Psychiatry Meeting

24th November 2016

Andrew Gallagher
Consultant Physician
and Endocrinologist
NHS Greater Glasgow & Clyde
 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
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 guises
 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.
 Obesity and Diabetes
• Mild 2 risk of developing diabetes

• Moderate 5 risk of developing diabetes

• Severe 10 risk of developing diabetes

 The Incretin System
• Orally 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)
 GLP-1 and GIP are Synthesized and Secreted
from the Gut in Response to Food Intake
L-Cell
(ileum) ProGIP

Proglucagon

GLP-1 [7-37] GIP [1-42]

K-Cell
GLP-1 [7-36NH2] (jejunum)
 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
 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 intake
• Potential to halt disease progression
Increased β-cell glucose sensitivity
Increased β-cell mass (shown in animal models)
 GLP-1 is Rapidly Degraded by the Enzyme DPP-4

How can we resolve this problem Pharmacologically?

Baggio & Druker Gastroenterology 2007;132:2131-2157
The Family of Incretin Based Therapies

Incretin-Based DPP-4 Inhibitors lead to

physiological levels of GLP-1,
Therapies
whereas GLP-1 Receptor Agonists
achieve high Pharmacological
levels of GLP-1

DPP-4 inhibitors GLP-1 Receptor

Sitaglitin, Agonists
Vildagliptin, DPP-4 Resistant
Saxagliptin Analogues
Linagliptin
Alogliptin Exendin-Based Human GLP-1 Lixisenatide
Therapies Analogues Albiglutide
Dulaglutide
Exenatide, Liraglutide
Sodium-Glucose Transporters
 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.
 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 guises
GLP1 agonists: ↓ appetite, ↓ rate of gastric emptying, ↑ meal-
related insulin secretion, ↓ glucagon effects
 Treatment options for type 2 diabetes mellitus

GLP-1 agonist ↓ appetite

GLP-1 agonists ↓ rate of gastric emptying

↓ glucagon production
Sulphonylureas
DPP-4 inhibitors
GLP-1 Agonists ↑ insulin production

Biguanides
TZDs ↓ glucose production
DPP-4 inhibitors
GLP-1 agonists

SLGT2 Inhibitors ↑ glucose excretion

↑ glucose intake
TZDs
↓ fatty acid release

TZDs ↑ glucose metabolism

↓ insulin resistance
Special Examples Drug(s) Indicated Drug(s) Contra-Indicated
Considerations

Hypoglycaemia •Employment (drivers) Glitazones Sulphonylureas

•Living alone (especially Gliptins Insulin
elderly) GLP-1 receptor
agonists
SGLT-2 inhibitors

Weight gain •BMI>30 in Caucasians Gliptins Sulphonylureas

•BMI>28 in South Asians GLP-1 receptor Glitazones
•Obstructive sleep apnoea agonists Insulin
SGLT-2 inhibitors

Subcutaneous •Needle phobia Sulphonylureas Insulins

administration •Frail or elderly leading Gliptins GLP-1 receptor agonists
unacceptable loss of independence Glitazones
SGLT-2 inhibitors

Risk of bone fractures •Postmenopausal females Sulphonylureas Glitazones

•Known Osteoporosis Gliptins
•Secondary causes GLP-1 receptor
agonists
SGLT-2 inhibitors
 Improving Diabetes Control &
Cardiovascular Risk
The 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
treatments
 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<0.001
 LEADER
Hypothesis
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=0.007
In the Pipeline – Type 2 DM
• Glucokinase activators
DS-7309, PF04937319, TTP399
In the Pipeline – Type 2 DM
• Glucokinase activators
DS-7309, PF04937319, TTP399
• iBat inhibitors
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 stimulants
‘Dr Gallagher, can I be excused?
My brain is full’
 Diabetes & Schizophrenia
• Long-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 ?
 Postulated theories
• Peripheral interaction with 5-HT1A receptors in the
gut.
• Interaction with the GLUT-4 transport system
(work on rat PC12 cell line).
• WEIGHT GAIN   Insulin Resistance
 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.