Should Psychiatrists be diagnosing (and treating) metabolic syndrome

Should Psychiatrists be diagnosing (and treating) metabolic syndrome David Hopkins Clinical Director, Diabetes King s College Hospital, London

Diabetes prevalence (thousands) Diabetes in the UK: 1995-2010 3000 2500 Type 1 Type 2 2000 1500 1000 500 0 1995 2000 2010

Type 2 Diabetes in the Psychiatry UK Annual Conference 2013 Overall prevalence 4.4 % 13.8 % of over 60s @ 2 x greater among Afro-Caribbean @ 4-5 x greater among S. Asians Source: DUK

Diabetes causes morbidity microvascular & macrovascular complications

The risk of diabetes in relation to weight and weight change. 25 21.1 20 15 10 5 0 9.1 5.3 2.1 6.3 3.6 1.0 2.5 1.0 <5 kg 5-10 kg 11+ kg Weight change since age 21 <22 22-23 BMI at 21 years 24+ From: Chan et al. 1994, Diabetes Care,

Why does obesity lead to diabetes? Insulin resistance is the key Adipose tissue ( especially abdominal) impairs insulin action raised circulating lipids impair insulin action proinflammatory effects of visceral adiposity specific cytokine effects, e.g.tnfa, Resistin

Pre-diabetes metabolic syndrome Definition based on central obesity waist circumference > 94 cm men >80 cm women Plus any two of: HDL < 1.0 mmol/l men or < 1.3 women TG > 1.7 mmol/l BP > 130 /85 FPG > 5.6 mmol/l IDF consensus 2004

Coronary artery disease and metabolic syndrome P < 0.001 P < 0.01 300 250 200 150 100 50 0 WHO IDF NCEP Not metabolic syndrome Metabolic syndrome

Relative risk Influence of BMI on mortality: non-smokers 4.5 4 3.5 All cause mortality Cardiovascular mortality 3 2.5 2 1.5 1 0.5 0 <19 19-22 22-25 25-27 27-29 29-32 >32 BMI

Metabolic syndrome Prevalence varies by population 14%- 28% men 18% - 31 % women - highest rates in SE Asians In Bipolar disorder: overall prevalence ~ 37.3% Odds ratio to comparator population ~ 2 Use of antipsychotic drugs relative risk 1.7 In Schizophrenia: overall prevalence 32.5 % Vancampfort, Am J Psychiatry, Mitchell Schizoph Bull 2011

Relative risk of diabetes in atypical antipsychotics compared to typical antipsychotics: systematic review Pooled relative risk 1.26 (95% CI 1.10 to 1.53) Less diabetogenic More diabetogenic Smith et al BJPsych2006

Potential mechanisms Central effects on weight and insulin sensitivity Probably primarily mediated by antagonism at 5HT2 receptors Additional potential effects on a2 adrenergic receptors Additional inhibitory effects on b-cell function?

Antipsychotic induced weight gain Weight Change After 10 Weeks on Standard Drug Doses Allison et al American Journal of Psychiatry 1999

Metabolic syndrome at diagnosis of schizophrenia Rates of metabolic syndrome similar to background population at time of first- episode Very high prevalence of abdominal obesity and individual elements at diagnosis 58% 1 or more elements Progressive worsening of risk factors in early course of schizophrenia Eufest study group, 2012

So should we screen for metabolic syndrome?

So should we screen for metabolic syndrome?

So should we screen for metabolic syndrome? Physical Height weight BMI waist circumference Blood Pressure

So should we screen for metabolic syndrome? Biochemical Fasting glucose - 6 mmol/l HbA1c diagnostic 6.5% - abnormal 6% Lipid profile Urine ACR ( if DM or metabolic syndrome present) TFTs

Screening for cardiovascular risk factors Audit of 21 UK Trusts/Healthcare organisations 48 assertive outreach teams 1966 patients Barnes et al Schizophr Bull 2007

Managing cardiovascular risk in psychotic illness Life expectancy reduced by 20 years Cardiovascular related deaths Reasons: common risk factors e.g. smoking, poor diets, physical activity psychotropic medication inequitable access to health care institutionalisation

Reducing risk Behavioural change correcting adverse lifestyle factors Aggressive management of CVS risk factors Collaborative management of diabetes Lipids: Overwhelming evidence for benefits of statin: target LDL < 2 mmol/l BP: Target < 130/80 Supportive evidence for ACEI/ A2RB as first line agents

Treatments for type 2 diabetes - RCPsych old Faculty & of new Forensic Insulin secretagogues sulphonylureas gliclazide etc. 1940s DPP 4 inhibitors sitagliptin etc. 2006 Insulin sensitising biguanides metformin 1950s thiazolinediones pioglitazone 2000 Glucose absorbtion/ excretion a-glucosidase acarbose 1996 SGLT-2 Inhibitors dapagliflozin 2013 Injectable Insulin 1922 GLP-1 agonists 2006

Metformin introduced in 1950s in Europe, but only licensed in USA in 1995 reduces hepatic glucose output and increases glucose uptake in muscle very cheap weight neutral GI side effects limiting in some patients contra-indicated in renal impairment

The Thiazolinediones selective agonists of PPAR g nuclear transcription factor Multiple effects on downstream insulin signalling pathway Improve insulin sensitivity Positive effects on lipids and inflammatory markers Expected to have CVS benefits in metabolic syndrome but associated with increased CVS events! Troglitazone 1997 Rosiglitazone 2000-09 Pioglitazone 2000 -?

