lecture 10: managing and preventing metabolic syndrome

Question 1

How can we reformat the question?

Answer 1

• since obesity is the main driver of the metabolic syndrome it can be worded as ‘managing and preventing obesity’

Question 2

How does weight loss improve features of the metabolic syndrome?

Answer 2

• study performed in 2006
• entry criteria
  
  • BMI 30 - 35
  • age 20 - 50
  • identifiable problems
  • understand both treatment options
  • accept randomisation

Question 3

What were the treatment programmes?

Answer 3

• medical programme
  
  • individualised best medical practice including :-
  • very low calorie diet – Optifast (Novartis)
  • Orlistat (Roche) (perhaps wrong drug, should have used an appetite suppressant but it wasn’t available, so used a lipase inhibitor that causes steatorrhoea if you eat fat)
  • behavioural therapy
• surgical programme
  
  • placement of LAP-BAND system (Allergan Health)

Question 4

What was the % of excess weight lost between the two treatment options?

Answer 4

• up to 6 months the surgical and medical treatments were the same
• after the surgical kept losing weight (up to 87.2% of excess weight by 2 years)
• while the medical started to regain weight (after 2 years back to only losing 21.6% of excess weight)

Question 5

What was the effect of this weight loss on metabolic syndrome?

Answer 5

• 38% of medical arm had metabolic syndrome, same as surgical initial
• following review at two years after intervention:
  
  • 24% of medical had metabolic syndrome
  • only 3% of surgical had metabolic syndrome
• therefore can reverse metabolic syndrome by successfully achieving weight loss

Question 6

what is the importance of genetic differences?

Answer 6

• adoption studies - BMI of adopted child more strongly correlated with BMI of biological parent
• twin studies - heritability estimates ranging from 50-90%
  
  • highest for monozygote twins
• more than 250 genes and chromosomal regions associated with obesity
• while certain genes increase the susceptibility to obesity, the prevalence of obesity has almost doubled since 1980 making purely genetic causes unlikely

Question 7

What are changes in prevalence of obesity?

Answer 7

• obese BMI more than 30 kg/m2
• 1980: 7.1%
• 2000: 18.4%
• classical genetics cannot explain the current epidemic of obesity

Question 8

What was the experiment conducted by Berry Levin in america?

Answer 8

• took a group of rats and divided them into various groups
• one group was fed on chow
  
  • grew at a particular rate for most of their lives
• another group was fed on a high energy diet
  
  • 8% corn syrup (rich in fructose)
  • 42% sweetened condensed milk
  • got fat
  • at a certain point he divided them into two:
    
    • one group continued on the HE diet
    • the other group he switched to chow (low fat) and restricted them
      
      • lost weight
      • at a certain point he let them eat the healthy food as much as they wanted
      • grew and grew and got fat again
      • something happened early on, the HE diet changed the expression of genes in the body because they are now defending a higher weight
      • epigenetics
• now becoming clear that a lot of obesity is epigenetic
• a lot of this occurs in utero
• famine in holland after second world war
  
  • if baby was in first trimester during famine but not second or third, grew up to have obesity as an adult
• we need to figure out exactly what it is that causes obesity

Question 9

How do we best treat those with the metabolic syndrome?

Answer 9

• weight loss or
• treatment of each of the components separately

Question 10

How to treat obesity?

Answer 10

• a strategy for medical management of obesity
• assessment of obesity and its complications. If weight loss is medically advisable:
• commence a course of VLED if patient has tried other approaches before without success. Review every 2 weeks
• unable to tolerate VLED or significant weight loss (`0% or more of baseline weight), wean off VLED over 1-6 month period
• place on low fat redeuced carbohyrdate diet plus exercise, referral to group programme

Question 11

What are very-low-calorie diets?

Answer 11

• limit energy intake to 1.88 - 3.35 MJ daily
  
  • = 450 - 800 kcal per day
• provide more than 50g high-quality protein and amino acids
• provide essential fatty acids
• provide daily requirements of trace elements, vitamins and minerals

Question 12

When are VLCDs used?

Answer 12

• recommended only BMI > 30 kg/m2
  
  • or greater than 27 kg/m2 if one or more co-morbidities
• intensive phase (2-3 meal replacements)
  
  • usually lasts 8-16 weeks
• 2 cups of salad or low-starch vegetables are eaten in addition
  
  • provides fibre to lessen hunger, constipation
  • tablespoon of oil/butter to prevent gallstones
• no evidence for commencement as inpatient or starting low calorie diet prior

Question 13

What is the problem with diet and behavioural intervention?

