Insights into Diabetes Treatment Options

There is a discussion on the prevalence of diabetes, treatment options, need for new treatments, impact of obesity on diabetes risk, and the role of incretin hormones in glucose homeostasis. The content covers various aspects related to diabetes management and advancements in treatment options.

• Diabetes
• Treatment
• Obesity
• Incretin System
• Glucose Homeostasis

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1. Psychiatry Meeting 24thNovember 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 2 risk of developing diabetes Mild Moderate 5 risk of developing diabetes 10risk of developing diabetes Severe

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 -cells in a glucose- dependent manner Suppress glucagon release from islet -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 -cell glucose sensitivity Decreased glucagon secretion (glucose dependent) Delayed gastric emptying Increased -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 -cell glucose sensitivity Increased -cell mass (shown in animal models)

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

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 GLP-1 Receptor Agonists Sitaglitin, Vildagliptin, Saxagliptin Linagliptin Alogliptin DPP-4 Resistant Analogues Lixisenatide Albiglutide Dulaglutide Exendin-Based Therapies Human GLP-1 Analogues Exenatide, 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.

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 TZDs fatty acid release glucose metabolism TZDs insulin resistance

19. Examples Drug(s) Indicated Drug(s) Contra-Indicated Special Considerations 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 Gliptins GLP-1 receptor agonists SGLT-2 inhibitors Sulphonylureas Glitazones Insulin Needle phobia Frail or elderly leading loss of independence Sulphonylureas Gliptins Glitazones SGLT-2 inhibitors Insulins GLP-1 receptor agonists Subcutaneous administration unacceptable Risk of bone fractures Sulphonylureas Gliptins GLP-1 receptor agonists SGLT-2 inhibitors Glitazones 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, PF04937319, TTP399

25. In the Pipeline Type 2 DM Glucokinase activators DS-7309, PF04937319, TTP399 iBat inhibitors

27. 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

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 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 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.