes before treatment. Overweight (adult BMI above
23kg/sqm, or body fat mass above about 15kg) precedes type 2 diabetes
T2DM by years. Few folk achieve the right balance of exercise, lean mass
and fat mass. In the non-obese, BMI is a poor guide to adiposity - and in
all long term studies (USA, UK, Dutch), future risk rises relentlessly
with youthful BMI above 22kg/sqm.
Metformin is the only proven drug which – titrated to tolerance -
stops or reverses lipidemia, thrombotic disease, insulin resistance, and
weight gain (metformin lowers obesity by about 8% - eg Glueck 2006).
The 20year UKPDS 1998 showed that metformin was associated with no
weight increase, and (as in the 5year Saskatchewan diabetic health
database –Johnson 2002) reduction in all-cause mortality including cancer
by almost 40%.
Modest doses of metformin for 3-4years in diabetes prevention
studies (USA -DPPRG 2002, India -Ramachandran 2006 and China- Y Wenying
2001) lowered incidence of new diabetes respectively by 31%, 33% and 70%.
No other synthetic drug heavily used long term- in primary chronic
prevention of all the major common degenerative diseases - safely achieves
what metformin does – psychotropes, statins, sulphonylureas, glitazones,
antihypertensives, oral sex hormones, nonsteroidal anti-inflammatories
etc. Intolerance to metformin is always relative: start with eg ¼ tab/day,
and build up slowly to just avoid nausea and diarrhoea. 3gm/day may be
well tolerated.
Before considering any newer anti-diabetic drugs - all of which have
no proven long term safety record, and major hazards eg silent
hypoglycemia, weight gain, cance, cardiovascular disease)- one should
minimize other major iatrogenic risks eg diuretics, cortisone,
psychotropes and oral sex hormones (OC, HT).
Thus, consider low dose co-amiloretic and low dose reserpine for
hypertension; 5-hydroxytryphan for depression; the Mirena for
contraception; and appropriate physiological human sexhormone replacement
with systemic testosterone, plus systemic estradiol for women.
This requires simply that from “middle age”, and in the overweight
from any age, a fasting sex hormone profile should be measured as
routinely as glucose, insulin, blood pressure and body composition
(height, weight, waist girth, and calculated if not measured body fat and
lean mass).
Competing interests:
None declared
Competing interests: No competing interests
I am slightly surprised to see that Heine and colleagues have not
mentioned the evidence of anti obesity agents in diabetes. As more than
80% of patients with type 2 diabetes are overweight or obese at
presentation,and most patients gain weight over a period of time on oral
therapy, agents that promote weight loss should be considered. There is
now good evidence that Rimonabant, a CB 1 receptor antagonist, can induce
weight loss and reduce HbA1c by 0.6% in type 2 diabetes (RIO - Diabetes
Study, Lancet, 2006). Similar results are avialable for Orlistat. One
would be inclined to think that such agents should have a role in
management of obese type 2 diabetes patients unable to lose weight on
metformin alone.
Competing interests:
None declared
Competing interests: No competing interests
The hemorheologic parameters need to be considered for evaluating
patients affected by type 2 diabetes because those variables contribute to
the development of their microangiopathy and ensuing complications (1, 2).
