Treatment Options for Diabetes: An Update

Transcription

1 Treatment Options for Diabetes: An Update A/Prof. Marg McGill Manager, Diabetes Centre Dr. Ted Wu Staff Specialist Endocrinologist Diabetes Centre Centre of Health Professional Education Education Provider Please direct any program-related questions to:

2 Sponsors Proudly sponsored by: In collaboration with: Not so long ago...life was simple. Life is more complex now!

3 Diabetes medications in the past Tablets Metformin Sulfonylurea Insulin Short acting insulin Long acting insulin Diabetes medications now Tablets Metformin Sulfonylureas Thiazolidinediones Meglitinides -glucosidase inhibitors Incretin-based therapies DPP-4 inhibitors GLP-1 analogues Insulins Rapid acting analogues Short acting insulin Intermediate acting insulin Basal analogues Premixed insulins

4 Diabetes medications now Tablets Metformin Sulfonylureas Thiazolidinediones Meglitinides -glucosidase inhibitors Incretin-based therapies DPP-4 inhibitors GLP-1 analogues Insulins Rapid acting analogues Short acting insulin Intermediate acting insulin Basal analogues Premixed insulins Metformin - mechanisms Since 1970s (except US 1990s!) Mechanism of action: hepatic gluconeogenesis major effect insulin resistance minor effect Has greatest effect on fasting sugars HbA 1c by about 1-2% Weight neutral Does not cause hypos alone

5 Metformin Side effects GI upset common, but minor Nausea, Vomiting Diarrhoea, Cramping Taste disturbance Lactic acidosis very rare, but severe Only occurs if egfr <40 Dehydrated/fasting Contrast cardiac cath, radiology Metformin - usage Starting low, building up dose helps to decrease GI upset First line treatment in Type 2 Can also combine with almost any other tablet Can combine with insulin Can use in Type 1, esp later life Stop if egfr <30-40

6 Metformin Extended release Diabex XR Slow release formulation Take once a day, after dinner risk of GI upset 60-70% Sulfonylureas Since the 1960 s Stimulates insulin release from pancreas fasting and post-prandial sugars HbA 1c by about 1-2%

7 SU s Side Effects Hypos: Prolonged hypos Esp glibenclamide, glimepiride Weight gain Due to insulin Hypersensitivity sulfur allergy (in theory) Metallic taste SU s - Usage Usually second line, in combo with metformin Can combine with other tablets ( triple therapy ) or with insulin also Not useful in Type 1 or end stage Type 2 Requires some pancreas function

8 Meglitinides Glinides Repaglinide - NovoNorm now discontinued in Australia Not in Australia Nateglinide - Starlix Mitiglinide Glufast Relatively recent early 2000 s Meglitinides - Mechanisms Stimulates insulin release from pancreas Wt gain Shorter half life than SU s Supposedly more insulin release at meal times, less when fasting

9 Meglitinides Usage No real advantage over SU No fewer hypos fasting No better control after meals No better HbA 1c Can be used in place of SU e.g. allergy No longer available in Australia Thiozolidinediones Glitazones Troglitazone Rezulin No longer used due to liver toxicity Rosiglitazone Avandia Pioglitazone Actos Relatively recent late 1990 s

10 Glitazones - Mechanisms PPAR s (peroxisome proliferator-activated receptors) Nuclear receptors Glitazones activate the PPARs Rosiglitazone pure PPAR activation Pioglitazone mostly PPAR, some PPAR Increases insulin sensitivity Adipocyte differentiation Visceral fat subcut fat HbA 1c by about 1-1.5% Glitazones side effects Oedema Heart failure from oedema Wt gain Some oedema, some subcut fat Not bad weight Osteoporosis and fractures Possible CV disease Rosiglitazone (Avandia ) only NB. Pioglitazone decreases CV disease

