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Metabolic and cardiovascular effects of very-low-calorie diet therapy in obese patients with type 2 diabetes in secondary failure: outcomes after 1year
VLCD therapy in obese patients with diabetes in secondary failure P. Dhindsa et al. Metabolic and cardiovascular effects of very-low-calorie diet therapy in obese patients with Type 2 diabetes in secondary failure: outcomes after 1 year Abstract
School of Medical & Surgical Sciences, University of
To evaluate the short-term and 1-year outcomes of an intensive very-low-
Nottingham, and Jenny O'Neil Diabetes Centre,
calorie diet (VLCD) on metabolic and cardiovascular variables in obese patients
Southern Derbyshire Acute Hospitals, NHS Trust,
with Type 2 diabetes (T2DM) and symptomatic hyperglycaemia despite combi-
nation oral anti-diabetic therapy ± insulin, and to assess patient acceptability
and the feasibility of administering VLCD treatment to this subgroup of patientsin a routine practice setting.
Forty obese patients with T2DM (22 M, mean age 52 years, body
mass index (BMI) 40 kg /m2, duration of T2DM 6.1 years) and symptomatic hyper-glycaemia despite combination oral therapy (n = 26) or insulin + metformin(n = 14) received 8 weeks of VLCD therapy (750 kcal /day) followed by standarddiet and exercise advice at 2-3-month intervals up to 1 year. Insulin was dis-continued at the start of the VLCD, and anti-diabetic therapy was adjusted indi-vidually throughout the study, including (re)commencement of insulin as required.
Immediate improvements in symptoms and early weight loss reinforced
good compliance and patient satisfaction. After 8 weeks of VLCD, body weightand BMI had fallen significantly: 119 ± 19-107 ± 18 kg and 40.6-36.6 kg/m2,respectively, with favourable reductions in serum total cholesterol (5.9- 4.9 mM),blood pressure (10/6 mmHg) and fructosamine (386 ± 73-346 ± 49 µM) (equatesto an HbA reduction of approximately 1%). Sustained improvements were
evident after 1 year, with minimal weight regain, e.g. mean body weight 109 ± 18 kgand BMI 37 ± 4 kg/m2. Glycaemic control tended to deteriorate after 1 year. Conclusions
The absence of a control group is a major limitation, but the results
indicate that 8 weeks of VLCD treatment may be effective and well tolerated insymptomatic obese patients with T2DM in secondary failure, producing sus-tained cardiovascular and metabolic improvements after 1 year. VLCD therapyis a treatment option that deserves greater consideration in this difficult-to-treatpatient population. Keywords
VLCD, secondary failure, obesity, Type 2 diabetes, hyperglycaemic
combination oral anti-diabetic therapy can be particularly
Introduction
difficult. Few, if any, therapeutic strategies optimally achieve
The clinical management of obese patients with Type 2
the desired outcomes of promoting weight loss and improving
diabetes (T2DM) and symptomatic hyperglycaemia despite
glycaemic control. Energy restriction and weight reductionhave independent, additive effects on metabolic and cardiovas-cular function [1]; for example, projections based on observa-
Correspondence to: Professor Richard Donnelly MD, PhD, FRCP, FRACP,
tional data suggest that a sustained 10-kg weight loss would
University of Nottingham Division of Vascular Medicine, Derbyshire Royal Infirmary, Derby DE1 2QY, UK. E-mail: Richard.donnelly@nottingham.ac.uk
result in a 15% reduction in HbA , 10-20 mmHg fall in blood
2003 Diabetes UK. Diabetic Medicine, 20, 319 - 324
VLCD therapy in obese patients with diabetes in secondary failure • P. Dhindsa et al.
pressure (BP) and a 20-25% reduction in total mortality
750 calories and 50 g of protein per day. Patients were also
[2,3], but aggressive weight reduction programmes are not
instructed to drink at least 1.5 l of calorie-free fluid per day.
