Obesity, Diabetes and Mental Illness.WE DO HAVE A PROBLEM!!

Susanne Miedlich, MDAssistant Professor of Medicine

Division of Endocrinology, Diabetes, and Metabolism

Obesity and diabetes in the general population?

Obesity and diabetes in the US are increasing:

Low Middle High

Low

M

iddl

e

High

<29% >36%

<9%

<1

3.9%2004 2016

Per CDC, as of 2018 in the US:- 13% of adults had diabetes, - 42.4% of adults were obese.

Obesity and diabetes in patients with mental illness?

An old observation…• “Diabetes is a disease which often shows itself in

families in which insanity prevails.”

Henry Maudsley, 1879

What does science tell us?

Patients with schizophrenia are at risk for obesity:

Allison DB et al., 1999, J Clin Psych

p=0.01-0.07 p<0.02

Men Women

Natl Health Interview Survey 1989:Nonschizophrenic individuals: n=80,130Patients with schizophrenia/schizoaffective Dz: n=150.

• MetS in patients with- schizophrenia 33.4%- psychosis 34.6%- bipolar disease 31.7%- depression 31.3%

• Relative Risk (RR) of MetS versus healthy controls (age- and gender-matched): - 1.87 (1.53-2.29) in patients with schizophrenia - 1.58 (1.24-2.03) in patients with bipolar disease- 1.57 (1.38-1.79) in patients with depression

• RR not different for schizophrenia versus bipolar disease• Higher risk in patients with first episode (13.7%, 10.4-16.9) versus multiple

episodes (34.2%, 30.8-36%), even when adjusted for age

Patients with serious mental illness are at risk for Metabolic Syndrome (MetS):

Vancampfort D et al., 2015, World Psychiatry

Abdominal obesity 50-63%

Patients with schizophrenia are at risk for diabetes:

Goff DC et al., 2005, Schizophr Res

Diabetes rates 4-8fold ↑

Patients with schizophrenia are at risk forcardiovascular disease:

Risk for CVD 1.4-2.3-fold ↑

Foguet-Boreu Q et al., 2016, BMC Psychiatry

Patients with schizophrenia have a high cardiovascular mortality:Swedish Population Register 1987-2010:General population: n>10 millionPeople with schizophrenia: n>47000 (0.44%).

Westman J et al., 2018, Epidem Psychiatr Sci

Mortality Rate Ratio: 1.5-10fold ↑

Statistics at Rochester Psychiatric Center (RPC):

Overweight and obese patients: 75.2%Prediabetic and diabetic patients: 30.6%

2015/2016 Adult Inpatients in NY State Psychiatric Centers:

How does it all work

It’s complicated.

Adapted from Henderson DC et al., 2015, Lancet Psychiatry

AntiPsychotic Medication (APM) use is associated with weight gain:

Allison DB et al., 1999, Am J Psych

Olanzapine use is associated with weight gain and hyperglycemia:

Lieberman JA et al., 2005, NEJM

Lamberti JS et al. 2006, Am J Psychiatry

>2-8fold ↑, especially age <45 yrs

Clozapine use is associated with high rates ofMetS:

53% are prediabetic, 21% are diabetic per oGTT.3 patients were newly diagnosed with prediabetes. 4 patients were newly diagnosed with diabetes per oGTT.

Prospective diabetes screening of patients on APM at Strong Ties and MIPS:

• N=19 patients on olanzapine or clozapine screened per oGTT and HbA1c. • Elevated fasting glucose levels determined most diagnoses of prediabetes or diabetes per oGTT, one

patient was identified per 2h elevated glucose only.

Normal (5) Prediabetes (10) Diabetes (4)

Fasting Glucose (mg/dl) 86 110 132

2h Glucose (mg/dl) 102 108 214

HbA1c (%) 5.1 5.7 6.2

Triglycerides (mg/dl) 108 117 186

PHQ-9 score 5 6.6 2

BMI (kg/m2) 28 31 35

Waist/Hip Ratio 1 1.05 1.16

UKDDQ (diet) score 42 39 48

Steps/d 5223 5705 2728

Serretti A, Mandelli L, 2010, J Clin Psychiatr

Use of some, but not all AntiDepressantMedications (ADM) is associated with weight gain:

Metabolic side effects of psychotropic -mechanisms?

