New Treatments for Type 2 Diabetes Dr David Hopkins Clinical Director, Division of Ambulatory Care King s College Hospital NHS Foundation Trust
Treatments for type 2 diabetes - old & new insulin sulphonylureas biguanides a-glucosidase meglitinides thiazolinediones GLP-1 analogues DPP IV inhibitors SGLT-2 inhibitors gliclazide etc. metformin acarbose repaglinide pioglitazone exenatide/liraglutide e.g. sitagliptin e.g. dapagliflozin
Treatments for type 2 diabetes - old & new Drugs that stimulate insulin secretion sulphonylureas gliclazide etc. meglitinides repaglinide Drugs that influence insulin action biguanides metformin thiazolinediones rosiglitazone Drugs that mimic/ increase GLP-1 GLP-1 analogues exenatide/liraglutde/ DPP IV inhibitors..gliptin Drugs that promote glycosuria SGLT-2 inhibitors dapagliflozin/canagliflozin
Sulphonylureas sulphonamide derivatives - first oral anti-diabetic agents stimulate insulin secretion from the pancreas act via K ATP channels on b-cell
Sulphonylureas strong evidence supporting use - first line agent in main UKPDS study cause significant weight gain significant risk of hypoglycaemia
Evolution of sulphonylureas 1st generation: chlorpropamide/glibenclamide long action, renal excretion high risk of hypos 2nd generation: gliclazide / glipizide etc hepatic metabolism - safer in elderly market leaders in UK 3 rd generation: glimepiride Once daily dosing Little difference from 2 nd generation
Metformin introduced in 1950s in Europe, but only licensed in USA in 1995 reduces hepatic glucose output and increases glucose uptake in muscle use now supported by UKPDS very cheap weight neutral GI side effects limiting in some patients contra-indicated in renal impairment
% risk reduction UKPDS 34. Lancet 1998;352:854 865 UKPDS - effects of metformin 50 45 40 35 P=0.0023 P=0.02 P=0.010 P=0.017 P=0.011 30 25 20 15 10 5 0 diabetes infarction related mortality related death
The Thiazolinediones selective agonists of PPAR g Troglitazone Glaxo 1997 (RIP) Rosiglitazone GSK 2000-2010 (RIP) Pioglitazone Takeda 2000
PPAR -nuclear hormone receptors Receptors Thyroid Steroid Orphans PPARs Retinoic acid Thyroid hormones Steroid hormones PPARa PPAR PPARg RAR RXR
Troglitazone licensed in UK in 1997 as monotherapy or add-on treatment for type 2 diabetes rapidly withdrawn due to reports of liver toxicity Rosiglitazone Global blockbuster in top 10 of all drug sales Cardiovascular safety concerns raised in 2007 Subsequently withdrawn from the market
Pioglitazone Remains available and is an effective drug improves insulin action Some safety concerns fluid retention risk of exacerbation CCF increased fragility fractures possible association with bladder cancer
Venous Plasma Glucose (mmol/l) C-peptide (nmol/l) The Incretin effect Oral Glucose IV Glucose 11 2.0 * 5.5 1.5 1.0 * * * * Incretin Effect * 0.5 * 0 0.0 0 1 0 2 60 120 180 0 1 0 2 60 120 180 Time (min) Time (min) Mean ± SE; N = 6; *P.05; 0 1-0 2 = glucose infusion time. Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1996. The Endocrine Society.
Insulin (mu/l) The Incretin Effect Is Reduced in Patients With Type 2 Diabetes Intravenous Glucose Oral Glucose 80 Control Subjects 80 Patients With Type 2 Diabetes 60 60 40 40 20 * * * * * * * 20 * * * 0 0 30 60 90 120 150 180 Time (min) 0 0 30 60 90 120 150 180 Time (min) *P.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag 1986.