In this regard, recovering still unpublished preliminary results ethically
obtained in 25 diabetic patients (13 with microangiopathic skin lesions
and 12 without) and in 25 healthy controls, we characterized two models
using a linear discriminant analysis to determine which variables
discriminate between two or more naturally occurring groups (3):(a)
Discriminant function in Model 1 = 0.55 Aggregate Shape Parameter (ASP) –
0.60 Whole Blood Viscosity (WB Visc) 230 + 0.83 serum fibrinogen when
discriminating healthy individuals from diabetic patients with skin
lesions, and (b) Discriminant function in Model 2 = 6.303 ASP – 0.339 WB
Visc 230 + 0.010 serum fibrinogen when discriminating healthy controls
from diabetic patients with and without skin lesions. Both models were
validated through the coefficient of canonic correlation, the Mahalanobis
distance, the percentage of classification and the centroids of each
group(Model 1: 0,920, P <10-3, 100%, 0.90 and 5.59, respectively;
Model 2: 0,890, P <10-3, 86 %, -1.7, 1.7 and 2.2, respectively).In
line with the relevance of managing hyperglycaemia in type 2 diabetes
according to Heine et al., some authors reported an improvement in some
hemorheologic parameters when a strict glycaemic control was carried out
in type 2 diabetic patients (4). Furthermore, we estimate that both models
here characterized may be also helpful for their biochemical monitoring.
1. Le Devehat C, Vimeux M, Khodabandehlou T: Blood rheology in patients
with diabetes mellitus. Clinical Hemorheology and Microcirculation 2004;
30: 297-300
2. Marton Z, Kesmarky G, Vekasi J, Cser A, Russai R, Horbath B, Toth K:
Red blood cell aggregation measurements in whole blood and in fibrinogen
solutions by different methods. Clinical Hemorheology and Microcirculation
2001; 24: 75-83.
3. Altman D: Practical Statistics for medical Research Ed. Chapman &
Hall. London (UK), 1997
4. Babu N, Singh M: Influence of hyperglycemia on aggregation,
deformability and shape parameters of erythrocytes. Clinical Hemorheology
and Microcirculation 2004; 31: 273-80
Competing interests:
None declared
Competing interests: No competing interests
I was disappointed with Heine, et al's paper because it contained
nothing whatever to help diabetics. The reason for the "recurrent failure"
is that the population is advised to consume a dietary regime that causes
diabetes and when the disease becomes apparent, only the symptoms are
treated with drugs.
Reliance on drugs will never cure the disease; they actually worsen
the prognosis.
It is no secret that diabetes is a disease of carbohydrate
metabolism. We have known since 1935 that excess carbs are the cause of
Type-2 diabetes;[1] and more recent studies have shown that reducing
dietary carbs cures existing diabetes and prevents its occurrence.
In my experience, Type-2 diabetes is the easiest condition to
prevent; and it can be totally cured in as little as one day.
Despite this wealth of evidence, diabetics are still told by their
trained(?) advisers to eat foods that will raise their serum glucose
levels and are then prescribed drugs to reduce those levels to prevent
complications. Can someone please explain to me where the sense is in
that?
Why are patients not advised to reduce their intakes of foods rich in
cereals and/or sugars (including fruit)?
Incidentally, such a dietary strategy has also been shown to benefit
or even cure Type-1.[2] Beta cells in Type-1 diabetics can regenerate even
after 60 years from first diagnosis.[3] If the pancreas is relieved of the
constant pressure to lower excessive glucose levels from incorrect diet,
it can often cope so well with the low glucose levels found on a low-carb,
high-fat diet, that insulin injection can be discontinued.
References
1. Given H D C. A New Angle on Health. John Bale, Sons &
Danielsson Ltd. 1935.
2. Kwasniewski. J, Chylinski M. Homo Optimus. Wydawnictwo WGP,
Warsaw, 2000: 163-6.
3. Butler PC. Beta-Cells Regenerate Even In Type 1 Diabetes. ADA 57th
Scientific Sessions, June 2005.
