24 th November 2016 Andrew Gallagher Consultant Physician and Endocrinologist NHS Greater Glasgow amp Clyde Prevalence 2015 data WORLDWIDE Almost 300 million people with diabetes aged 2079 ID: 594911
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Slide1
Psychiatry Meeting24th November 2016
Andrew Gallagher
Consultant Physician
and Endocrinologist
NHS Greater Glasgow & ClydeSlide2Slide3
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
Slide10
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 TransportersSlide14Slide15Slide16
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, TTP399Slide24Slide25
In the Pipeline – Type 2 DM
Glucokinase activators
DS-7309, PF04937319, TTP399
iBat inhibitorsSlide26Slide27
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 ?
Slide30
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.