Oral Agents. Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK

Transcription

1 Oral Agents Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK

2 What would your ideal diabetes drug do? Effective in lowering HbA1c No hypoglycaemia No effect on weight/ weight loss? Reduce CV risk Also reduce lipids and B.P.? Few/ no side effects Safe Ian Gallen 2

3 Main classes of oral drugs available Biguanides (Metformin) Sulphonylureas (Gliclazide, Glimiperide, Glibencalmide etc) Thiozolendinediones (Pioglitazone) Glinides (Replaglinide, nataglinide) Alpha-glucosidase inhibitors (Acarbose) DDP-4 inhibitors or Gliptins (Sitagliptin, Saxagliptin,Linagliptin, Vildagliptin, Allogliptin) SGLT2 inhibitor agents (empagliflozin, cangligliflozin, dapagliflozin) Coming soon dual SGLT1/2 inhibitor agents Ian Gallen 3

4 Metformin Is the basis for the oral treatment of most people type II diabetes Introduced in 1957, has a proven track record of efficacy and safety Lowers blood glucose with a low risk of hypoglycaemia with modest weight loss UK PDS suggest that it reduces cardiovascular events although subsequent studies less certain. Generally well-tolerated

5 Metformin mechanisms of action Metformin decreases hyperglycemia primarily by suppressing glucose production by the liver Mechanism of metformin is incompletely understood Increases insulin sensitivity, enhances peripheral glucose uptake to muscle

6 Adverse effects of metformin Gastrointestinal intolerance Risk of acute kidney injury with other medications add x-ray contrast material Lactic acidosis with renal impairment Heart failure Liver disease Reduced TSH B12 deficiency

7 Sulphonylureas First generation drugs carbutamide, acetohexamide, chlorpropamide, and tolbutamide. Second generation drugs glipizide, gliclazide, glibenclamide, glyburide, glibornuride,gliquidone, glisoxepide, and glyclopyramide. Third generation drugs glimepiride

8 Sulphonylureas Increase insulin secretion through opening up a potassium channel in islets cells Cause insulin release unrelated to blood glucose Are powerful glucose lowering agents in early type II diabetes but are less effective with longer duration diabetes Adverse effects are hypoglycaemia weight gain and there are concerns about increased risk of cardiovascular events Accumulate in in the elderly and should be used with caution

9 Glinides Repaglinide and Nataglinide Act in a similar manner to sulphonylureas but has shorter duration Excreted via GI Tract, so safe in renal impairment and elderly And hypoglycaemia and sulphonylureas Useful to control post meal glucose

10 Pioglitazone Effective No hypoglycaemia as monotherapy or with metformin Long duration of effectiveness Reduction in CVS events May help with NAFLD Weight gain Can cause osteoporosis Can precipitate heart failure due to fluid overload Ian Gallen 10

11 PROactive: Reduction in primary outcome All-cause mortality, nonfatal MI (including silent MI), ACS, revascularization, leg amputation, stroke Proportion of events (%) % RRR HR* 0.90 ( ) P = Placebo (572 events) Pioglitazone (514 events) *Unadjusted Time from randomization (months) Number at risk Pioglitazone Placebo Ian Gallen Dormandy JA et al. Lancet. 2005;366:

12 PROactive: Reduction in secondary outcome Combined nonfatal MI, all-cause mortality, stroke Proportion of events (%) % RRR HR* 0.84 ( ) P = Placebo (358 events) Pioglitazone (301 events) *Unadjusted Number at risk Time from randomization (months) Pioglitazone Placebo Ian Gallen Dormandy JA et al. Lancet. 2005;366:

13 PROactive: Reduced need for insulin Proportion of events (%) % RRR HR* 0.47 ( ) P < Placebo (362 events) Pioglitazone (183 events) Time from randomization (months) Number at risk Pioglitazone *Unadjusted Placebo Ian Gallen Dormandy JA et al. Lancet. 2005;366:

14 Physiology of postprandial glucose regulation Meal ❶ ❷ Insulin Rising plasma glucose stimulates pancreatic β-cells to secrete insulin 1 Glucagon Insulin Glucagon Gastric emptying Plasma glucose inhibits glucagon secretion by pancreatic α-cells 1 PPG ❸ Gastric emptying Delaying and/or slowing gastric emptying is a major determinant postprandial glycaemic excursion 2 of Hepatic glucose output + Glucose uptake PPG = postprandial glucose 1 DeFronzo RA. Med Clin North Am 2004;88: Horowitz M et al. Diabet Med 2002;19:177-94

15 DPP4 inhibitors Increases GLP one and hence increase insulin secretion with hyperglycaemia Glucose lowering effect limited Some weight gain but reduced risk of hypoglycaemia Very well tolerated Concerns about heart failure with Saxogliptin and alogliptin