Competing interests:
None declared
Competing interests: No competing interests
The Dutch call diabetes simply 'suikerziekte' meaning 'sugar
disease', a condition defined by high blood sugar levels. Glucose in the
mouth, glucose
out in the blood stream. Shouldn't all control of diabetes start by
focusing on the type and amount of blood sugar triggering foods? "The
[lifestyle and multiple drug] algorithm described here will probably not
slow down the clinical outcome of type 2 diabetes," bluntly conclude
Heine et al (1). The low(2) or 'slow' carb intake approach is not part of
their algorithm; it should be, we're talking 'suikerziekte'.
melchior.meijer{at}planet.nl
1. R J Heine, et al. Management of hyperglycaemia in type 2
diabetes:the end of recurrent failure? BMJ 2006;333:1200-4
2. Nielsen JV, Joensson E. Low-carbohydrate diet in type 2 diabetes.
Stable improvement of bodyweight and glycemic control during 22 months
follow-up. Nutr Metab (Lond). 2006 Jun 14;3:22. Medline 16774674
http://www.nutritionandmetabolism.com/content/pdf/1743-7075-3-22.pdf
Competing interests:
None declared
Competing interests: No competing interests
In reference to Heine and colleagues’ article on the management of
type 2 diabetes [1] Uffe Ravnskov summarises the research which supports
the use of low-carbohydrate diets in this respect [2]. Much of this
research focuses on the use of diets which have low ‘glycaemic index’
(GI). The GI is essentially a measure of the extent of sugar release from
a food. It is noteworthy that in a meta-analysis of intervention studies
comparing low- and high-GI diets, the lower-GI approach was, overall,
found to reduce HbA1c levels by 0.43 per cent points [3].
Perhaps an even more useful measure of the influence of diet on
glycaemia is what is known as the glycaemic load (GL) – calculated by
multiplying the GI by the amount of carbohydrate found in a standard
portion of food. Starchy carbohydrates such as bread, potatoes rice,
pasta and breakfast cereals turn out to have generally high glycaemic load
[4]. Yet, it is these very same foods that diabetics are usually
encouraged to have their fill of.
For instance, the website of Diabetes UK, the UK’s leading diabetes
charity, advises individuals to include starchy carbohydrates at each meal
[5]. In reference to this, the site adds: “The amount of carbohydrate you
eat is important to control your blood glucose levels”. The cryptic
message here seems to be that diabetics somehow require starchy
carbohydrates to maintain blood sugar control. But does logic not dictate
that the less carbohydrate one eats, the less disruption there will be in
blood glucose levels?
Starchy carbohydrates have been proven to have high GIs and the more
we eat of them, the greater the resultant glycaemia. Should we really be
encouraging individuals who have a fundamental problem with blood sugar
control to emphasise in the diet foods known to have considerable capacity
to raise blood sugar levels?! There is plenty of science which supports
the use of low-carb/GI/GL diets in the management of diabetes. But forget
the science for a moment – another reason why this approach has obvious
merit relates to the fact that it is based on common sense.
References:
1. R J Heine, et al. Management of hyperglycaemia in type 2 diabetes:
the end of recurrent failure? BMJ 2006;333:1200-4
2. Ravnsov U. Beware of the carbs! BMJ 8th December 2006 (rapid
response)
3. Brand-Miller J, et al. Low–glycemic index diets in the management
of diabetes: a meta-analysis of randomized controlled trials. Diabetes
Care 26:2261–2267, 2003
4. Kaye Foster-Powell, et al. Susanna International table of glycemic
index and glycemic load values: 2002 Am J Clin Nutr 2002;76:5-56.
Contact:
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir.
The focus upon glycaemic control which once dominated management of
T2 diabetes has been tempered since the relatively overwhelming
effectiveness of antihypertensive treatment has been more widely accepted.
In primary insulin-deficiency (T1) it is both logical and well-
established that accurate insulin replacement is effective, ..it is
worrying that this is quoted in a discussion of the wholly different
condition of primary insulin resistance..T2.
Although the breathless enthusiasm of the reviewers makes it hard to
be sure, would it be fair to say the only reliable information about the
outcomes produced by various treatments for T2 comes from the UKPDS..?
The UKPDS results clearly show that attempts to improve outcome thro'
intensive glycaemic control are ineffective.:
With intensive glycaemic control HgA1C could be reduced from 7.9% to
7.0%....but..