routinely provided in many diabetes services, especially in theUK, often because of concerns about early weight regain
Blood glucose monitoring and adjustment of anti-diabetic
and the lack of evidence of sustained medium to long-term
treatment
Very-low-calorie diets (VLCDs) are defined as diets of
All patients were regularly performing home blood glucose
< 800 kcal /day [5]. They were developed to achieve maximum
monitoring throughout the study, and those on insulin therapy
weight loss while preserving lean body mass, and are usually
at baseline had their insulin discontinued at the start of the VLCD. Insulin was commenced or recommenced, as required, during
given for 8-12 weeks as a liquid formula containing high levels
subsequent follow-up, and similarly oral anti-diabetic treatments
of protein enriched with vitamins, minerals, electrolytes and
(metformin and sulphonylureas only) were adjusted to individual
fatty acids. First-generation VLCDs were associated with
patient needs in accordance with routine practice. Other medical
sudden cardiovascular collapse [6], but the safety and toler-
therapies were unchanged during the 8-week VLCD.
ability of newer formulations have been well established, albeitmainly in healthy non-diabetic subjects > 30% above idealbody weight [5,7]. Favourable effects of VLCD therapy on
Statistical analysis
body weight and glycaemic control have also been reported in
Clinical and biochemical parameters at baseline, following 8
patients with T2DM [8-10], but mostly in short-term studies
weeks of VLCD and at 1 year, were compared by repeated meas-
and following use of a VLCD as primary therapy in newly
ures analysis of variance. All data are expressed as mean ± SD.
diagnosed patients [11,12]. In contrast, there is relatively littleinformation about metabolic and cardiovascular outcomes
following VLCD treatment among symptomatic patients withT2DM in secondary failure and /or those recently commenced
Forty-four patients agreed to participate in the study (approx.
on insulin with suboptimal glycaemic and symptom control.
half of all consecutive obese patients in secondary failure
Thus, the purpose of this study was to evaluate short-term and
attending our service during recruitment); four withdrew, all
1-year outcomes of an intensive 2-month VLCD as part of the
within the first 5 days of starting the VLCD, mainly because of
routine care of obese patients in secondary failure.
distaste and poor compliance, but there were no further drop-outs. Thus, 40 obese patients with a mean duration of T2DMof 6.1 years (22 male, mean age 52 years, range 33-69 years)
Patients and methods
completed the study; one-half had evidence of micro- or macro-
Consecutive obese patients with hyperglycaemic symptoms
vascular complications. All patients were symptomatic of poor
and poorly controlled T2DM despite maximum tolerated doses
glycaemic control despite treatment with combined (sulphony-
of oral anti-diabetic therapy (sulphonylurea and metformin)
lurea and metformin) oral anti-diabetic therapy (n = 26) or
± insulin were invited to participate in a 12-month study divided
insulin + metformin (n = 14). The average dose of insulin was
into two phases: (i) 8 weeks of VLCD therapy with review by
102 ± 26 U/day among insulin-treated patients (n = 14). Base-
the dietician after 2, 4 and 8 weeks (patients also had telephone
line clinical parameters for the group were was follows: body
access between visits); and (ii) a follow-up phase (week 8 to
weight 115 ± 15 kg, body mass index (BMI) 40 ± 9.4 kg/m2,
week 52) in which a standard low-calorie weight-maintenancediet was recommended together with simple advice about
BP 152/82 ± 17/9 mmHg, serum triglycerides 3.4 ± 1.7 mM,
exercise at bi-monthly visits to the Diabetes Centre. Clinical,
total cholesterol 6.0 ± 1.2 mM, and fructosamine 387 ± 71 µM.
