Psychiatry Meeting - PowerPoint Presentation

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Psychiatry Meeting24th November 2016

Andrew Gallagher

Consultant Physician

and Endocrinologist

NHS Greater Glasgow & ClydeSlide2
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Prevalence – 2015 data

WORLDWIDE

Almost 300 million people with diabetes aged 20-79

There is a very slight female predominance

GREATER GLASGOW & CLYDE 2015

61,457 people with diabetes

6,244 Type1: 56% male, 44% female

54,515 Type2: 55.5% male, 44.5% female

698 Other Slide4

Treatment options for T2DM until relatively recently

Tablets

Biguanides

: ↑ insulin sensitivity, ↓ liver production of glucose

Sulphonylureas

: stimulate pancreas to release insulin

Thiazolidinediones

:↑ insulin sensitivity, ↓ liver production of glucose

Injections

Insulin:

In its many guisesSlide5

Why do we continue to need new treatments for Type 2 diabetes?Glycaemic control deteriorates over time.

Until recently the treatments available increased the risk of hypoglycaemia and weight gain.Slide6

Obesity and DiabetesMild

2 risk of developing diabetes

Moderate 5 risk of developing diabetes

Severe 10 risk of developing diabetesSlide7

The Incretin SystemOrally ingested glucose leads to a much higher insulin response than iv glucose -

Incretin

Effect.

Comprises 60% postprandial insulin secretion.

Two predominant incretins

Glucagon-like peptide (GLP-1)

Glucose-dependent insulinotropic peptide (GIP)Slide8

L-Cell

(ileum)

Proglucagon

GLP-1 [7-37]

GLP-1 [7-36NH

2

]

K-Cell

(jejunum)

ProGIP

GIP [1-42]

GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food IntakeSlide9

Role of Incretin Hormones in Glucose Homeostasis

Secreted in response to food intake and help regulate post-meal glucose homeostasis

Glucose Regulation

Stimulate insulin secretion from islet

β

-cells in a glucose- dependent manner

Suppress glucagon release from islet

α

-cells

Gastrointestinal Effects

Regulate gastric emptying, feeling of satiety and fullness, and energy intake

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GLP-1 Has Multiple Desirable Effects

Efficacious glucose lowering

Increased insulin secretion (glucose dependent)

Increased insulin biosynthesis

Increased

β

-cell glucose sensitivity

Decreased glucagon secretion (glucose dependent)

Delayed gastric emptying

Increased

β

-cell mass (shown in animal models)

Body weight lowering

Delayed gastric emptying Increased fullness and satiety Decreased food intakePotential to halt disease progression Increased β-cell glucose sensitivity Increased β-cell mass (shown in animal models)Slide11

Baggio & Druker Gastroenterology 2007;132:2131-2157

How can we resolve this problem Pharmacologically?

GLP-1 is Rapidly Degraded by the Enzyme DPP-4Slide12

The Family of Incretin Based Therapies

Incretin-Based Therapies

DPP-4 inhibitors

Sitaglitin, Vildagliptin, Saxagliptin Linagliptin Alogliptin

GLP-1 Receptor Agonists

Exendin-Based Therapies

Exenatide,

Human GLP-1 Analogues

Liraglutide

DPP-4 Inhibitors lead to physiological levels of GLP-1, whereas GLP-1 Receptor Agonists achieve high Pharmacological levels of GLP-1

DPP-4 Resistant Analogues

Lixisenatide

Albiglutide

DulaglutideSlide13

Sodium-Glucose TransportersSlide14
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SGLT2 Inhibitors

Dapagliflozin, Canagliflozin, Empagliflozin

These offer the potential to primarily increase renal excretion of glucose by up to 70g daily and create a negative energy balance without affecting intestinal function.

They will not stimulate insulin release.

They may be renoprotective.Slide17

Current treatment options for T2DM

Tablets

Biguanides

: ↑ insulin sensitivity, ↓ liver production of glucose

Sulphonylureas

: stimulate pancreas to release insulin

Thiazolidinediones

:↑ insulin sensitivity, ↓ liver production of glucose

DPP4 inhibitors:

↑ meal-related insulin secretion

SLGT2 inhibitors:

↑ renal excretion of glucose

Injections

Insulin:

In its many guisesGLP1 agonists: ↓ appetite, ↓ rate of gastric emptying, ↑ meal-related insulin secretion, ↓ glucagon effectsSlide18

