Preventing Diabetes and Obesity in Patients with Mental HealthPROFESSOR STEVEN C. BOYAGESTHE UNIVERSITY OF SYDNEY, TUESDAY 18 T H OCTOBER 2016WORLD FEDERATION FOR MENTAL HEALTH INTERNATIONAL CONFERENCE, CAIRNS AUSTRALIA

Outline 1. What is diabetes and its relation to obesity (prediabetes and metabolic syndrome)

2. Diabetes and Mental Health Co-Morbidity

3. Treatment of MH disorders may increase the incidence of diabetes and metabolic disorders

4. Premature vascular disease is the biggest killer of patients with MH

5. Treatment of other vascular risk factors is essential

6. Prevention and early identification of diabetes and metabolic syndrome is the key

Diabetes and Mental Health Co-Morbidity

1. Depression, anxiety disorders, dementia, schizophrenia, and bipolar disorder (BD) occur more commonly in DM patients.

2. DM may be involved in the development of the first three conditions. The exact mechanism by which DM may be linked to these conditions is not fully understood.

3. There appears to be a bidirectional relationship between DM and depression.

4. About 7% of DM cases are thought to be attributed to depression.

5. Depression is associated with a 60% to 65% increased risk of DM

6. DM appears to double the risk of dementia

Other risk factors Smoking Hypertension Hyperuricemia Hyperlipidemia Sleep apnea Drug induced diabetes

Male Gender Genetic factors

Leading cause of death is vascular disease

1. Despite the increased risk of suicide in psychiatric patients, the leading cause of death in patients with schizophrenia or BD is cardiovascular disease (CVD).

2. This is especially true in younger patients, with the risk of CVD and stroke more than two to three times greater than in a nonpsychiatric population.

3. MetS occurs in 37% to 63% of schizophrenia patients and in 30% to 49% of BD patients.

4. Psychotropic medications used for managing mental illness can contribute to the development of MetS.

Drug induced obesity and diabetes

Atypical antipyschotics (AA)Among AAs, clozapine and olanzapine are associated with the greatest weight gainQuetiapine and risperidone with intermediate weight gainAripiprazole, paliperidone, and ziprasidone with the least weight gain

Possible mechanisms for psychotropic-related WG include WG secondary to improved mood/affect; increased food cravings; alterations in resting metabolic state; sedation; increased cellular lipogenesis; and changes in neurotransmitters (e.g., 5-HT [serotonin] 1 and 2A/C receptor antagonism) and neuropeptides (e.g., leptin, ghrelin, cytokines such as TNF)

Diabetes

Prediabetes

Obesity/Metabolic Syndrome

Mechanism: Obesity is the result of long-term energy imbalance whereby energy intake surpasses expenditure

9

This imbalance may be caused by a variety of intrinsic and

extrinsic factors

Hill JO et al. Circulation. 2012;126(1):126–32

Cause: Factors contributing to energy imbalance

10

Energy imbalance

GeneticsInheritability

Epigenetic changesEarly life experience

Behaviour Poor dietary habits

and physical inactivity

Medications

Social, political and economic environment

Common medical conditionsLeptin resistanceHypothyroidism

Cushing’s syndromeDepression

Sleep disturbances

Hormones

Hill JO et al. Circulation. 2012;126(1):126–32; Baqai N and Wilding JPH Obesity and metabolic complications 2015;43(2):73–76; National Health and Medical Research Council (2013) Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. Melbourne: National Health and Medical Research Council.

Psychological factors

StressPersonal issuesMood disorders

DepressionDisturbed eating

patternsEating disorders

Sociodemographic factors

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Who are the overweight or obese??

Who are the overweight or obese??

1.88 m

113 kg

BMI = 32Obese, class I

1.57 m

130 kg 90 kg

1.75 m

BMI = 29.4Overweight

BMI = 52.7Obese, Class III

Based on weight and height alone

Healthy weight

Taking into consideration the individual patient type

1.94 m

104 kg

BMI = 27.6Overweight

12

Obesity is defined by the World Health Organisation as abnormal or excessive fat accumulation that may impair health1

Definition and measure of obesity

13

1. WHO. Fact sheet 311. Updates January 2015. Available at www.who.int/. 2. National Health and Medical Research Council (2013) Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. Melbourne: National Health and Medical Research Council.