Incretin hormones polypeptides secreted by cells in the small intestines in response to a meal major action is stimulation of insulin secretion in a glucose dependent manner also have negative influence on glucagon secretion and slow gastric emptying 2 principle hormones: GLP-1: Glucagon-like peptide- 1 GIP: Glucose insulinotropic polypeptide (gastric inhibitory peptide)
GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucosedependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Multiple Actions of GLP-1 Act to Reduce Hyperglycaemia GLP-1 has multiple actions that reduce hyperglycaemia, including: Glucose-dependent stimulation of insulin secretion Glucose-dependent suppression of glucagon secretion Slowing of gastric emptying
GLP-1 is short-lived Rapid inactivation (DPP-IV), Short elimination half-life (~1-2 min) GLP-1 must be administered continuously (infusion) Need to extend action for therapeutic effect
Two pharmacological approaches 1. DPP-IV inhibitors extend action of native GLP-1 by inhibiting breakdown - oral agents but potential for off-target effects 2. DPP-IV resistant incretins extended action compared to native GLP-1 peptide therefore parenteral administration more predictable / specific action
The Therapeutic Potential of GLP-1 Is Limited by its Rapid Inactivation Rapid inactivation (DPP-IV), Short elimination half-life (~1-2 min) GLP-1 must be administered continuously (infusion) Inconvenient for treating a chronic disease like type 2 diabetes
Therapeutic approach to DPP-IV inhibition 1. Inhibit DPP-IV enhance the action of native GLP-1 Sitagliptin & Vildagliptin 2. Develop DPP-IV resistant GLP_1 analogues - exenatide: synthetic form of lizard exendin-4 - liraglutide analogue based on human GLP-1
DPP IV inhibitors -gliptins Five drugs now on UK market Effective - but modest improvements in A1c in clinical trials Weight neutral, but no associated weight loss in contrast to GLP-1 analogues Effective add-on to metformin - exact place in management not yet defined
GLP-1 Analogues Exenatide, Liraglutide, Lixisenatide There are now four licensed products in the UK Exenatide Liraglutide Lixisenatide Once weekly exenatide
Characteristics and function of GLP-1 analogues Action : Bind to human GLP-1 receptors to increase glucose- dependent insulin secretion Longer half life compared to native GLP-1 Resistant to DPP-IV degradation Slow gastric emptying Suppresses glucagon secretion Stimulate islet-cell neogenesis and proliferation Regulate food intake
Exenatide in UK practice Now widespread use Data colleceted in ABCD audit for over 5000 patients and initial presentations made based on 3913 patients Mean BMI 39 most on > 2 oral agents 999 patients on insulin 704 continued 861 total in audit used both exenatide and insulin
Mean HbA1c before, and last after, exenatide in 3054 patients 10.5 10 p < 10-126 HbA1c % 9.5 9 9.41% 8.65% 0.75% 8.5 8 7.5 7 Before exenatide After exenatide
Mean weight before, and last after, exenatide in 2977 patients 120 p < 10-15 Weight Kg 115 110 114 kg 109.1 kg 4.9 kg 105 100 Before exenatide After exenatide
Number of patients Difference between last HbA1c after exenatide and HbA1c before exenatide 1000 800 855 849 600 400 200 0 >7% 530 367 270 174 1 4 9 29 74 105 51 16 7 6% 5% 4% 3% 2% 1% 0% -1% -2% -3% -4% -5% -6% -7% Change in HbA1c after exenatide
SGLT-2 inhibitors gliflozins A new class of drugs Dapagliflozin and Canagliflozin now in UK Work by inhibition of the glucose transport protein SGLT-2 in kidney The kidney filters and reabsorbs @ 200g glucose/day about 70g lost with SGLT-2 inhibition
Normal glucose homeostasis Net balance ~0 g/day Glucose input ~250 g/day: Glucose uptake ~250 g/day: Dietary intake ~180 g/day Glucose production ~70 g/day Gluconeogenesis Glycogenolysis Brain ~125 g/day Rest of the body ~125 g/day + The kidney filters circulating glucose The kidney reabsorbs and recirculates glucose Glucose filtered ~180 g/day Glucose reabsorbed ~180 g/day 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18. 2. Gerich, JE. Diabetes Obes Metab 2000;2:345 50. 30
Normal renal glucose handling 1 3 Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule SGLT2 Glucose Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion Glucose filtration SGLT, sodium-glucose co-transporter. 31 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21.