Answer 13

• VLCD works fine
• the problem is that people lose weight and then put it on again

Question 14

What are the long term effects of weight loss through diet?

Answer 14

• ad lib low fat
  
  • weight loss 1-2 years: - 3.9 kg
  • more than 2 years: - 2.7 kg
• low energy
  
  • 1-2 years: -6.7 kg
  • 2+ years: -1.1 kg
• very low energy:
  
  • 1-2 years : -11.8kg
  • 2+ years: -4.1kg
• meal replacement:
  
  • 1-2 years: -5.5kg
  • 2+ years: -6.5kg
• popular diets: not known

Question 15

What are the long term effects of weight loss through physical activity?

Answer 15

• physical activity:
  
  • 1-2 years: -1.8kg
  • 2+ years: -1.3kg
• diet + activity:
  
  • 7.5kg
  • 3.1kg

Question 16

What are the long term effects of weight loss through behaviour therapy?

Answer 16

• 1-2 years: -4.7kg
• 2+ years: - 2.8kg

Question 17

Why do diets nearly always fail?

Answer 17

• long-term persistence of hormonal adaptations to weight loss
• recruited 50 people who had a BMI of ~34, over half female
• brought them into clinical research
• put drip in arm, took blood sample
• gave hearty breakfast
• took sample every half hour for four hours
• put them on VLCD
• lost 12-13kg over 10 weeks
• did study again
• followed for a year
• brought them back and did the study again
• measured 4-5 of the hormones that regulate hunger
  
  • weight is regulated in the hypothalamus
  • within this there is an area called the arcuate nucleus
  • within this are two classes of nerves:
    
    • neuropeptide Y nerves: make neuropeptide Y and agouti related peptide, both make us very hungry
    • pomC nerves: produce pomC from which is cleaved a peptide called MSH, MSH together with another hormone called Cart inhibit hunger powerfully, when they fire we don’t want to eat
  • these hormones are controlled by hormones circulating in the blood
  • at least 10 hormones in the blood that regulate hunger
  • the strange thing is that out of these 10 there is only one that makes us hungry and 9 that take hunger away
  • grellin is released by empty stomach → make us hungry
  • small bowel releases ~ 5 hormones that take hunger away, e.g. cholycystokinin, glucagon-like peptide 1, PYY, oxtimodulin, uroguanaline
  • the fat makes leptin → inhibits food intake
  • leptin is the reason why you can’t get fat (unless you are genetically predisposed) → very important, powerful hormone
  • pancreas produces amylin, pancreatic polypeptide and insulin
• measured these circulating hormones in this study
• weight dropped by about 13 kg after 10 weeks, but despite best efforts they started to regain
• leptin almost disappeared from the blood (70% reduction)
• without leptin you feel hungry
• it only increased with the regain in weight
• after weight loss there were higher levels of ghrelin (makes you hungry)
• whereas the levels of the other hormones decreased
• i.e. four hunger suppressing hormones that become lower after weight loss while hunger inducing hormone went up
• net result is that you are more hungry after weight loss than before lost weight
• these hormones stay altered until you regain weight
• even at three years these hormones haven’t gone back to baseline

Question 18

What are changes in energy expenditure?

Answer 18

• as you lose weight you become more fuel efficient
• non-resting energy expenditure/resting energy expenditure

Question 19

what are the final protocols at austin health obesity clinic?

Answer 19

• previous blah is the reason why patients are followed even if they are losing weight
• losing weight or maintaining weight loss
  
  • continue diet and exercise programme
  • don’t discharge completely
• unable to maintain weight loss
  
  • regained 10% of lost weight
• after re-enforcing diet and exercise start Doromine 15 and Tpamax 25
  
  • regaining weight → stop pharmacotherapy → refer for consideration of surgery
  • maintaining adequate weight loss
    
    • continue wiht diet and excerise plus pharmacotherapy

Question 20

What pharmacotherapy is there for treating obesity in Australia?

Answer 20

• available in australia:
  
  • phentermine (Duromine)
  • topiramate (topamax) → off label use
  • combination of duromine (15mg) and topamax (25mg) → off label use
• for patients with diabetes:
  
  • exenatide (byetta)
  • liraglutide (victoza)

Question 21

What is topiramate?

Answer 21

• not tolerated at such high doses

Question 22

How successful was the combination therapy?

Answer 22

• Gadde KM et al.: effects of low dose, controlled release, phentermine plus topiramate combination on weight associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial
• found that it worked

Question 23

What are the side effects of Phentermine and Topiramate?

