Mark Thomas, Dept of Nephrology, RPH CHANGING DIRECTIONS IN DIABETES

Transcription

1 Mark Thomas, Dept of Nephrology, RPH CHANGING DIRECTIONS IN DIABETES

2 The size of the problem

3 Micro and macrovascular disease

4 Too tight vs too loose control: oral Rx vs insulin Oral Rx Insulin Rx UK GP database : patients > 50yrs intensified from monotherapy to either oral combination (n= 28,000) or regimen inc insulin (n = 20,000) Currie, Lancet 2010

5 Avoiding disaster

6 Multifactorial Rx in T2DM & legacy effect Trial: intensive vs conventional 80 Post-trial: all intensive Cumulative incidence of any CV event (%) Hazard ratio = 0.47 (95% CI, ; p = 0.008) Conventional therapy 53% reduction in CVD Intensive therapy N=160 T2DM microalbuminuria Years STENO 2 TRIAL N Engl J Med 2008;358:

7 CV events prevented by different interventions per 1000 patient yrs of treatment Preiss D, and Ray K K BMJ 2011;343:bmj.d4243

8 Individualise and prioritise therapy targets Individualise targets Tight targets: for young motivated compliant patients, short duration of DM, no micro/macrovascular disease, few co-morbidities Gentle targets: treat the elderly with respect E.g. Systolic BP 110 vs 140, HbA1c 6 vs 8% Prioritise targets 1. BP and lipids: easier to achieve, bigger mortality benefit 2. Glucose control and weight loss

9 Deeper analysis

10 Worse DM control & complications in ATSI vs non-atsi despite same Rx: NEPHRON GP study 144 ATSI (53y) vs 449 non-atsi (64y) at same GP (vs 3893 total) CKD Similarities: Same obesity 50%, waist 106cm, DM duration 8yrs Same BP 132/80 & BP Rx, LDL 2.5 & lipid Rx Differences: More smoking (38 vs 9%), family history DM x2, CVD x3, CKD x5 Macrovascular Worse HbA1c 8.9 vs 7.4%, but same Met/SU/insulin rates M Thomas & M Thomas BMC Pub Health 2007

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12 ATSI ESKD: esp women in remote Qld Hoy e al. Nephrol 2016

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14 Missing factors in ATSI T2DM: chronic stress Cause: Chronic stress Socio-economic Family health Consequence: Cortisol Insomnia Constant hunger with central obesity Insulin resistance with acanthosis Resistant hypertension with relatively low K+ Muscle weakness and fatigue Recurrent infections Schmitt & Spargo Bio Soc Sci 1995

15 Sweeter options

16 Therapy PRO CON Metformin Experience / Proven outcomes / Cost GI symptoms/ CKD Sulfonylurea Experience / Cost Hypo s/ Wt. gain / CKD DPP4-i (gliptin) TZD (glitazone) SGLT2-i (gliflozin) Acarbose GLP-1 (incretin analogue) Wt. neutral / Low risk of hypo s Low risk of hypo s Wt. loss / SBP reduction / Low risk of hypo s Low risk of hypo / Wt. neutral / Cost Wt. loss / Low risk of hypoglycaemia Cost / CCF (saxa, not sita) / CKD (except lina) / LFT s (vilda) Cost / Fluid retention / Wt. gain / Fracture risk /?Bladder ca (pio) New / Dehydration / DKA $ / UTI & thrush / CKD inefficacy Limited efficacy / GI tolerability Cost / Injection / GI symptoms Insulin Experience / Effective Injection / Wt. gain / Hypo s 16

17 Pathophysiology of Hyperglycaemia: missing 3? Pancreas Decreased Insulin Secretion Increased Glucagon Secretion Hyperglycaemia Gut Decreased Incretin Effect Muscle Decreased Glucose Uptake Kidney Increased Glucose Reabsorption Adapted from DeFronzo RA. Diabetes. 2009;58:

18 Sites/Modes of Action of Pharmacotherapy for T2DM Pancreas Sulfonylureas Meglitinides GLP-1/DPP-4i Gut Hyperglycaemia α-glucosidase inhibitors GLP-1/DPP-4i Muscle TZDs Metformin Kidney SGLT2 inhibitors Adapted from DeFronzo RA. Diabetes. 2009;58:

19 Don t beat up your beta-cells Maintain beta-cell mass Avoid pancreatitis Tight BSL control Statins: lipotoxicity Incretins: proliferation, apoptosis Glitazones: proliferation, apoptosis ACE-I/ARB: fibrosis?immunotherapy for Type I (rituximab 2009; anti IL ) Reduce insulin demand Small meals with low glycaemic index Tight control Avoid high-dose SU s Early insulin Increase insulin sensitivity Increase exercise & muscle Reduce body fat mass & stress Use metformin +/-?glitazones