SGLT-2 inhibitors: A novel insulin-independent approach to remove excess glucose SGLT2 Dapagliflozin Proximal tubule InhibitorDapagliflozin SGLT2 Glucose Glucose filtration Increased urinary glucose excretion Dapagliflozin and Canagliflozin selectively inhibits SGLT2 in the renal proximal tubule 1 32 1. FORXIGA Summary of Product Characteristics
HbA 1c change from baseline, % (mean adjusted for baseline values) Dapagliflozin addition to metformin: reductions in HbA 1c compared to placebo at 24 weeks 0.5 1.0 Dapagliflozin 10 mg + metformin 0.84% ( 9 mmol/mol) (n=132) (95% Cl 0.98, 0.70%) Mean baseline HbA 1c 7.92% (63 mmol/mol) Placebo + metformin 0.30% ( 3 mmol/mol) (n=134) (95% Cl 0.44, 0.16%) 0.54% (6 mmol/mol) difference p<0.0001 Mean baseline HbA 1c 8.11% (65 mmol/mol) 0 5 10 HbA 1c change from baseline, mmol/mol (mean adjusted for baseline values) Adapted from Bailey CJ et al, 2010. 33 Changes reported for Week 24 are adjusted for baseline values and are based on last observation carried forward (LOCF). CI, confidence interval. Bailey CJ et al. Lancet 2010; 375(9733):2223 2233..
HbA 1c (%) mean change from baseline Dapagliflozin addition to metformin: Reductions in HbA 1c were sustained over 102 weeks 0.2 0.0 0.2 0.4 0.6 0.8 1.0 (n=133) (n=132) Primary endpoint Placebo + metformin (Mean baseline HbA 1c 8.11% [65 mmol/mol]) Dapagliflozin 10 mg + metformin (Mean baseline HbA 1c 7.92% [63 mmol/mol]) 1.2 0 8 16 24 37 50 63 76 89 102 Study week +0.02% (0.2 mmol/mol) (95% Cl, 0.20 to 0.23%; n=28) 0.80% (8.8 mmol/mol) difference 0.78% ( 8.5 mmol/mol) (95% Cl, 0.97 to 0.60%; n=57) 0 5 10 HbA 1c (mmol/mol) mean change from baseline 34 Adapted from Bailey CJ et al. Poster #988-P. Poster presented at 71 st Scientific Sessions of the American Diabetes Association, San Diego, California, June 24 28, 2011.
Adjusted mean change from baseline body weight (kg) Dapagliflozin: weight loss compared to placebo 24 weeks (LOCF analysis) 1 Dapagliflozin 10 mg + metformin 2.9 kg (n=133) 95% CI (-3.3 to -2.4) Placebo + metformin 0.9 kg (n=136) 95%CI -1.4 to -0.4 2.0 kg difference p<0.0001 102 weeks (repeated measures analysis) 2 Dapagliflozin 10 mg + metformin 1.70 kg (n=95) 95% Cl (-2.48 to -0.91) Placebo + metformin +1.36 kg (n=73) 95% Cl (0.53 to 2.20) 3.1 kg difference p value not calculated Adapted from Bailey CJ, et al. (2010) & Bailey CJ, et al. (2011) 35
Metformin as first-line therapy First-line therapy in overweight and nonoverweight patients Some insulin sensitising properties Gastrointestinal side-effects occur 3 Contraindicated in renal or hepatic impairment
Next steps Sulphonylurea remains the appropriate second-line treatment for most patients DPP-IV and SGLT-2 are possible alternatives in specific cases Early escalation of treatment needed for many subjects failing oral treatment For many this will mean insulin but strong case for considering GLP-1 analogue treatment in the obese