This had no significant effect on diabetes-related deaths, nor on all-
cause mortality, nor on vascular diseases.
In fact, the best outcomes in UKPDS were associated with use of
metformin, but its slight effect on HbA1c suggests this had little or
nothing to do with glycaemic control.
It would help debate if the authors could clarify any support for
their enthusiasm from outcome data, and explain why, in their conclusion,
they conflate antihypertensive treatment (uncontroversial), when their
paper was about glycaemic treatment(Contentious)?
The issue is of much more than academic interest, since there is a
vast potential market for glycaemic agents, and much NHS resource is
already consumed in attempts at glycaemic control...
1.McCormack J, Greenhalgh T. Seeing what you want to see in
randomised controlled trials: versions and perversions of UKPDS data. BMJ
2000;320:1720-1723.
2.UKPDS Group. Intensive blood glucose control with sulphonylureas or
insulin compared with conventional treatment and risk of complications in
patients with type 2 diabetes Lancet 1998;352:837-853.
Yours faithfully
David Leopold
Competing interests:
None declared
Competing interests: No competing interests
Editor
The recent article by Heine et al. on the management of
hyperglycaemia in type 2 diabetes provides a helpful clinical review of
existing pharmacological strategies (1).
The authors’ rightly suggest that the meglitinide and alpha-
glucosidase inhibitors drug classes are less widely prescribed presumably
because of lack of efficacy, cost, multiple daily dosing or due to
gastrointestinal side-effects (1). However, I wish to draw attention to
inaccuracies within Table 1 regarding licensed indications for existing
oral hypoglycaemic agents in the United Kingdom.
The British National Formulary clearly states that alpha-glucosidase
inhibitors and meglitinides are licensed for management of type 2
diabetes in the UK (2). In the case of acarbose, the drug may be used for
patients inadequately controlled by diet or by diet with oral antidiabetic
drugs (2). The meglitinides, nateglinide and repaglinide, are also
licensed in the UK for treatment of type 2 diabetes. The former may be
used in combination with metformin, whereas the latter is licensed as
monotherapy or with metformin when metformin alone is inadequate (2).
It is unclear whether the treatment algorithm in Figure 3 in respect
of the timing of introduction of the thiazolidinedione drug class in type
2 diabetes will be altered by the results of the recently published ADOPT
study (A Diabetes Outcome Progression Trial) (3). In this study the
authors examine the efficacy of thiazolidindiones as compared with other
glucose-lowering medications in maintaining long-term glycaemic control in
type 2 diabetes. Cumulative incidences of failure with monotherapy at 5
years were 15% with rosiglitazone, 21% with metformin and 34% with
glibenclamide for patients with recently diagnosed type 2 diabetes. An
accompanying Editorial in the New England Journal of Medicine by Dr Nathan
suggests that metformin will remain the first option when commencing
pharmacological therapy. I support this assertion; I also concur that
ultimately the choice between the glitazones and sulphonylurea drug
classes for add on therapy will depend on ‘the relative costs of these
medications, their profiles of adverse events, and their potential risks
and benefits’ (4).
1. Heine RJ, Diamant M, Mbanya JC, Nathan DM. Management of
Hyperglycaemia in type 2 diabetes. British Medical Journal 2006;333:1200-
4.
2. Joint Formulary Committee. British National Formulary. 51 ed. London:
British Medical Association and Royal Pharmaceutical Society of Great
Britain; 2006.
3. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al.
Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy.
N Engl J Med 2006;355(23):2427-2443.
4. Nathan DM. Thiazolidinediones for Initial Treatment of Type 2 Diabetes?
N Engl J Med 2006;355(23):2477-2480.
