1. Psychiatry Meeting 24th November 2016
Andrew Gallagher
Consultant Physician
and Endocrinologist
NHS Greater Glasgow & Clyde

3. 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

4. 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

5. 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.

6. Obesity and Diabetes Mild 2 risk of developing diabetes
Moderate 5 risk of developing diabetes
Severe 10 risk of developing diabetes

7. 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)

8. 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
(jejunum)
GLP-1 [7-36NH2]

9. 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

10. 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
Increased fullness and satiety
Decreased food intake
Potential to halt disease progression

11. GLP-1 is Rapidly Degraded by the Enzyme DPP-4
How can we resolve this problem Pharmacologically?
Baggio & Druker Gastroenterology 2007;132: 11

12. The Family of Incretin Based Therapies
DPP-4 Inhibitors lead to physiological levels of GLP-1, whereas GLP-1 Receptor Agonists achieve high Pharmacological levels of GLP-1
Incretin-Based Therapies
DPP-4 inhibitors
Sitaglitin, Vildagliptin, Saxagliptin Linagliptin Alogliptin
GLP-1 Receptor Agonists
DPP-4 Resistant Analogues
Lixisenatide
Albiglutide
Dulaglutide
Exendin-Based Therapies
Exenatide,
Human GLP-1 Analogues
Liraglutide

13. Sodium-Glucose Transporters

16. 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.
They may be renoprotective through effects on glycaemia, glomerular haemodynamics and glucose toxicity of tubular cells.

17. 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

18. Treatment options for type 2 diabetes mellitus
↓ appetite
GLP-1 agonist
GLP-1 agonists
↓ rate of gastric emptying
↓ glucagon production
Sulphonylureas
DPP-4 inhibitors
GLP-1 Agonists
↑ insulin production
Biguanides
TZDs
DPP-4 inhibitors
GLP-1 agonists
↓ glucose production
↑ glucose excretion
SLGT2 Inhibitors
↑ glucose intake
↓ fatty acid release
TZDs
↑ glucose metabolism
↓ insulin resistance
TZDs

19. 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 Asians
Obstructive sleep apnoea
Subcutaneous administration unacceptable
Needle phobia
Frail or elderly leading
loss of independence
Insulins
Risk of bone fractures
Postmenopausal females
Known Osteoporosis
Secondary causes

20. 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

21. 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

22. 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

23. In the Pipeline – Type 2 DM
Glucokinase activators
DS-7309, PF , TTP399
Pramlintide is a synthetic amylin analogue. The structural changes improve solubility. Given by sc injection 2-3 times daily. Reduces post-prandial glucose levels. 23

25. In the Pipeline – Type 2 DM
Glucokinase activators
DS-7309, PF , TTP399
iBat inhibitors
Pramlintide is a synthetic amylin analogue. The structural changes improve solubility. Given by sc injection 2-3 times daily. Reduces post-prandial glucose levels. 25

27. In the Pipeline – Type 2 DM
Glucokinase activators
DS-7309, PF , TTP399
iBat inhibitors
Fibroblast Growth Factor 21
LY , AMG876
GPR119 agonists
Glucagon receptor antagonists
LGD6972, LY
Glut 4 stimulants 27

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

29. 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 age group.
19% prevalence in the age group.
Recognised with Phenothiazines since 1956.
Almost all the atypicals have been associated with diabetes development.
Does a hierarchy of effect exist ?

30. 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

31. 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.