APM - metabolic side effects?• Dopamine D2 receptor antagonists• Serotonin antagonists• Histamine antagonists• Adrenergic antagonists• Anticholinergic agents

• Metabolic side effects:-Hyperphagia-Weight gain-Hyperglycemia- Insulin resistance, altered incretin secretion?

Discussed for ADM as well.

How does it work?

Mice without histamine 1 receptors become obese and insulin resistant.

Masaki T et al., 2004, Diabetes

Neuroleptic affinities to H1R correlate withorexigenic effects of APM:

Histamine receptor affinities in rat brain membranes:

PhosphoAMPK activation (orexigenic):

Kim SF et al., 2007, PNAS

Olanzapine causes weight gain and hyperglycemiathrough serotonin receptor 2C antagonism:

Wildtype mice:

Serotonin receptor 2C KO mice:

Lord CC et al. 2017, JCI

GLP-1 levels are reduced after APM injection in rats:

0h after SC injection of vehicle/drug = white1h after SC injection of vehicle/drug = black

Smith, GC et al., 2009, Schizophr Res

Food intake↓

GLP-1↑↓

Insulin↑Glucagon ↓Appetite↓

• Glucagon levels were significantly increased after quetiapine or clozapine injection.• Hyperglycemia (following glucose injection) but not weight gain was noted as well.

Back to humans…

How can we fix the problem?

Means to tackle obesity in patients on APM:

DPP study, patients aged 45-59:

DPP Research Group, 2009, Lancet

Patients on APM, mean age 45:

Daumit GL et al., 2013, NEJM

Means to tackle obesity in patients on ADM:

Imayama I et al., 2013, Prev Med

Means to tackle obesity AND diabetes in patientson APM/ADM:

• Medications of interest → mediating diabetes control, weight loss andpotentially CV benefits• Patients on APM:

1) Metformin (most had prediabetes)- Weight loss 1-6 kg, HbA1c reduction -0.08%

Taylor J et al., 2017, PLOS ONESiskind DJ et al., 2016, PLOS ONE

2) GLP-1 analogues (most had prediabetes)- Weight loss 2-5 kg, HbA1c reduction -0.26%

Larsen JR et al., 2017, JAMA PsychiatrySiskind DJ et al., 2018, Diab Obesity Metab

Ishoy PL et al., 2017, Diab Obesity Metab

3) SGLT2-inhibitors - No data

SGLT2↓ SGLT2-inhibitorProximal renal tubule glucose re-absorption↑

Food intake↓Incretin (GLP-1)↑↓Insulin↑, Appetite↓

Retrospective analysis of diabetic patients on APM seen at URMC Endocrinology:

Descriptive Statistics

Controls (n=35) Cases (n=11)

Mean SE Mean SE

Age (years) 51.66 2.99 55.55 4.39

Height (m) 1.70 .018 1.61 .06

Weight (kg) 103.28 5.0 119.69 9.07

BMI (kg/m2) 35.57** 1.62 47.17** 3.69

HbA1c (%) 9.72 .49 9.60 .42

Systolic BP (mm Hg) 132.21 4.09 134.63 5.21

Diastolic BP (mm Hg) 74.0 1.68 77.09 3.58

Perlis L et al., 2020, Prim Care Companion CNS Disord

Rx with GLP-1 analogue

GLP-1 analogues mediate HbA1c and weightreductions in diabetic patients on APM:

-2,50

-2,00

-1,50

-1,00

-0,50

0,00

HbA

1c c

hang

e (%

)

3 6 12 months

Controls

Cases

Cases: On GLP-1 analogues (n=11).Controls: On alternative regimens (n=35).