biochemical and haemodynamic parameters were recorded atbaseline, 8 weeks and 1 year. The effects of VLCD therapy on
Tolerability
glycaemic control after 8 weeks and during subsequent follow-up were assessed by measurements of serum fructosamine
Four patients were unable to tolerate the VLCD and withdrew
(normal range 205-285 µm/l; a serum fructosamine of 400 µm/l
in the first week of the study. There were no subsequent with-
is approximately equivalent to an HbA of 10%). Patients gave
drawals, and the VLCD was generally well tolerated with
informed consent and a detailed protocol was approved by the
favourable early effects on glycaemic symptoms and body
weight reinforcing patient compliance. There were no signifi-cant electrolyte disturbances. VLCD treatment
Patients were instructed to replace their entire diet with Slimfast,
Short-term effects on body weight, metabolic and
a commercially available liquid meal replacement, for 8 weeks. cardiovascular parameters
In addition to three Slimfast meal replacements per day, patientswere allowed one bowl of low-calorie vegetable soup, one bowl
Following 8 weeks of VLCD therapy the average weight loss
of vegetables or salad, two portions of fresh fruit and 300 ml
was 12 kg, and mean BMI had fallen from 40 to 36 kg /m.
of skimmed milk for drinks. This provided approximately
Hyperglycaemic symptoms were improved considerably
2003 Diabetes UK. Diabetic Medicine, 20, 319 - 324 Figure 1 Mean values at baseline (ᮀ), after 2 months very-low-calorie diet (hatched) and after 1 year () for (a) body weight, (b) body mass index, (c) serum fructosamine, (d) total cholesterol, (e) systolic blood pressure (BP), and (f ) diastolic BP (n = 40).
following the VLCD and serum fructosamine was reduced
for a typical patient who stopped and restarted insulin (at a
from 386 to 341 µM (Fig. 1). There were additional improve-
much lower dose) are illustrated in Fig. 3.
ments in serum lipids (e.g. 1.0 mmol / l reduction in totalcholesterol) and BP (average reduction 10/6 mmHg) (Fig. 1). Discussion
VLCDs have become widely established in the treatment of
Outcomes at 1 year
uncomplicated obesity [5], but historical concerns about cardio-
Average body weight and BMI after 1 year were 109.5 kg and
vascular safety in patients with co-morbid conditions, and
37 kg/m2, respectively. Mean fructosamine for the group was
somewhat pessimistic assumptions about early weight regain,
371 ± 41 µM, and 15 patients were on insulin (average dose
have greatly limited the consideration of VLCDs as a treatment
41 U/day). Improvements in total cholesterol and BP were
option in patients with diabetes, especially in the UK. Most
previous studies have evaluated VLCDs as primary weight-losstherapy in small numbers of patients with newly diagnoseddiabetes [11,12], but this is the first report describing the short-
Effects of VLCD on insulin requirements
term and 1-year outcomes of VLCD therapy in symptomatic
Fourteen patients were treated with metformin + insulin prior
patients with obesity and T2DM in secondary failure, includ-
to starting the VLCD (average insulin dose 102 U/day). After
ing a subgroup who had recently switched to insulin and
8 weeks, 10 patients had (re)commenced insulin (average dose
metformin with a suboptimal effect on glycaemic and symptom
36 U/day), and after 1 year 15 patients were treated with insulin
control. Compliance with three liquid meal replacements per
(Fig. 2). The effects of the VLCD on home blood glucose levels
day and only a small amount of solid foodstuff represents a
2003 Diabetes UK. Diabetic Medicine, 20, 319 - 324
VLCD therapy in obese patients with diabetes in secondary failure • P. Dhindsa et al.Figure 2 Proportion of patients treated with insulin (and average daily dose) at baseline, after 2 months' very-low-calorie diet (VLCD) and after 1 year. Figure 3 Home blood glucose recordings for an individual patient who was taking 70 U/day of insulin prior to commencing the very-low-calorie diet (VLCD). Insulin was discontinued on starting the VLCD and recommenced 9 weeks later. However, during follow-up, blood glucose levels were considerably better on less than half the pre-VLCD dose of insulin (20-30 U/day), illustrating sustained improvements in insulin sensitivity and dose requirements following the VLCD.