Competing interests:
None declared
Competing interests: No competing interests
Heine et al propose several important measures to improve glycemic
control, a major problem which looks like the Grail.1 However, acting on
the misrepresentation of the importance of changes in HbA1c is a missing
point
« Small » absolute change such as a 1% reduction in HbA1c is
associated with reductions in risk of 21% for deaths related to diabetes
and 37% for microvascular complications.2 However, the patient’s
misrepresentation of the importance of changes in HbA1c has been
demonstrated by changing the scale of the results.3
We think a new scale for HbA1c could improve the concern of both patients
and physicians for metabolic control: John would be more concerned by a
change from 790 IU to 750 UI than from 7,9% to 7,5% (0.4% absolute
change). More complex mathematical transformations may be even more
stimulating
References
1. Heine R J, Diamant M, Mbanya JC, Nathan DM. Management of
hyperglycaemia in type 2 diabetes: the end of recurrent failure? BMJ
2006;333:1200-1204
2. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia
with macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational study. BMJ. 2000;321:405–412.
3. Hanas R. Psychological impact of changing the scale of reported
HbA(1c) results affects metabolic control. Diabetes Care. 2002;25:2110-1.
Competing interests:
None declared
Competing interests: No competing interests
Lifestyle changes have great potential in the prevention and treatment of type 2 diabetes
EDITOR -In their clinical review on the management of hyperglycaemia in
type 2 diabetes Heine et al (1) conclude that despite the demonstrated
efficacy, evidence for the successful and durable lifestyle modification in
diabetes is lacking. The view is based on a recent Cochrane analysis, but this
approach may not be totally valid and fair to evaluate the impact of diet and
other lifestyles in the treatment of type 2 diabetes. This is because lifestyle
intervention trials are demanding to carry out due to the lack of expertise,
enthusiasm and financial support. The common concern has been that it is much
more difficult to get money for lifestyle interventions than for long-term drug
trials financed by big pharmaceutical companies. The success of lifestyle modification
is based on the changes achieved. If you are not able to change lifestyles of
your patients you can not expect any major effects, either. We see that a
Cochrane analysis or meta-analysis combining the data from lifestyle
intervention studies carried out with quite different management strategies
with regard to dietary and exercise counseling and follow-up measurements, may
result in too pessimistic view in terms of long-term benefit of lifestyle
changes in type 2 diabetes. It is of note that the
expert group of the Diabetes and Nutrition Study Group of the EASD has recently
given evidence-based nutritional approaches to the treatment and prevention of
diabetes. These emphasise the key role of diet therapy not only with regard to
the treatment and prevention oftype 2 diabetes but also the
prevention of atherosclerotic vascular complications (2).
Now, we have strong evidence that type 2 diabetes is
preventable by lifestyle changes (3). Even modest long-term weight reduction
(with qualitative changes in diet and increased physical activity) improves
insulin sensitivity in long-term and may halt the progressive decline in
insulin secretion in persons with IGT (4). When it comes to the known risk
factors and pathogenesis of type 2 diabetes, lifestyle changes are also “most
specific” approach among various treatment modalities.
We analysed the effect of lifestyle changes separately in
two hyperglycaemic groups in the Finnish Diabetes Prevention Study (3).
Lifestyle changes had a significant improvement in glycaemia irrespective of
baseline 2-h glucose level at OGTT (Table). Furthermore, during the 7-year
follow-up the risk of diabetes was similarly reduced in both intervention
subgroups formed by median 2-h glucose value. This is in line with the results
of our earlier controlled study with recently diagnosed type 2 diabetes; one
year after a 12 months intensified lifestyle intervention the intervention
group had 0.5 % unit lower HbA1c level than the control group did, and 55.3% in
the intervention vs. 31.8% of the control patients had HbA1c under 7.0%,
P=0.016. Furthermore, only 12.5% needed oral drugs in the intervention group
vs. 34.8% in the control group, P=0.0059 (5). Weight reduction and healthy diet
also modify different adipokines and inflammatory factors to the direction,
which may halt the progression of type 2 diabetes. Treatment should be started
as early as possible in the prediabetic phase, but lifestyles belong to the
treatment of type 2 diabetes at its all phases. Finally, weight reduction,
healthy diet and physical activity do not harm the diabetic patient as the
newer drugs may do, since the long-term safety of these drugs remains unknown.