Treatment options for type 2 diabetes mellitus

GLP-1 agonist

GLP-1 agonists

Sulphonylureas

DPP-4 inhibitors

GLP-1 Agonists

Biguanides

TZDs

DPP-4 inhibitors

GLP-1 agonists

SLGT2 Inhibitors

TZDs

TZDs

↓ appetite

↓ rate of gastric emptying

↓ glucagon production

↑ insulin production↓ glucose production↑ glucose excretion↑ glucose intake↓ fatty acid release↑ glucose metabolism↓ insulin resistanceSlide19

Special

Considerations

Examples

Drug(s) Indicated

Drug(s) Contra-Indicated

Hypoglycaemia

Employment (drivers)

Living alone (especially

elderly)

Glitazones

Gliptins

GLP-1 receptor agonists

SGLT-2 inhibitors

Sulphonylureas

Insulin

Weight gain

BMI>30 in Caucasians

BMI>28 in South AsiansObstructive sleep apnoeaGliptins

GLP-1 receptor agonists

SGLT-2 inhibitors

Sulphonylureas

Glitazones

Insulin

Subcutaneous administration unacceptable

Needle phobiaFrail or elderly leading loss of independenceSulphonylureasGliptins

Glitazones

SGLT-2 inhibitors

Insulins

GLP-1 receptor agonists

Risk of bone fractures

Postmenopausal females

Known Osteoporosis

Secondary causes

Sulphonylureas

Gliptins

GLP-1 receptor agonists

SGLT-2 inhibitors

GlitazonesSlide20

Improving Diabetes Control & Cardiovascular RiskThe Holy Grail?

Evidence that glucose lowering reduces the rates of cardiovascular events and death has not been convincingly shown.

Concern has been raised about the cardiovascular safety of some glucose lowering drugs.

Regulatory authorities have mandated cardiovascular safety assessments of new diabetes treatmentsSlide21

EMPA-REG

Hypothesis

Empagliflozin would be non-inferior to Placebo with regard to the primary outcome.

A Safety Outcome Trial

7020 patients randomised, median follow up 3.1 years.

Primary outcome: death from CVD, non-fatal MI, non-fatal stroke.

Results

490 / 4687 (10.5%) Empagliflozin v 282 / 2333 Placebo(12.1%) P<0.001 non-inferiority, P=0.04 for superiority.

Death from CVD 172 (3.7%) Empagliflozin v 137 (5.9%) Placebo P<0.001Slide22

LEADERHypothesis

Liraglutide would be non-inferior to Placebo with regard to the primary outcome.

A Safety Outcome Trial

9340 patients randomised, median follow up 3.8 years.

Primary outcome: death from CVD, non-fatal MI, non-fatal stroke.

Results

608 / 4668 (13.0%) Liraglutide v 694 / 4672 Placebo (14.9%) P<0.001 for non-inferiority, P=0.01 for superiority.

Death from CVD: 291(4.7%) Liraglutide v 278 Placebo (6.0%) P=0.007Slide23

In the Pipeline – Type 2 DM

Glucokinase activators

DS-7309, PF04937319, TTP399Slide24
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In the Pipeline – Type 2 DM

Glucokinase activators

DS-7309, PF04937319, TTP399

iBat inhibitorsSlide26
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In the Pipeline – Type 2 DM

Glucokinase activators

DS-7309, PF04937319, TTP399

iBat inhibitors

Fibroblast Growth Factor 21

LY2405319, AMG876

GPR119 agonists

Glucagon receptor antagonists

LGD6972, LY2409021

Glut 4 stimulantsSlide28

‘Dr Gallagher, can I be excused? My brain is full’Slide29

Diabetes & SchizophreniaLong-standing association which pre-dates use of antipsychotics and mood stabilisers.

2-3 increased incidence compared with the general population.

13% prevalence in the 50-59 age group.

19% prevalence in the 60-69 age group.

Recognised with Phenothiazines since 1956.

Almost all the atypicals have been associated with diabetes development.

Does a hierarchy of effect exist ?

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Postulated theoriesPeripheral interaction with 5-HT1A

receptors in the gut.

Interaction with the GLUT-4 transport system (work on rat PC12 cell line).

WEIGHT GAIN

  Insulin ResistanceSlide31

What to do ?Accept the fact our current therapies are here to stay.

Accept there

may

be a risk of detrimental metabolic change with the armamentarium we have.

Vigilance required :

Education in nutrition and diet.

Prescribing the lowest effective dose.

Avoid ancillary therapy which may exacerbate the problem e.g. mood stabilisers.

Take a good and thorough history e.g. F.H. and physical activity.