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: 1014331
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1. Psychiatry Meeting24th November 2016Andrew GallagherConsultant Physicianand EndocrinologistNHS Greater Glasgow & Clyde
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3. Prevalence – 2015 dataWORLDWIDE Almost 300 million people with diabetes aged 20-79 There is a very slight female predominanceGREATER GLASGOW & CLYDE 201561,457 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 recentlyTablets Biguanides: ↑ insulin sensitivity, ↓ liver production of glucoseSulphonylureas: stimulate pancreas to release insulinThiazolidinediones:↑ insulin sensitivity, ↓ liver production of glucoseInjectionsInsulin: 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 DiabetesMild 2 risk of developing diabetesModerate 5 risk of developing diabetesSevere 10 risk of developing diabetes
7. 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)
8. L-Cell(ileum)Proglucagon GLP-1 [7-37]GLP-1 [7-36NH2]K-Cell(jejunum)ProGIPGIP [1-42]GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food Intake
9. Role of Incretin Hormones in Glucose HomeostasisSecreted 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 EffectsEfficacious 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)
11. Baggio & Druker Gastroenterology 2007;132:2131-2157How can we resolve this problem Pharmacologically? GLP-1 is Rapidly Degraded by the Enzyme DPP-4
12. The Family of Incretin Based TherapiesIncretin-Based TherapiesDPP-4 inhibitorsSitaglitin, Vildagliptin, Saxagliptin Linagliptin AlogliptinGLP-1 Receptor AgonistsExendin-Based Therapies Exenatide, Human GLP-1 AnaloguesLiraglutideDPP-4 Inhibitors lead to physiological levels of GLP-1, whereas GLP-1 Receptor Agonists achieve high Pharmacological levels of GLP-1DPP-4 Resistant AnaloguesLixisenatideAlbiglutideDulaglutide
13. Sodium-Glucose Transporters
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16. SGLT2 Inhibitors Dapagliflozin, Canagliflozin, EmpagliflozinThese 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.
17. Current treatment options for T2DMTablets Biguanides: ↑ insulin sensitivity, ↓ liver production of glucoseSulphonylureas: stimulate pancreas to release insulinThiazolidinediones:↑ insulin sensitivity, ↓ liver production of glucoseDPP4 inhibitors: ↑ meal-related insulin secretionSLGT2 inhibitors: ↑ renal excretion of glucoseInjectionsInsulin: In its many guisesGLP1 agonists: ↓ appetite, ↓ rate of gastric emptying, ↑ meal-related insulin secretion, ↓ glucagon effects
18. Treatment options for type 2 diabetes mellitusGLP-1 agonistGLP-1 agonistsSulphonylureas DPP-4 inhibitorsGLP-1 Agonists Biguanides TZDsDPP-4 inhibitors GLP-1 agonistsSLGT2 InhibitorsTZDsTZDs↓ appetite↓ rate of gastric emptying↓ glucagon production↑ insulin production↓ glucose production↑ glucose excretion↑ glucose intake↓ fatty acid release↑ glucose metabolism↓ insulin resistance
19. Special ConsiderationsExamplesDrug(s) IndicatedDrug(s) Contra-IndicatedHypoglycaemiaEmployment (drivers)Living alone (especially elderly)GlitazonesGliptinsGLP-1 receptor agonistsSGLT-2 inhibitorsSulphonylureasInsulinWeight gainBMI>30 in CaucasiansBMI>28 in South AsiansObstructive sleep apnoeaGliptinsGLP-1 receptor agonistsSGLT-2 inhibitorsSulphonylureasGlitazonesInsulinSubcutaneous administration unacceptableNeedle phobiaFrail or elderly leading loss of independenceSulphonylureasGliptinsGlitazonesSGLT-2 inhibitorsInsulinsGLP-1 receptor agonistsRisk of bone fracturesPostmenopausal femalesKnown Osteoporosis Secondary causesSulphonylureasGliptinsGLP-1 receptor agonistsSGLT-2 inhibitorsGlitazones
20. 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 treatments
21. EMPA-REGHypothesis Empagliflozin would be non-inferior to Placebo with regard to the primary outcome. A Safety Outcome Trial7020 patients randomised, median follow up 3.1 years. Primary outcome: death from CVD, non-fatal MI, non-fatal stroke.Results490 / 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. LEADERHypothesis Liraglutide would be non-inferior to Placebo with regard to the primary outcome. A Safety Outcome Trial9340 patients randomised, median follow up 3.8 years.Primary outcome: death from CVD, non-fatal MI, non-fatal stroke.Results608 / 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 DMGlucokinase activators DS-7309, PF04937319, TTP399
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25. In the Pipeline – Type 2 DMGlucokinase activators DS-7309, PF04937319, TTP399iBat inhibitors
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27. In the Pipeline – Type 2 DMGlucokinase activators DS-7309, PF04937319, TTP399iBat inhibitorsFibroblast Growth Factor 21 LY2405319, AMG876GPR119 agonistsGlucagon receptor antagonists LGD6972, LY2409021Glut 4 stimulants
28. ‘Dr Gallagher, can I be excused? My brain is full’
29. 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 ?
30. 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 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.