Perlis L et al., 2020, Prim Care Companion CNS Disord

-10,00

-8,00

-6,00

-4,00

-2,00

0,00

2,00

4,00

6,00

Wei

ght c

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*

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*p<0.05

GLP-1 analogues are superior to alternative antidiabetics in patients on APM and ADM:Patients on APM AND antidepressant medications: n=22, Cases/on GLP analogues (n=7), Controls/on alternative regimens (n=15).

Perlis L et al., 2020, Prim Care Companion CNS Disord

-2,50

-2,00

-1,50

-1,00

-0,50

0,00

HbA

1c c

hang

es (%

)

3 6 12 months

Controls

Cases

*

*

*p<0.05

Retrospective analysis of diabetic patients on ADM seen at URMC Endocrinology:

Controls GLP-1 Analogues SGLT-2 Inhibitors

Frequency (%) 134 (65.7%) 61 (29.9%) 9 (4.4%)

BMI 32.2 38.9* 29.4

HbA1c 8.848 8.769 8.588

Age 56.5 58.2 59.6

HTN Treatment 94 (70.1%) 45 (73.8%) 6 (66.7%)

Nicotine Use 29 (22%) 8 (13%) 5 (42%)

Insulin Use 104 (77.6%) 61 (100%) 5 (55.6%)

Systolic BP Mean 137 134 137

Diastolic BP Mean 75 76 75

Gonzalez C et al., in preparation

GLP-1 analogues mediate HbA1c and weight reduction in diabetic patients on ADM:

Controls GLP-1 analogues SGLT2-inhibitors Controls GLP-1 analogues SGLT2-inhibitors

HbA1c and weight changes after 12 months of follow up:

p<0.001

Gonzalez C et al., in preparation

Effects:Increased appetite, hyperphagia

Weight gainInsulin resistance

HyperglycemiaHypertriglyceridemia

Therapy options:1. Lifestyle 2. Metformin3. GLP-1 analogues4. SGLT2-inhibitors?

Summary:Neurotransmitter dysfunction in mental illness/

on APM/ADM:

Let us conclude with a case:

• 45yo male patient referred to your clinic for diabetes control with HbA1c of 8.8% (from 6.1%) in 2015. Glucose levels per recall 130-150 mg/dl fasting, slightly higher up to 200 mg/dl later in the day, he has gained 15 pounds since 2013. He eats three meals and likes to snack on chips too. He does not exercise but walks daily (no steps recorded). • PMH: DM, schizophrenia, obesity, HTN, COPD.• Medications: metformin, olanzapine, venlafaxine, metoprolol, tiotropium,

albuterol, pantoprazole, loratadine.• P/E: BMI 35.9 kg/m2, BP 138/86, no cushingoid features, wheezing

noted over upper anterior lung fields, no edema.• Labs: HbA1c 8.8%, electrolytes, crea normal, ALT 105, AST 61, GGT

130, TG 400, LDL 96, HDL 42.

• 45yo male patient referred to your clinic for diabetes control with HbA1c of 8.8% (from 6.1%) in 2015. Glucose levels per recall 130-150 mg/dl fasting, slightly higher up to 200 mg/dl later in the day, he has gained 15 pounds since 2013. He eats three meals and likes to snack on chips too. He does not exercise but walks daily (no steps recorded). • PMH: DM, schizophrenia, obesity, HTN, COPD.• Medications: metformin, olanzapine, venlafaxine, metoprolol, tiotropium,

albuterol, pantoprazole, loratadine.• P/E: BMI 35.9 kg/m2, BP 138/86, no cushingoid features, wheezing

noted over upper anterior lung fields, no edema.• Labs: HbA1c 8.8%, electrolytes, crea normal, ALT 105, AST 61, GGT

130, TG 400, LDL 96, HDL 42.

℞:Start a GLP-1 analogue

(exenatide, liraglutide, dulaglutide, semaglutide)

Questions?