11 Glitazones - Usage Third line agent Use in combination with metformin and SU Can use with insulin (pioglitazone only) Contraindicated: NYHA class III or IV heart failure -glucosidase inhibitors Acarbose Glucobay Not in Australia: Miglitol, Voglibose Late 1990s Inhibits -glucosidase in brush border of the small intestines Slows digestion of poly monosaccharides Slows absorption of CHO less rise in BSLs after meals

12 Acarbose Only affects post-prandial sugars Has no effect on fasting sugars No effect on insulin secretion No effect on insulin sensitivity HbA 1c by 0.5% Weight neutral Acarbose GIT upset Flatulence (almost 80%) Diarrhoea (15%) Dose related, therefore: Take just before meals Use lowest dose, and build up dose slowly Will not cause hypos by itself If hypos do occur (eg combo Rx), must use glucose as oral treatment Third line agent

13 Summary Oral hypoglycaemics Site of action of diabetic drugs: Pancreas Liver Muscle/Fat GI tract Sulfonylureas Metformin /- Acarbose Glitazones Glinides Diabetes medications now Tablets Metformin Sulfonylureas Thiazolidinediones Meglitinides -glucosidase inhibitors Incretin-based therapies DPP-4 inhibitors GLP-1 analogues Insulins Rapid acting analogues Short acting insulin Intermediate acting insulin Basal analogues Premixed insulins

14 Diabetes medications now Tablets Metformin Sulfonylureas Thiazolidinediones Meglitinides -glucosidase inhibitors Incretin-based therapies DPP-4 inhibitors GLP-1 analogues Insulins Rapid acting analogues Short acting insulin Intermediate acting insulin Basal analogues Premixed insulins What are Incretins? Incretins are GIT hormones: GLP-1 (glucagon-like peptide) GIP (glucose-dependent insulinotropic polypeptide) Both decreased in Type 2 Diabetes Novel target of diabetes treatment Incretin-based therapies: GLP-1 analogues DPP-4 inhibitors

15 Mode of action - Incretins Ingestion of food Glucose-dependent Insulin Muscle glucose uptake GI tract Incretin release GLP-1 & GIP β cells α cells Pancreas Glucose-dependent Glucagon Liver glucose production Glucose (fasting/prandial) Glucose-Dependent Effects of GLP-1 on Insulin Glucose mmol/l * * * * * GLP-1 Infusion * * *P<0.05 T2DM (N=10) Insulin pmol/l * * * * * 0 * * * When glucose levels approach normal values, insulin levels decrease. Nauck MA et al. Diabetologia 1993; 36: Placebo GLP-1

16 Glucose-Dependent Effect of GLP-1 on Glucagon Glucose mmol/l * * * * * GLP-1 Infusion * * Low risk of hypos *P<0.05 T2DM (N=10) Insulin Glucagon pmol/l pmol/l * * * * * 0 * * * Nauck MA et al. Diabetologia 1993; 36: * * * * Minutes When glucose levels approach normal values, insulin levels decrease. When glucose levels approach normal values, glucagon levels rebound. Placebo GLP-1 Incretins additional effects Insulin (glucose dependent) Glucagon (glucose dependent) Glucose Stomach emptying Central hunger signals Weight

17 Incretins GLP-1 Why not just inject GLP-1? Insulin Incretin GLP-1 Blood Glucose Glucagon Incretins GLP-1 Why not just inject GLP-1? Insulin GLP-1 broken down very quickly (1-2 min) By DPP-4 Incretin GLP-1 Glucagon Blood Glucose DPP-4

18 Getting around DPP-4 Native human GLP-1 Create GLP-1 analogues that are structurally resistant to DPP-4 97% amino acid homology to human GLP-1 1 Liraglutide Exenatide GLP-1 analogue Half-life Injection Frequency Liraglutide ~13 hrs Once-daily 1 53% amino acid homology to human GLP-1 2 Exenatide 2.4hrs Twice-daily 2 1. Liraglutide Product Information. 2. Exenatide Product Information. Getting around DPP-4 Exendin-4: From the Gila Monster Found to act like human GLP-1 Resistant to DPP-4 Longer half-life Twice-daily injections Exenatide (Byetta ) Dose: First of the GLP-1 analogues Many others to follow 5 10 g sci with food twice-daily Exenatide Product Information.

