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

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

GLP-1 is Rapidly Degraded by the Enzyme DPP-4 How can we resolve this problem Pharmacologically? Baggio & Druker Gastroenterology 2007;132:2131-2157 11

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

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

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 ↓ 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

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

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 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

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

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 27

‘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.