Answer 23

• Phentermine (Duromine)
  
  • increase in heart rate and blood pressure
  • dry mouth
  • difficulties falling asleep
  • cannot be used in conjuction with SSRI’s (antidepressants)- possible risk of serotonergic syndrome
• Topiramate (topamax)
  
  • parasthesiae
  • depression
  • memory loss
  • renal stones
  • glaucoma
  • foetal abnormalities (cleft lip and palate) 1.4% risk
• these side effects are significant, need to be used with great caution, but we don’t have anything else

Question 24

What was the first australian experience of combination phentermine and topiramate for maintenance of lost weight?

Answer 24

• objective: to investigate the tolerability, adverse effect profile and efficacy of combination phentermine and topiramate (Ph/T) for maintenance of lost weight
• design, setting and participants: retrospective audit of patients at the austin health weight control clinic prescribed Ph/T from 22 jan 2010 to 16 july 2012
• main outcome measures: cessation rates, duration of use and adverse effects. mean weights and blood pressures at initial clinic visit, at commencement of pharmacotherapy and at last observation
• results
  
  • 103 patients were analysed
  • 61 patients ceased combination pharmacotherapy, 41 ceasing due to adverse effects including paraesthesia, cognitive changes, dry mouth and depression
  • the mean duration of use was 11 months. mean weight loss of 10% (13kg) achieved by the VLCD was successfully maintained
  • 30 patients continued pharmacotherapy, mean duration 22 months, with an additional mean weight loss of 6.7kg during pharmacotherapy
  • so it does work, but is not well tolerated
  • have now reduced starting dose of topirumate to 12.5 mg
• conclusion
  
  • Ph/T is not well tolerated with high cessation rates due to adverse effects, mainly attributable to topiramate
  • however, Ph/T is effective in weight maintenance and assists further weight loss in those able to continue with pharmacotherapy

Question 25

Why can’t patients yet be referred to surgery for treating obesity?

Answer 25

• no funding for treating obesity in public hospitals
• austin allows surgery and funding of drugs
• wait lost for surgery had become so long - 5 years - that they have to stop referring patients until the list gets shorter (1 year)
• not doing enough surgery due to lack of funding

Question 26

What is bariatric surgery?

Answer 26

• adjustable gastric banding
  
  • band around stomach and reservoir under skin
  • tending to move away from this operation because of high failure rate and revision rate
  • stops hunger by bolus squeezes stomach → vagus nerve → feeling of fullness
• sleeve gastrectomy
  
  • remove the bulk of the stomach and throw it away
  • doing this gets rid of ghrelin
• roux-en-Y bypass
  
  • causes undigested food to go into the terminal ileum which causes release of PYY and GLP1 both of which inhibit food intake
• each of these operations have a different way of suppressing hunger but they all do

Question 27

What are components of managing diabetes?

Answer 27

• diet
• exercise
• metformin
  
  • lowers sugar for a while but eventually starts to drift up again
• sulphonylureas
• acarbose
  
  • alpha-glucosidase inhibitor
  • slows the uptake of carbohydrates
• GLP-1 enhancing drugs
  
  • exenatide, liraglutide
  • DPP4 inhibitors (Sitagliptin, Vildagliptin, Saxagliptin)
  • stimulates insulin release, suppresses glucagon, hunger
• insulin
• SGLT2 inhibitor: renal glycaguria
  
  • lose glucose through urine
  • powerful in people who are insulin resistant
  • few issues e.g. thrush and dehydration

Question 28

How can hypertension be managed?

Answer 28

• reduction in salt intake
• thiazide diuretics
• angiotensin converting enzyme (ACE) inhibitors
• angiotensin II receptor blockers
• calcium channel blockers
• Beta blockers
• more

Question 29

How can dyslipidaemia be managed?

Answer 29

• diet
• exercise
• fibrates (fenofibrate; gemfibrozil)
• statins (HMG Co enzyme A reductase inhibitors) (Simvastatin, atorvastatin etc)
  
  • used for cholesterol not triglycerides
• ezetimibe (ezetrol)
• nicotinic acid
  
  • hardly used due to side effects

Question 30

How can hyperuricaemia be managed?

Answer 30

• allopurinol
• lowers uric acid
• new powerful drug

Question 31

What are conclusions about the treatment/prevention of the metabolic syndrome?

Answer 31

• the best treatment for the metabolic syndrome is weight loss
• if that fails each of the component abnormalities need to be corrected