16 Incretin-based therapies GLP-1 receptor agonists and DPP-4 inhibitors GLP-1 receptor agonists Short-acting BD Exenatide (Byetta) OD Lixisenatide (Lyxumia) Long-acting OD Liraglutide* (Victoza) Longer-acting QW Exenatide (Bydureon) Dulaglutide (Trulicty) Subcutaneous injection DPP-4 inhibitors Sitagliptin OD Vildagliptin BD Saxagliptin OD Linagliptin OD Tablets Mimics endogenous GLP-1 Enhance endogenous GLP-1 *Human GLP-1 analogue, others are exendin-based DPP-4 = dipeptidyl peptidase-4; OD = once daily; BD = twice daily; QW = once weekly Drucker DJ, Nauck MA. Lancet 2006;368:

17 SGLT2 inhibitors

18 SGLTs Canagliflozin mg od ( 39.20) Empagliflozin 10-25mg od ( 36.59) Dapagliflozin 10 mg ( 36.59)

19 SGLT2 is a sodium glucose cotransporter 1,2 Segment S1 2 SGLT2 Basolateral membrane GLUT2 Glucose Na + Glucose Glucose Na + Na + K + K + Lateral intercellular space Na + /K + ATPase pump SGLTs transfer glucose and sodium (Na + :glucose coupling ratio for SGLT1 = 2:1 and for SGLT2 = 1:1) from the lumen into the cytoplasm of tubular cells through a secondary active transport mechanism GLUT, glucose transporter; SGLT, sodium glucose cotransporter. 1. Wright EM, et al. Physiology. 2004;19: Bakris GI, et al. Kidney Int. 2009;75: Mather A, Pollock C. Kidney Int Suppl. 2011;120:S1 S6.

20 Renal glucose re-absorption in patients with diabetes 1,2 Filtered glucose load > 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% When blood glucose increases above the renal threshold (~ 11 mmol/l), the capacity of the transporters is exceeded, resulting in urinary glucose excretion SGLT, sodium glucose cotransporter. 1. Adapted from: Gerich JE. Diabet Med. 2010;27: ; 2. Bakris GL, et al. Kidney Int. 2009;75;

21 Urinary glucose excretion via SGLT2 inhibition 1 Filtered glucose load > 180 g/day SGLT2 inhibitor SGLT1 SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis SGLT, sodium glucose cotransporter. *Loss of ~ 80 g of glucose per day = 240 cal/day. 1. Bakris GL, et al. Kidney Int. 2009;75;

22 Adjusted mean (95% CI) change from baseline in body weight (kg) 24-week empagliflozin monotherapy versus placebo and sitagliptin Change in body weight at Week Placebo (n = 228) mg QD (n = 224) Empagliflozin 25 mg QD (n = 224) Sitagliptin 100 mg QD (n = 223) (95% CI: -2.4, -1.5) p < Comparison with placebo -2.2 (95% CI: -2.6, -1.7) p < (95% CI: 0.0, 1.0) p = EMPA-REG MONO : study Mean baseline CI, confidence interval; QD, once daily. ANCOVA, FAS (LOCF). Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:

23 Adjusted mean (SE) HbA 1c (%) 52-week extension of empagliflozin monotherapy versus placebo and sitagliptin HbA 1c over time Placebo Empagliflozin 10 mg Empagliflozin 25 mg Sitagliptin EMPA-REG EXTEND TM MONO Week Number of patients analysed Placebo EMPA 10 mg EMPA 25 mg Sitagliptin EMPA, empagliflozin; HbA 1c, glycosylated haemoglobin; SE, standard error. MMRM in FAS (OC). Roden M, et al. ADA 2014, Abstract 264-OR.

24 Adjusted mean (SE) change from baseline in body weight (kg) 52-week extension of empagliflozin as add-on to metformin in T2D Change from baseline in body weight over time 0 Placebo Empagliflozin 10 mg QD Empagliflozin 25 mg QD Week EMPA-REG EXTEND TM MET Number of patients analysed Placebo EMPA 10 mg QD EMPA 25 mg QD EMPA, empagliflozin; QD, once daily; SE, standard error; T2D, Type 2 Diabetes. MMRM in FAS (OC). Merker L, et al. ADA 2014, Abstract 1074-P.

25 Adjusted mean (95% CI) HbA 1c (%) 104-week study with empagliflozin H2H versus glimepiride Change in HbA 1c over time Glimepiride Empagliflozin 25 mg QD Difference in change from baseline at Week 104: -0.11% (95% CI: -0.21, -0.01) p = EMPA-REG H2H-SU : study Weeks Analysed patients Glimepiride Empagliflozin CI, confidence interval; H2H, head-to-head; HbA 1c, glycosylated haemoglobin; QD, once daily. MMRM. FAS (OC). Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:

26 Adjusted mean (95% CI) change from baseline in body weight (kg) 104-week study with empagliflozin H2H versus glimepiride Change in body weight over time Glimepiride Week Empagliflozin 25 mg QD -4.6 kg (95% CI: -5.0, -4.2) p < EMPA-REG H2H-SU : study Analysed patients -4 Glimepiride Empagliflozin CI, confidence interval; H2H, head-to-head; QD, once daily; SE, standard error. MMRM. FAS (OC). Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:

27 Adjusted mean (95% CI) change from baseline in body weight (kg) 104-week study with empagliflozin H2H versus glimepiride Change in body weight over time Glimepiride Week Empagliflozin 25 mg QD -4.6 kg (95% CI: -5.0, -4.2) p < EMPA-REG H2H-SU : study Analysed patients -4 Glimepiride Empagliflozin CI, confidence interval; H2H, head-to-head; QD, once daily; SE, standard error. MMRM. FAS (OC). Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:

28 and SGLT2 agonist do this too! N Engl J Med 2015; 373:

29 Across all studies and empagliflozin Improves Glycaemic control Reduction of HbA1c as monotherapy or with Metformin, Pioglitazone and as part of triple therapy or with insulin Sustained weight loss Reduction in SBP and DBP Well tolerated Reduce death rates (RRR 32% in Empa-Reg)

30 SGLT2 Use In Berkshire Number 265 Male 158 Female 98 Age 58.3±0.5 BMI (kg/m2) 33.7±0.5 Source IG Eclipse audit 3/8/2016

31 Outcomes of SGLT2 Use In Berkshire Start 6 months P Value HbA1c % 9.33± ±0.1 P < Weight Kg ± ±1.3 P < Total cholesterol 3.93± ±0.07 NS (mmol/l) Triglycerides (mmol/l) 0.8± ±0.1 P < egrf (ml/min) 63.5± ±0.9 P < Haemoglobin (g/dl) 13.9± ±0.1 P < ALT (iu/l) 42.4± ±1.0 P < 0.03 ALT (iu/l) Raised at start 76.1± ±5.0 P < 0.03 Source IG Eclipse audit 3/8/2016

32 GLP-1 agonists

33 Actions of GLP-1 agonists Promote 1 st phase insulin secretion Reduce glucagon release Delay gastric emptying Weak satiety effect Thus lowering blood glucose with modest weight loss without hypoglycaemia

34 Choice of GLP-1 receptor agonist: short acting versus long acting The pharmacological profile and half-life of a GLP-1 receptor agonist influences its effects on postprandial and basal (fasting) glycaemia SHORT ACTING GLP-1 receptor agonists Lixisenatide OD, Exenatide BD or LONG ACTING GLP-1 receptor agonists Liraglutide OD, Exenatide/Dulaglutide QW Effect on FPG Effect on PPG Effect on FPG Effect on PPG FPG = fasting plasma glucose PPG = postprandial glucose Fineman MS et al. Diabetes Obes Metab 2012;14:675-88

35 IDegLira; Side effects

36 GLP1 agonist and cost per month Lixisenatide 20mg od; Exenatide (10µg bd); Byduron; Liraglutide (1.2mg od); Liraglutide (1.8mg od); Dulaglutide (1.5mg) ; 73 pm IDegLira (50 dose daily);

37 When to use GLP1-agonists HbA1c>58 mmol/l +oral agents; Overweight. With metformin/pioglitizone/sglt2 inhibitors. Stop DPP4 and Sulphonylureas. Or with basal insulin; To avoid further weight gain. To reduce hypoglycaemia.

38 How to use GLP1-agonists With Oral Treatment; Use least expensive agent (lixisentatide). Continue with Metformin and/or Pioglitazone. Add SGLT2 inhibitor if post-prandial hyperglycaemia. Move from lixisenatide/exenatide to a Glutide; if nauseous or sub-optimal response. Transfer to biphasic insulin (Humulin M3); if no weight loss or improved glycaemic control. With OD human basal (Humulin I); with dose increasing by 10% alternate days to reduce FBG < 6mmol.

39 NICE 2015 For adults with type 2 diabetes managed either by lifestyle and diet, or by lifestyle and diet combined with a single drug not associated with hypoglycaemia, support the person to aim for an HbA1c level of 48 mmol/mol (6.5%). For adults on a drug associated with hypoglycaemia, support the person to aim for an HbA1c level of 53 mmol/mol (7.0%).

40 NICE 2015 In adults with type 2 diabetes, if HbA1c levels are not adequately controlled by a single drug and rise to 58 mmol/mol (7.5%) or higher: reinforce advice about diet, lifestyle and adherence to drug treatment and support the person to aim for an HbA1c level of 53 mmol/mol (7.0%) and intensify drug treatment.

41 NICE 2015 Consider relaxing the target HbA1c level on a case-by-case basis, with particular consideration for people who are older or frail, for adults with type 2 diabetes: who are unlikely to achieve longer-term risk-reduction benefits, for example, people with a reduced life expectancy for whom tight blood glucose control poses a high risk of the consequences of hypoglycaemia, for example, people who are at risk of falling, people who have impaired awareness of hypoglycaemia, and people who drive or operate machinery as part of their job for whom intensive management would not be appropriate, for example, people with significant comorbidities.