This document summarizes a presentation on preventing diabetes and obesity in patients with mental health issues. It discusses how mental health disorders are associated with higher risks of diabetes and metabolic syndrome due to genetic and lifestyle factors as well as some medications used to treat mental health conditions. Treatment of diabetes and other vascular risk factors is essential for patients with mental health issues since premature death is often due to cardiovascular disease rather than suicide. The presentation emphasizes preventing and early identification of diabetes and metabolic syndrome through lifestyle counseling, monitoring weight and metabolic markers, and treating obesity and diabetes when present.

1. Preventing Diabetes and
Obesity in Patients with
Mental Health
PROFESSOR STEVEN C. BOYAGES
THE UNIVERSITY OF SYDNEY, TUESDAY 18 TH OCTOBER 2016
WORLD FEDERATION FOR MENTAL HEALTH INTERNATIONAL CONFERENCE, CAI RNS AUSTRALIA

2. 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

4. 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

5. Other risk factors
Smoking
Hypertension
Hyperuricemia
Hyperlipidemia
Sleep apnea
Drug induced diabetes
Male Gender
Genetic factors

6. 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.

7. Drug induced obesity and diabetes
Atypical antipyschotics (AA)
Among AAs, clozapine and olanzapine are associated with the
greatest weight gain
Quetiapine and risperidone with intermediate weight gain
Aripiprazole, 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)

8. Diabetes
Prediabetes
Obesity/Metabolic
Syndrome

9. 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

10. Cause:
Factors contributing to energy imbalance
10
Energy
imbalance
Genetics
Inheritability
Epigenetic changes
Early life experience
Behaviour
Poor dietary habits
and physical inactivity
Medications
Social, political and
economic environment
Common medical
conditions
Leptin resistance
Hypothyroidism
Cushing’s syndrome
Depression
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
Stress
Personal issues
Mood disorders
Depression
Disturbed eating
patterns
Eating disorders
Sociodemographic
factors

11. Who are the overweight or obese??
11

12. Who are the overweight or obese??
1.88 m
113 kg
BMI = 32
Obese, class I
1.57 m
130 kg 90 kg
1.75 m
BMI = 29.4
Overweight
BMI = 52.7
Obese, Class III
Based on weight and
height alone
Healthy weight
Taking into
consideration the
individual patient type
1.94 m
104 kg
BMI = 27.6
Overweight
12

13. 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
14
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
BMI
Classification
Waist
Circumference
Measured midway
between the lower rib
margin 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.

15. 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.

16. Core Defects of Type 2 Diabetes
Disease 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 resistance
Hepatic 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

17. 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, PP
Gut Adipose tissue Pancreas
Satiety signals
Hypothalamus
Ghrelin
Gut
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

18. Treatment options for weight
management and recommendations
18
Treatment intensification
Low
Meanweightloss
HighMedium
BMI 25-26.9
BMI 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 or
BMI ≥40

19. 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

20. 5–10% weight loss is clinically meaningful
20
-20-15-10-50
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
Weight loss required for therapeutic benefit (%)
Obesitycomplication
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.

21. 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

22. 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)

23. Patients maintained a clinically meaningful
weight loss with liraglutide 3.0 mg
23
Week
Changeinweightfrom
baseline(%)
p<0.0001
-8.0%
-2.6%
-9.2%
-12
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
-3.5%
Liraglutide 3.0 mg + diet and exercise
72% completed 56 weeks of treatment
Diet and exercise alone
64% 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 kg
Mean baseline BMI: 38.3

24. 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
inhibitors
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.

25. 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
Pancreas
α
β
Ingestion of
food
GI tract Hepatic glucose
production
Glucose uptake
by peripheral
tissue
Liver
Glycogenesis
Gluconeogenesis

Incretins
GLP-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.

26. 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)

27. 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*†

28. 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

29. 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
Distal
tubule
Loop of
Henle
Glomerulus
Proximal
tubule

30. 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

31. 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