Weighty Issues in Type 2 diabetes - Joseph Proietto University of Melbourne Department of Medicine and - ESA Seminar
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Weighty Issues in Type 2 diabetes
Joseph Proietto
University of Melbourne
Department of Medicine and
Department of Diabetes and Endocrinology
Austin Health
j.proietto@unimelb.edu.au
Dennis Wilson
2
Declaration of Possible Conflicts of Interest JP is or was a member of the Medical Advisory Boards for: –Exenatide (Byetta) for AstraZeneca –Liraglutide (Victoza) for Novo Nordisk –Liraglutide 3 mg (Saxenda) for Novo Nordisk –Sitagliptin (Januvia) for MSD –Dapagliflozin (Forxiga) for AstraZeneca And has given lectures on the management of obesity for iNova marketers of Duromine
Australian guideline recommendations1
Lifestyle modification:
• diet
• weight control
• physical activity
Metformin
SU as monotherapy
or combination
therapy
Acarbose DPP-4 TZD* GLP-1 SGL-T2
inhibitor# Associated with analogues inhibitors
increased risk of heart
failure, oedema and
fractures Insulin
1. Colagiuri et al. National evidence based guideline for blood glucose control in type 2 diabetes. Diabetes Australia and the NHMRC, Canberra 2009.
2. 2. Pharmaceutical Benefits Scheme (PBS) –EXENATIDE www.pbs.gov.au/medicine/item/3423E-3424F [Accessed 17.4.11].
Obesity
Hepatic insulin Peripheral insulin
resistance resistance
Impaired β cell function in
genetically susceptible
individuals
Type 2 Diabetes
It follows that: The best way to treat type 2 diabetes is to achieve weight loss
Dixon JB, Playfair J, Skinner S, Proietto J, Schachter LM, Chapman L, Anderson M, Bailey M, and O’Brien PE. Surgically Induced Loss Of Weight for management of Type-2 Diabetes: Randomized Trial. JAMA 2008; 299:316-23
Gastric Banding http://www.waggaweightlosssurgery.com/procedures.htm
Inclusion Criteria • BMI 30 – 40 • Age 20 – 60 • Type 2 Diabetes diagnosed within the last 2 years • No evidence of renal impairment or diabetic retinopathy • Understand both treatment options • Accept randomization
Outcome Measures
• Proportion achieving “diabetes remission” defined as all of the
following
–Fasting plasma glucose < 7mmol/l
–A1c < 6.2 %
–Not requiring any hypoglycaemic medication or insulin
At 2-years after randomization
• Proportion with A1c levelsBaseline Characteristics
Surgical Group Conventional Therapy Group
(Mean, Median or %) (Mean, Median or %)
Number 30 30
Age (years) 46.6 (7.4) 47.1 (8.7)
Male n (%) 15 (50%) 13 (43%)
BMI (kg/m2) 37.0 (2.7) 37.2 (2.5)
Weight (kg) 105.6 (13.8) 105.9 (14.2)
Waist Circumference (cm) 114.1 (10.2) 116.0 (10.0)
Waist:Hip Ratio 0.96 (0.09) 0.96 (0.10)
HbA1c (%) 7.8 (1.2) 7.6 (1.4)Diabetes Remission at 2 years
Lifestyle Surgery
% weight loss 1.7 20.7*
HbA1c < 7% 50% 87%*
% remission 13% (ITT) 73% (ITT)*
* P < 0.001• But with ~ 23% of the population obese there are not
enough surgeons and operating theatres to treat even a
small percentage of patients that need treatment.
• Not everyone wants an operation
13What is the best way to lose weight medically?
14The Lancet Diabetes and Endocrinol 2: 954-62 2014
Methods
Randomly allocated
Rapid program
(12-week intervention)
Obese but otherwise
healthy participants, ≥12.5% Weight maintenance diet
18-65 years of age (144 weeks)
Gradual program
(36-week intervention)
Phase 1: weight loss Phase 2: weight maintenanceResults
Baseline characteristics
Variable Rapid Group Gradual Group
(n=97) (n=103)
Age (years) 49.6 ± 10.9 50.1 ± 11.1
Sex (female) 73.2% 75.7%
Weight (kg) 96.4 ± 13.8 97.2 ± 14.2
BMI (kg/m2) 35.2 ± 3.7 35.5 ± 4.0
Waist circumference (cm) 108.2 ± 10.6 107.9 ± 10.0
Hip circumference (cm) 118.1 ± 9.5 118.9 ± 10.9
Systolic BP (mmHg) 130.4 ± 15.7 131.5 ± 13.8
Diastolic BP (mmHg) 82.6 ± 9.3 81.9 ± 8.8
Fat mass (kg) 48.5 ± 12.2 50.9 ± 13.1
Mean daily steps 7107 ± 2599 7530 ± 3021
Mean ± SD. No significant differences were detect between the two treatment groups (P>0.05 for all comparisons)Results Rate of weight loss during phase 1 for successful participants (mean % change, 95% CI)
Achievement of ≥12.5% weight loss during phase 1
pDoes rapid weight loss lead to faster weight regain?
Weight regain % during phase 2
Gradual WL
group
regained
71.2%
Rapid WL
group
regained
70.5%
*n=61 in rapid weight loss and n=43 in gradual weight loss groupSummary of findings • Using rapid weight loss program (VLED): 1. More likely to achieve target weight loss 2. Less likely to drop out 3. No difference in weight regain Why did we find a higher success rate with the stricter diet?
