Weighty Issues in Type 2 diabetes

Transcription

1 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

2 Dennis Wilson 2

3 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

4 Australian guideline recommendations 1 Lifestyle modification: diet weight control physical activity Metformin SU as monotherapy or combination therapy Acarbose DPP-4 inhibitor # TZD* Associated with increased risk of heart failure, oedema and fractures GLP-1 analogues Insulin SGL-T2 inhibitors 1. Colagiuri et al. National evidence based guideline for blood glucose control in type 2 diabetes. Diabetes Australia and the NHMRC, Canberra Pharmaceutical Benefits Scheme (PBS) EXENATIDE [Accessed ].

5 Obesity Hepatic insulin resistance Peripheral insulin resistance Impaired β cell function in genetically susceptible individuals Type 2 Diabetes

6 It follows that: The best way to treat type 2 diabetes is to achieve weight loss

7 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

8 Gastric Banding

9 Inclusion Criteria BMI Age Type 2 Diabetes diagnosed within the last 2 years No evidence of renal impairment or diabetic retinopathy Understand both treatment options Accept randomization

10 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 levels <7%, and A1c was also examined as a continuous variable Weight

11 Baseline Characteristics Surgical Group (Mean, Median or %) Conventional Therapy Group (Mean, Median or %) Number Age (years) 46.6 (7.4) 47.1 (8.7) Male n (%) 15 (50%) 13 (43%) BMI (kg/m 2 ) 37.0 (2.7) 37.2 (2.5) Weight (kg) (13.8) (14.2) Waist Circumference (cm) (10.2) (10.0) Waist:Hip Ratio 0.96 (0.09) 0.96 (0.10) HbA1c (%) 7.8 (1.2) 7.6 (1.4)

12 Diabetes Remission at 2 years Lifestyle Surgery % weight loss * HbA1c < 7% 50% 87%* % remission 13% (ITT) 73% (ITT)* * P < 0.001

13 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 13

14 What is the best way to lose weight medically? 14

15 The Lancet Diabetes and Endocrinol 2:

16 Methods Randomly allocated Obese but otherwise healthy participants, years of age Rapid program (12-week intervention) Gradual program (36-week intervention) 12.5% Weight maintenance diet (144 weeks) Phase 1: weight loss Phase 2: weight maintenance

17 Results Variable Baseline characteristics Rapid Group (n=97) Gradual Group (n=103) Age (years) 49.6 ± ± 11.1 Sex (female) 73.2% 75.7% Weight (kg) 96.4 ± ± 14.2 BMI (kg/m 2 ) 35.2 ± ± 4.0 Waist circumference (cm) ± ± 10.0 Hip circumference (cm) ± ± 10.9 Systolic BP (mmhg) ± ± 13.8 Diastolic BP (mmhg) 82.6 ± ± 8.8 Fat mass (kg) 48.5 ± ± 13.1 Mean daily steps 7107 ± ± 3021 Mean ± SD. No significant differences were detect between the two treatment groups (P>0.05 for all comparisons)

18 Results Rate of weight loss during phase 1 for successful participants (mean % change, 95% CI)

19 Achievement of 12.5% weight loss during phase 1 p<0.001 Dropped out: 3 18

20 Does rapid weight loss lead to faster weight regain?

21 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 group

22 Summary 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?

23 Results Phase 1 median (IQR) Beta-hydroxybutyrate concentration at baseline, and 5%, 10% and 15% weight loss * P = 0.035; P< 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.

24 How do ketones suppress hunger? 24

25 The brain can metabolise ketones 25

26 26

27 Conclusion The results are.. consistent with the hypothesis that human nervous tissue can metabolize ketones acutely. 27

28 How should rapid weight loss be achieved safely?

29 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.

30 VLED Provide only kj ( kcal/day Very low in fat and carbohydrate Supply all the needed vitamins, minerals and amino acids.

31 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

32 Are VLED s safe?

33 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):

34 Does the VLED approach work in patients with type 2 diabetes? 34

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36 Aims 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

37 Change in weight n = 51 T2DM: 8.5 ± 1.3 kg vs. CON: 9.4 ± 1.2 kg P = 0.64

38 Tips 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. 38

39 Why has obesity not been tackled earlier for the treatment of Type 2 diabetes? 39

40 Weight change (kg) Diet and behavioural intervention Very-low-calorie diet Modified diet plus behaviour therapy Very-low-calorie diet plus behaviour therapy intervention Years after intervention

41 Why do most subjects regain weight? 41

42 Diagram of the central regulation of body weight (from Proietto J. MJA 195: )

43 Changes in leptin levels with dieting BMI (kg/m 2 ) or Leptin (pmol/dl) BMI Leptin BMI, body mass index Weeks Geldszus et al. Eur J Endocrinol 1996;135:659 62

44 Ghrelin levels after diet-induced weight loss Cummings et al. N Engl J Med 2002;346:

45 Post-breakfast CCK release pre- and post-weight loss Plasma CCK (pmol/l) CCK AUC (pmol/l/4h) p=0.016 Week 0 Week 9 Week 0 Week Time (min) Chearskul et al. Am J Clin Nutrition 2008;87:

46 Body weight is defended Sumithran P et al. N Engl J Med 2011; 365:

47 Residual values (kcal/d) Total, resting and non-resting energy expenditure TEE REE NREE Wt initial Wt loss-recent Wt loss-sustained NREE, non-resting energy expenditure; REE, resting energy expenditure; TEE, total energy expenditure. Rosenbaum M et al. Am J Clin Nutr 2008; 88:

48 What strategies should we adopt to help our patients to maintain weight loss long term?

49 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.

50 Weight Loss Agents : - Saxenda (Liraglutide 3.0 mg) - Phentermine (Duromine) - [Topiramate (Topamax)] [ ] off label use

51 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).

52 The Team Clinical research Unit Priya Sumithran Cilla Haywood Luke Prendergast Rebecca Sgambellone Kira Edwards Cheryl Adams Nicola Robinson Katrina Purcell Jodie Prendergast Mary Caruana Basic Science Lab Sof Andrikopoulos Barbara Fam Nicole Wong Ben Lamont Salvatore Mangiafico Zheng Ruan Chrisa Xirouchaki Steven Weng Maria Stathopoulos Christo Ioannides