We do agree with the authors than well-conducted lifestyle intervention studies
are urgently needed, but they are not possible without financial support,
multicentre approach and changes of our attitude as for how to value different
treatment modalities.
Matti Uusitupa
(1), Jaana Lindström (2), Markku Peltonen (2) and Jaakko Tuomilehto (3)
1 School of Public Health and Clinical Nutrition, Clinical
Nutrition,
Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention,
National Public Health Institute, Finland; 3 Department of Public Health,
University of Helsinki, Finland
Correspondence: Matti Uusitupamatti.uusitupa{at}uku.fi
1. Heine RJ, Diamant M, Mbanya J-C, Nathan DM. Management of
hyperglycaemia in type 2 diabetes. BMJ 2006;333;1200-04.
2. Mann JI, De Leeuw I, Hermansen K, Karamanos N, Riccardi
G, Karlaström B et al. Evidence-based nutritional approaches to the treatment
and prevention of diabetes mellitus. Nutr Metab Cardiovasc Dis 2004;14:373-94.
3. Lindström J,
Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemiö K et al. Sustained
reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up
of the Finnish Diabetes Prevention Study. Lancet 2006;368:1673-9.
4. Uusitupa M, Lindi V, Louheranta A, Salopuro T, Lindström
J, Tuomilehto J for the Finnish Diabetes Prevention Study Group. Long-term improvement in insulin sensitivity by changing lifestyles
of people with impaired glucose tolerance. 4-year results from the
Finnish Diabetes Prevention Study. Diabetes 2003;52:2532-8.
5. Uusitupa M, Laitinen J, Siitonen O, Vanninen E, Pyörälä
K. The maintenance ofimproved
metabolic control after intensified diet therapy in recent type 2 diabetes.
Diab Res Clin Pract 1993;19:227-38.
Table. Changes in body weight, 2h
glucose, and HbA1c from baseline to 1-year follow-up, and diabetes incidence by
treatment group and baseline 2h glucose at baseline in the Finnish Diabetes
Prevention Study (DPS).
Baseline 2h glucose (by median)
<8.7 mmol/l
>8.7 mmol/l
Control
Intervention
Control
Intervention
Number of
subjects
129
132
128
133
Body weight, kg:
Baseline
84.3
84.9
87.2
88.4
Year 1
83.4
80.3
86.1
84.1
Change:
-0.9
-4.6
-1.0
-4.3
Difference in
change (95% CI)
3.7 (2.7-4.7)
3.3 (2.1-4.5)
p-value for
equal change
<_0.001o:p xmlns:_0.001o="urn:x-prefix:_0.001o"/>
<_0.001o:p xmlns:_0.001o="urn:x-prefix:_0.001o"/>
2h glucose, mmol/l:
Baseline
7.7
7.7
10.1
10.1
Year 1
8.0
7.4
9.2
8.6
Change:
0.25
-0.28
-0.86
-1.45
Difference in
change(95% CI)
0.53 (0.08-0.98)
0.59 (0.05-1.13)
p-value for
equal change
0.022
0.031
HbA1c, %:
Baseline
5.6
5.6
5.6
5.7
Year 1
5.6
5.4
5.8
5.6
Change:
-0.00
-0.15
0.12
-0.13
Difference in
change (95% CI)
0.15 (0.01-0.29)
0.24 (0.06-0.42)
p-value for
equal change
0.039
0.008
Incidence of diabetes during 7-year
follow-up:
Rate per 100
person-years
5.0
3.0
10.3
5.9
Hazard ratio
0.58 (0.36-0.94)
0.55 (0.38-0.79)
p
0.027
0.001
Competing interests:
None declared
Competing interests: EDITOR