Body Mass Index (BMI) provides the most convenient population-level measure of overweight and obesity1

Waist circumference is a good indicator of total body fat and a useful predictor of visceral fat2

Compared with BMI, waist circumference is a better predictor of cardiovascular risk, type 2 diabetes in women and metabolic syndrome2

14

Measures of obesity Thresholds based on Caucasian population

Classification BMI (kg/m2)

Underweight <18.5

Normal range ≥18.5 and <24.9

Overweight ≥25 and <29.9

Obese ≥30

- Obese class I ≥30 and <34.9

- Obese class II ≥35 and <39.9

- Obese class III ≥40

Gender Increased disease risk

High disease risk

Males ≥ 94 cm ≥ 102 cm

Females ≥ 80 cm ≥ 88 cm

BMIClassification

WaistCircumference

Measured midwaybetween the lower ribmargin and iliac crest

BMI = weight (kg) height (m)2

National Health and Medical Research Council (2013) Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. Melbourne: National Health and medical Research Council.

BMI and waist circumference thresholds

15

Patient groups

Waist circumference threshold

Women Men

South Asian, Chinese, Japanese adults ≥ 80 cm ≥ 90 cm

Other ethnic groups, e.g. Pacific Islanders

Higher than those of European descent, not yet determined

Patient groups Distribution of fat BMI (kg/m2) thresholds

Aboriginal people High limb to trunk ratio Lower

Pacific Islander populations (including Torres Strait Islander peoples and Maori)

Higher proportion of lean body mass Higher

South Asian, Chinese and Japanese population groups More body fat at lower weights Lower,

e.g. >23

People with high muscle mass (e.g. athletes) Lower proportion of body fat Higher

Older individuals More body fat than a younger individual at the same BMI Lower

Adjustments are needed for different patient groups

National Health and Medical Research Council (2013) Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. Melbourne: National Health and Medical Research Council.

Core Defects of Type 2 DiabetesDisease Progression Starts Early1

Conceptual representation. Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier.

Insulin level

Insulin resistanceHepatic glucose

production

Beta-cell function

Progression of Type 2 Diabetes Mellitus

Impaired Glucose Tolerance

Diabetes Diagnosis

Frank Diabetes

4–7 years

Development of Macrovascular Complications

Development of Microvascular Complications

Badman MK and Flier JS Science 2005;307:1909–14

Cause: Hormonal regulation of energy balance

17

GLP-1, CCK, PYY, OXM Leptin Insulin, Amylin, PPGut Adipose tissue Pancreas

Satiety signals

Hypothalamus

GhrelinGut

Hunger signal

Anorexigenic neurons

Orexigenic neurons

GLP-1, glucagon-like peptide-1; CCK, cholecystokinin; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY

Appetite

Hunger

Appetite

Satiety

Arcuate nucleus

Treatment options for weight management and recommendations

18Treatment intensification

Low

Mea

n we

ight

loss

High

Med

ium

BMI 25-26.9BMI 27-29.9

with risk factors and/or comorbidities or

BMI > 30

Grima M and Dixon JB AFP 2013;42(8):532-41; National Health and Medical Research Council (2013) Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. Melbourne: National Health and Medical Research Council.

Lifestyle & Behavioural changes: Healthy eating, physical activity and psychological intervention

Reduced calorie diet/Very Low Energy diet

Anti-obesity medications with weight loss of 5–10%

Bariatric surgery

BMI 35-39.9 with risk factors and/or

comorbidities orBMI ≥40

Prevention of Obesity and Diabetes: Principles

1. Record weight and other measures

2. Record degree of obesity

3. Check for diabetes and prediabetes and metabolic syndrome

4. Lifestyle advice, smartphone apps

5. Physical activity

6. Smoking cessation

7. Treat hypertension and lipids

8. Medication for obesity and diabetes

5–10% weight loss is clinically meaningful

20

Diabetes (Prevention)