major challenge, but these patients were highly motivated by
and there is evidence that VLCDs have a modest satiating
their symptoms, lack of success with previous therapeutic and
effect due to the high protein content and the ketosis induced
dietary interventions, and a realization that energy restriction
in the short term and major weight loss in the medium term
The VLCD was generally well tolerated and highly effective
were unavoidable objectives for improved well-being and
in reducing body weight (on average by 12 kg) and BMI, with
glycaemic control. Patients reported an almost immediate
favourable reductions in BP (10/6 mmHg) and levels of serum
improvement in diabetic symptoms which, combined with early
cholesterol (17%) and fructosamine (40 µM, equivalent to
weight loss even in the first week, probably encouraged good
0.8-1% HbA ) after 2 months. The short-term metabolic and
compliance with the VLCD and explains why there were no
haemodynamic changes are entirely consistent with improved
drop-outs beyond the first few days. Feelings of hunger during
peripheral and hepatic insulin sensitivity [14], although energy
VLCD treatment are generally less than might be expected,
restriction, independent of weight loss, has an important effect
2003 Diabetes UK. Diabetic Medicine, 20, 319 - 324
on glycaemic control, especially in the early phase of VLCD
modest difference in body weight (3.5 kg favouring the VLCD
treatment [15]. There were no gender-related differences in
group) did not justify further use of pulsed VLCDs, but alter-
weight loss in the present study, even though some evidence
native VLCD regimes, e.g. frequent short periods of 1-5 days,
has suggested that male (non-diabetic) subjects lose more
weight than women [7]. The secondary benefits on other
There has been a long history of debate over the safety and
cardiovascular risk factors, especially BP, should not be under-
utility of VLCDs in routine clinical practice [6,7], but modern
estimated. For example, a reduction of 10/6 mmHg is equiva-
formulations are effective, well tolerated and associated with
lent to the difference in average BP (10/5 mmHg) between the
high levels of patient satisfaction. Importantly, in the present
'tight' and 'less-tight' BP control groups of the UK Prospective
study VLCD therapy was administered and supervised by a
Diabetes Study, an effect which, maintained over 10 years,
specialist dietician working within the framework of a routine
produced a 32% reduction in diabetes-related deaths [16].
diabetes service using an agreed protocol. Dieticians have
In the post-VLCD follow-up period, patients received stand-
often been reluctant to use VLCDs without close medical
ard levels of diabetes care, including diet and exercise advice
supervision, but this study has demonstrated the feasibility of
from a specialist dietician at 2-3-month intervals. Even
a dietician-led programme of VLCD education and treatment
without intensive behavioural or dietary counselling, sustained
for those obese patients with T2DM in secondary failure in
improvements in various parameters were still apparent after
whom the physician has made a referral. There should be
1 year. In particular, although there had been some weight
greater consideration given to VLCDs as a treatment option in
regain and a deterioration in glycaemic control, levels of body
this difficult-to-manage and symptomatic patient group.
weight, BMI and fructosamine were still significantly lowerthan baseline pre-VLCD values. This also applied to those
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Il giorno 27 Dicembre 2007 un’allegra combricola di ragazzi dai 14 ai 41 anni, accompagnati da Don Sante e da due sciatori della Colfranculana, è partita da Colfrancui per una gita sulla neve. I ragazzi, tutti animatori di Colfrancui con qualche eccezione di caminensi, si è ritrovata davanti al salone parrocchiale alle 6.50 del mattino (è stato molto difficile svegliarsi a quell’ora) p
OFFICE OF SPECIAL MASTERS *************************************SHANNON E. CASEY,Clifford J. Shoemaker, Vienna, Virginia, for Petitioner. Mark C. Raby, United States Department of Justice, Washington, D.C., for Respondent. DECISION1 SWEENEY , Special Master On September 4, 1997, Shannon E. Casey filed a petition for compensation under theNational Childhood Vaccine Injury Act (“Vaccine