GLP-1 Effects in Humans GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucosedependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying

GLP-1 and DPP- 4 Rapid inactivation (DPP-4), Short elimination half-life (~1-2 min) GLP-1 must be administered continuously (infusion) Limited therapeutic utility

Two Therapeutic approaches DPP-4 inhibitors Protect native GLP-1 from inactivation by DPP-4 GLP-1 receptor agonists Mimic native GLP-1 but resistant to degradation by DPP-4 Sitagliptin Saxagliptin Linagliptin Exenatide Liraglutide Oral agents, modest efficacy Weight neutral Alternative to SU Injectable drug Weight reducing Alternative to insulin

Exenatide The first incretin drug Synthetic form of reptilian incretin, Exendin -4 Exendin -4 shares 50% amino-acid sequence homology with human GLP- 1 Resistant to DPP-IV deactivation, last about 6hr, peak after 2hr Approved Nov 2006

Change in HbA 1c (%) Exenatide Phase 3 Studies Changes in HbA1c Over 30 Weeks Mean baseline A1c 8.2 to 8.7% Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID 0.5 MET (336) SFU (377) MET + SFU (733) 0.1 0.1 0.2 0-0.5-1 -0.4 * -0.8 * -0.5 * -0.9 * -0.6 * -0.8 * Refs: DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

Exenatide in routine UK practice HbA1c % 10.5 10 9.5 9 8.5 8 7.5 7 9.41% Before exenatide p < 10-126 8.65% N = 3054 After exenatide 0.75%

Exenatide in routine UK practice 120 115 p < 10-15 N = 2997 Weight Kg 110 114 kg 109 kg 4.9 kg 105 100 Before exenatide After exenatide

Exenatide once-weekly First once weekly drug for diabetes Given as deep subcutaneous injection Similar efficacy to daily GLP-1 Agonists Potential benefit where supervision of Rx required

120 Daily GLP-1 Weekly GLP-1 Weight kg 110 100 90 80 11 HbA1c % 10 9 8 7 6

Potential Pitfalls 29 year old African Male 2001: diagnosed with schizophrenia Rx Clozapine 2002: presented with diabetic ketoacidosis Weight 108kg, BMI 32, estimated weight gain 18 kg since original diagnosis 2002-2005: insulin treated, but compliance poor. 2006; Now on quetiapine. Insulin discontinued blood glucose control appeared satisfactory A1c @ 7.5%

Potential Pitfalls 29 year old African Male 2001: diagnosed with schizophrenia Rx Clozapine 2002: presented with diabetic ketoacidosis Weight 108kg, BMI 32, estimated weight gain 18 kg since original diagnosis 2002-2005: insulin treated, but compliance poor. 2006; Now on quetiapine. Insulin discontinued blood glucose control appeared satisfactory A1c @ 7.5% 2006: acute deterioration in mental health recurrent admissions Random BG noted to be high on several occasions 17 20 mmol/l but no action taken.

Potential Pitfalls 29 year old African Male 2001: diagnosed with schizophrenia Rx Clozapine 2002: presented with diabetic ketoacidosis Weight 108kg, BMI 32, estimated weight gain 18 kg since original diagnosis 2002-2005: insulin treated, but compliance poor. 2006; Now on quetiapine. Insulin discontinued blood glucose control appeared satisfactory A1c @ 7.5% 2006: acute deterioration in mental health recurrent admissions Random BG noted to be high on several occasions 17 20 mmol/l but no action taken. Dec 2006 found dead at home: Post mortem diagnosis ketoacidosis

Ketoacidosis and antipsychotic medication Multiple case reports of diabetic ketoacidosis in patients with diabetes associated with anti-psychotic medication, including quetiapine, olanzapine and risperidone May in part reflect background population ketosis prone type 2 diabetes particularly prevalent in patients of African and Afro- Caribbean descent and over-represented in reported fatal cases Highlights importance of cehcking for urine or blood ketones in patients with marked hyperglycaemia

Summary Very high prevalence of metabolic syndrome and type 2 DM in severe mental illness Interplay of unhealthy lifestyles, medication and poor access to physical health care greatly increases cardiovascular risk Potential to achieve better management with integrated approach including diabetes care in psychological management