Hypertension

Dyslipidaemia

Hyperglycaemia (elevated HbA1c)

Non-alcoholic fatty liver disease

Sleep apnoea

Osteoarthritis

Stress incontinence

Gastroesophageal reflux disease

Polycystic ovary syndrome

Health-related quality of life

-20-15-10-50

Weight loss required for therapeutic benefit (%)

Obes

ity c

ompl

icatio

n

Maximum benefit at 10%

Triglycerides still decreasing at >15%

HbA1C still decreasing at >15%

Improves steatosis, inflammation, and mild fibrosis

Improves symptoms and joint stress mechanics

5–10% in women; 10% in men>10% optimal; lowers androgens, improves ovulation, and increases insulin sensitivity

Continues to improve with weight-loss

Blood pressure still decreasing at >15%

Cefalu WT et al. Diabetes care 2015;38(8):1567-82. Wright F et al. J Health Psychol. 2013;18:574-86.

Approved anti-obesity medications in Australia

211. Duromine™ Approved Product Information, July 1991. 2. Metermine Approved Product Information, July 2004. 3. Xenical® Approved Product Information, April 2000

• Approved in 1991/ 2004• S4 • Private script• Sympathomimetic amine

Duromine™ / Metermine (Phentermine)1,2

• Approved in 2000• S3• Private script; available on the PBS under the Repatriation

Pharmaceutical Benefits Scheme• Potent, specific and reversible long acting inhibitor of

gastrointestinal lipases required for the systemic absorption of dietary triglycerides

Xenical® (Orlistat)3

New anti-obesity medication approved for weight management in Australia

22Saxenda® Approved Product Information, December 2015

• Approved December 2015• S4• Liraglutide is a human glucagon-like peptide (GLP-1)

analogue, with 97% amino acid sequence homology to endogenous human GLP-1

• Like endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor (GLP-1R)

• GLP-1 is a physiological regulator of appetite and calorie intake

Saxenda® (Liraglutide 3.0 mg)

Patients maintained a clinically meaningful weight loss with liraglutide 3.0 mg

23

Week

Chan

ge in

wei

ght f

rom

ba

selin

e (%

)

p<0.0001

-8.0%

-2.6%

-9.2%

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56-12

-10

-8

-6

-4

-2

0

-3.5%

Liraglutide 3.0 mg + diet and exercise72% completed 56 weeks of treatment

Diet and exercise alone64% completed 56 weeks of treatment

p<0.001

Adapted from Pi-Sunyer 2015. Circle represents weight-loss at week 56 using Last Observation Carried Forward (LOCF) imputation. Square represents weight-loss at week 56 using completer data set

Patients maintained a clinically meaningful weight loss over 56 weeks with liraglutide 3.0 mg

Pi-Sunyer X et al. N Engl J Med 2015;373:11–22. Saxenda® Approved Product Information, December 2015

Mean baseline weight: 106 kgMean baseline BMI: 38.3

Pathophysiology of diabetes

HYPERGLYCEMIA

Decreased incretin effect Increased

lipolysis

Increased glucose reabsorption

Decreased glucose uptakeNeurotransmitter

dysfunction

Increased hepatic glucose production

Impaired insulin secretion

Increased glucagon secretion

SGLT2 inhibitor

s

TZDs

GLP-1 RA; AGIs

GLP-1 RA; TZDs, DPP4i, SU

GLP-1 RA; DPP4i

Metformin, TZDs, GLP-1 RA

GLP-1 RA

TZDs, metformin

AGI, alpha-glucosidase inhibitor; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; TZD, thiazolidinedione.1. DeFronzo RA. Diabetes. 2009;58(4):773–795.