Results
• Phase 1 median (IQR) Beta-hydroxybutyrate concentration at baseline, and 5%, 10% and 15% weight loss
* P = 0.035; ‡ P< 0.0001. At baseline: gradual weight loss (n=18), rapid weight loss (n=20); At 5%: gradual weight loss (n=16), rapid weight loss
(n=19); At 10%: gradual weight loss (n=11), rapid weight loss (n=16); At 15%: gradual weight loss, 5%, 10% and 15% weight loss separated
according to treatment groups.How do ketones suppress hunger?
24The brain can metabolise ketones
2526
Conclusion
The results are ..”consistent with the hypothesis that
human nervous tissue can metabolize ketones acutely.”
27How should rapid weight loss be achieved
safely?To achieve rapid weight loss it is necessary to
have a large gap between energy intake and
energy expenditure.
However to obtain the necessary micronutrients
it is necessary to have and intake of at least
4920 kj (1200) kcal.VLED •Provide only 1640 – 3280 kj (400-800 kcal/day •Very low in fat and carbohydrate •Supply all the needed vitamins, minerals and amino acids.
VLED •1 sachet or bar twice daily (breakfast and lunch) with plenty of water • In the evening have a no carbohydrate dinner with protein vegetables and a salad •Oil on vegetables and or salad if gall bladder is present •Daily exercise
Are VLED’s safe?
Safe year-long use of a very-low-calorie diet for the treatment of severe obesity Priya Sumithran and Joseph Proietto Med J Aust 2008; 188 (6): 366-368.
Does the VLED approach work in patients with type 2
diabetes?
34Aims of the study To investigate the efficacy of a VLCD program in reducing weight and adiposity in obese subjects with type 2 diabetes or normal fasting glucose over a 24-week intervention
Change in weight
n = 51
T2DM: 8.5 ± 1.3 kg vs. CON: 9.4 ± 1.2 kg P = 0.64Tips for using VLED’s in patients with Diabetes
1. If the patient with diabetes is on glucose lowering drugs
that can cause hypoglycemia (insulin or sulphonylureas)
it is essential to tell the patient to reduce the dose in half
and to monitor glucose closely the first few days. The
doses of these agents are then manipulated to maintain
glucose control.
2. Check c-peptide before starting so that you may be able
to asses whether stopping insulin is a possibility
following substantial weight loss.
38Why has obesity not been tackled
earlier for the treatment of Type 2
diabetes?
39Diet and behavioural
intervention
5
Weight change (kg)
0
-5
-10 Very-low-calorie diet
Modified diet plus
behaviour therapy
-15 Very-low-calorie diet plus
behaviour therapy
-20
intervention 1 2 3 4 5
Years after interventionWhy do most subjects regain weight?
41Diagram of the central regulation of body weight (from Proietto J. MJA 195:144-146 2011)
Changes in leptin levels with dieting
60 BMI
Leptin
BMI (kg/m2) or Leptin (pmol/dl)
50
40
30
20
10
0
0 5 10 15 20 25
BMI, body mass index
Weeks
Geldszus et al. Eur J Endocrinol 1996;135:659–62Ghrelin levels after diet-induced weight loss
Cummings et al. N Engl J Med 2002;346:1623–30Post-breakfast CCK release
pre- and post-weight loss
CCK AUC (pmol/L/4h)
p=0.016
30
20
10
0
Week 0 Week 9
Plasma CCK (pmol/L)
Week 0
7.0
6.0 Week 9
5.0
4.0
3.0
2.0
1.0
0
0 60 120 180 240
Time (min)
Chearskul et al. Am J Clin Nutrition 2008;87:1238–46Body weight is defended
Sumithran P et al. N Engl J Med 2011; 365:1597-1604.Total, resting and non-resting
energy expenditure
TEE REE NREE Wtinitial
500
Residual values (kcal/d)
Wtloss-recent
300 Wtloss-sustained
100
–100
–300
–500
–700
–900
NREE, non-resting energy expenditure; REE, resting energy expenditure; TEE, total energy expenditure. Rosenbaum M et al. Am J Clin Nutr 2008; 88:906-912.What strategies should we adopt to help
our patients to maintain weight loss
long term?Lifestyle advice
• Healthy eating
• Regular Exercise
• Weigh yourself once weekly in the morning with an empty
bladder
• If you regain 2 kg, restart the intense diet and continue it
until you have lost the 2 kg again.Weight Loss Agents : - Saxenda (Liraglutide 3.0 mg) - Phentermine (Duromine) - [Topiramate (Topamax)] [ ] off label use
Weight Loss Agents : Major Points about Weight loss medications: • Nature combines nine gut and pancreatic hormones and several nutrients to suppress hunger so, it is better to use multiple drugs at their lowest doses to control hunger after weight loss rather than just one drug at a high dose. • Because weight is predominantly genetic, the hormonal and energy expenditure changes that occur after weight loss, designed to return the weight to its set point, are long lasting. It follows that drug use has to be long term (life-long).
The Team
Basic Science Lab
Sof Andrikopoulos
Barbara Fam
Nicole Wong
Ben Lamont
Salvatore Mangiafico
Zheng Ruan
Chrisa Xirouchaki
Steven Weng
Maria Stathopoulos
Christo Ioannides
Clinical research Unit
Priya Sumithran Cheryl Adams
Cilla Haywood Nicola Robinson
Luke Prendergast Katrina Purcell
Rebecca Sgambellone Jodie Prendergast
Kira Edwards Mary CaruanaYou can also read