19 GLP-1 analogues Advantages: HbA 1c by % Weight 3 kg in 6 months 5 kg in 2 years Low risk of hypos if used alone or with metformin But can potentiate hypos if used with SU s Exenatide can be used as triple therapy under PBS 1. Liraglutide Product Information. 2. Exenatide Product Information. GLP-1 analogues Disadvantages: Injection working on daily/weekly dosing Nausea mild 15-30% severe 5% Pancreatitis Exenatide full authority PBS No combo with insulin under PBS Liraglutide registered with TGA, not currently on PBS 1. Liraglutide Product Information. 2. Exenatide Product Information.

20 Achieving a clinically relevant composite outcome of an HbA 1c of <7% without weight gain or hypoglycaemia 7 randomised, controlled, Phase III clinical trials were combined to facilitate a meta-analysis. The predefined composite endpoint (HbA 1c <7.0%, no weight gain, and no hypoglycaemic events) after 26 weeks of treatment was analysed by a logistic regression with previous treatment (combination or monotherapy) and randomised treatment as fixed effects and baseline values of HbA 1c and body weight as covariates. Zinman B et al. Diabetes Obes Metab 2011; 14: Getting around DPP-4 What if we block DPP-4? Insulin Incretin GLP-1 Blood Glucose Glucagon DPP-4

21 Getting around DPP-4 What if we block DPP-4? Insulin GLP-1 glucose Incretin GLP-1 Blood Glucose Glucagon DPP-4 Inhibitor DPP-4 DPP-4 Inhibitors Block DPP-4 action GLP-1 action Sitagliptin Januvia Vildagliptin Galvus Saxagliptin Onglyza Linagliptin Trajenta

22 DPP-4 Inhibitors Advantages: Effect is like GLP-1 analogues Less nausea than GLP-1 analogues HbA 1c % Weight neutral Can be take as tablet Combo tablets with metformin Sitagliptin approved for use in ESRD No known serious long term side effects DPP-4 Inhibitors Disadvantages: Depends on endogenous production of GLP-1 Already in Type 2 diabetes No weight loss Slight nasopharyngitis and URTIs Streamlined Authority PBS Dual therapy only under PBS No combo with insulin under PBS Some DPP-4 inhibitors have hepatic effects or restrictions in renal disease

23 DPP-4 Inhibitors - specifics Lowers HbA 1c Low risk of hypos with metformin Source: Respective full PI s, MIMS April 2012 No need to monitor LFTs Approved in End Stage Renal Disease Linagliptin (Trajenta ) Sitagliptin (Januvia ) Saxagliptin (Onglyza ) Vildagliptin (Galvus ) Sample T2DM treatment algorithm Pancreatic function Metformin SU Insulin GLP-1 DPP-4 Acarbose Pioglitazone *PBS = must withdraw DPP-4 or GLP-1 on initiation of next agent

24 Diabetes medications now Tablets Metformin Sulfonylureas Thiazolidinediones Meglitinides -glucosidase inhibitors Incretin-based therapies DPP-4 inhibitors GLP-1 analogues Insulins Rapid acting analogues Short acting insulin Intermediate acting insulin Basal analogues Premixed insulins Even more exotic agents coming Ultra-long basal insulins (e.g. degludec) Ultra-long GLP-1 analogues (e.g. liraglutide) GLP-1 + insulin combination (e.g. liraglutide + degludec) SGLT-2 inhibitors (e.g. dapaglifozin) Amylin analogues (e.g. pramlintide) Sirtuins

25 Summary Choice is a good thing! Tablets Metformin Sulfonylureas Thiazolidinediones Meglitinides -glucosidase inhibitors Incretin-based therapies DPP-4 inhibitors GLP-1 analogues Insulins Rapid acting analogues Short acting insulin Intermediate acting insulin Basal analogues Premixed insulin analogues