Inactivated by DPP-4

DPP-4: dipeptidyl peptidase 4 enzyme; GLP-1: glucagon-like peptide-1; GIP: glucose-dependent insulinotropic polypeptide

Glucagon(GLP-1)

Insulin(GLP-1 and GIP)

Glucose dependent

Pancreasα

β

Ingestion of food

GI tract Hepatic glucose production

Glucose uptake by peripheral

tissue

LiverGlycogenesisGluconeogenesis

IncretinsGLP-1 and GIP

Blood glucose in fasting and

postprandial states

Skeletal muscle

INCRETIN ACTIVITY CAN BE ENHANCED1-3

Adapted from: 1. Drucker DJ. Cell Metab 2006; 3: 153–65. 2. Ludwig DS. J Am Med Ass 2002; 287: 2414–23. 3. Dunning BE and Gerich JE. Endo Rev 2007; 28: 253–83.

1. Diabetes in control.com Available from www.diabetesincontrol.com/contact-us/5139 [Accessed 2/2/13]

+ Dr John Eng in 1992

Exendin-4

Exenatide H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

Gila lizard saliva

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

+ Amylin Pharmaceuticals in 1996

DEVELOPMENT OF BYETTA (EXENATIDE)

1. Klonoff DC et al. Curr Med Res Opin 2008; 24: 275–86. 2. Byetta Approved Product Information.

• Weight loss >1.5 kg per week has been observed in patients treated with exenatide2

• Weight loss of this rate may have harmful consequences2

†Secondary endpoint.1 *Byetta is not indicated as a weight reduction agent.2

BYETTA 10 μg BID PROVIDED LONG-TERM GLYCAEMIC CONTROL WITHOUT WEIGHT GAIN AND WITH WEIGHT LOSS OVER 156 WEEKS1*†

Glucose input >250 g/day: Glucose uptake >250 g/day:4

Dietary intake >180 g/day

Increased glucose production3

– Gluconeogenesis*– Glycogenolysis

Brain ~125 g/day

Rest of the body >125 g/day

Increased reabsorption and recirculation of glucose

Glucose filtered~360 g/day†

Glucose levels exceed the glucose reabsorption

threshold, resulting in glucosuria1

*Elevated glucose production in patients with Type 2 diabetes attributed to hepatic and renal gluconeogenesis.3†Assumes a maximum renal absorption of 200 mg/dL2 and a daily filtration rate of 180 L/day3

1. Chao EC, et al. Nat Rev Drug Discov 2010;9:551–9; 2. Marsenic O. Am J Kidney Dis 2009;53:875–83. 3. Gerich JE. Diabet Med 2010;27:136–42. 4. Wright EM, et al. J Int Med 2007;261:32–43.

Type 2 diabetes glucose input and uptake1-4

Dapagliflozin:Removes excess glucose via the kidneys1,2 and acts independently of insulin mechanisms

1. Gerich JE, Bastien A. Expert Rev Clin Pharmacol 2011;4:669−683. 2. FORXIGA (dapagliflozin) Product Information.

Increased urinary excretion of excess glucose (~70 g/day)

Glucose filtration

SGLT2

SGLT2

Dapagliflozin

Glucose

Dapagliflozin

Reduced glucose reabsorption

Distaltubule

Loop of Henle

Glomerulus Proximal tubule

Dapagliflozin plus metformin IR: Change in Weight† Over 208 Weeks1-4(compared to SU plus metformin IR)

1. FORXIGA Product Information. 2. Del Prato S et al. Diabetes Obes Metab 2015; 17:581-590. 3. Nauck MA, et al. Diabetes Care 2011;34:2015–2022. 3. Nauck MA, et al. Diabetes Care 2011;34:2015–2022. 4. Nauck MA et al. Diabetes Obes Metab 2014; 16:1111-1120

*Data are adjusted mean change from baseline ±95% CI derived from a longitudinal repeated-measures mixed model.

Weight reduction with dapagliflozin at 52 weeks was maintained up to 208 weeks, whereas weight gain with glipizide at 52 weeks remained stable 1,2

Adapted from Del Prato S, et al.1,2

†Dapagliflozin is not indicated as a weight loss agent.

p value not available

Prevention of Obesity and Diabetes: Principles

1. Record weight and other measures

2. Record degree of obesity

3. Check for diabetes and prediabetes and metabolic syndrome

4. Lifestyle advice, smartphone apps

5. Physical activity

6. Smoking cessation

7. Treat hypertension and lipids

8. Medication for obesity and diabetes