20 50% of Australian Type 2 diabetics have CKD 10% GFR < 60 & normal uacr 25% uacr & normal GFR 50% Either or both NEPHRON study MJA 2006; 185 (3): uacr = spot urine albumin: creatinine ratio

21 Dose-related GI side-effects Renal excretion: Dose-adjust to GFR Metformin in CKD Idiosyncratic lactic acidosis Blocks liver glucose release & lactic acid uptake: Stop if unwell Rates of lactic acidosis/10^5 patient-years: 57 (12-168) on metformin (n = 3) 28 (3-100) off metformin (n = 2), p = ns Kamber, Davis et al. MJA 2008;188:446

22 Incretin Effect: normal vs T2DM Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) IR Insulin, mu/l Incretin Effect nmol/l IR Insulin, mu/l The incretin effect is diminished in type 2 diabetes nmol/l Time, min Time, min Oral glucose load Intravenous (IV) glucose infusion IR=Immune Reactive. Adapted from Nauck M et al. Diabetologia. 1986;29: Copyright 1986 Springer-Verlag. 9

23 Effects of incretins and incretin-based therapy 1 Incretin effects are enhanced by GLP-1 agonists and DPP-4 inhibitors Alpha cells: Reduction of postprandial glucagon secretion Stomach: Slowing of gastric emptying Liver: Glucagon Reduces hepatic glucose production Beta cells: Increase of glucosedependent insulin secretion GLP-1 secretion occurs after food intake Adapted from DeFronzoRA, Reference 1. DeFronzo RA, Diabetes 2009; 58:

24 1yr Gliptin vs SU in CKD & ESKD CKD ESKD Number HbA1c -0.8 v v -0.9 Hypo s 6 v 17% 6 v 11% Wt -0.6 v v +0.8 Other All equiv Cellulitis/headache Ferreira et al Diabetes Care 2012 Am J Kidney Dis 2013

25 DPP4i safety watch the BNP, not the lipase

26 BYDUREON Pen: Microsphere technology enables onceweekly dosing 1,2 Proven microsphere technology provides a continuous level of exenatide Biodegradable polymer that dissipates into CO 2 and water Technology used in extended-release products, e.g. risperidone & naltrexone Subcutaneous injection of microsphere suspension of exenatide Individual microspheres aggregate and initial release of exenatide Microsphere degradation and continued release of exenatide Further degradation and metabolism of microsphere polymer provide sustained level of exenatide Adapted from 1. DeYoung MBet al Reference 1. DeYoung MB et al. Diabetes Technol Ther 2011;13: BYDUREON Approved Product Information.

27 Exenatide QW Pharmacokinetics* Plasma Exenatide Concentration 1 Steady state maintained with subsequent doses 2 mg single dose releases exenatide over 9-11 weeks 1 Steady state concentrations reached by week Exenatide not detectable approximately10 weeks after last dose 1, Weeks PK/PD data does not necessarily predict clinical effect * Graphical representation of ExQW pharmacokinetics. Reference 1. Fineman, M et al. Clin Pharmacokinet. 2011;50(1):65-74; 2. BYDUREON Approved Product Information.

28 Effective FPG and PPG reduction 1 Exenatide QW Baseline Exenatide QW Week 14 Exenatide BID Baseline Exenatide BID Week Exenatide QW 2 mg 1 Exenatide BID 10 µg Glucose (mg/dl) Glucose (mg/dl) * Time (h) Time (h) Mean data; *P= vs. exenatideqw Reference 1. Drucker DJ, et al. Lancet 2008;372: ;

29 DURATION-2: BYDUREON vs sitagliptin or pioglitazone, on background metformin BYDUREON effective as first medication added to metformin 1,2 At the primary endpoint of 26 weeks, HbA 1c changes from baseline were 1.5% with BYDUREON, 0.9% with sitagliptin and 1.2% with pioglitazone (p<0.05 for BYDUREON vs both comparators) 1 HbA 1c reductions were sustained to week 52 throughout continued treatment with BYDUREON, or after switching from sitagliptin or pioglitazone to BYDUREON at week 26 2 Change in HbA 1c (%) HbA 1c Change from Week 26 to Week 52: SitagliptinBYDUREON 0.31% (95 % CI, 0.50 to 0.13), P< BYDUREON BYDUREON 0.06% (95 % CI, 0.13 to 0.25), P value not reported Pioglitazone BYDUREON 0.10% (95 % CI, 0.29 to 0.09), P value not reported Change in HbA 1c from baseline (mmol/mol) Time (weeks) Pioglitazone BYDUREON, BL=8.5% (69.4 Graph adapted from Wysham C, et al.2011, showing data for the evaluable population as least squares mean mmol/mol) ± standard error. 2 BL=baseline; CI=confidence interval. Reference 1. Bergenstal RM, et al. Lancet 2010;376:431 9; 2. Wysham C, et al. Diabet Med 2011;28: BYDUREON, BL=8.6% (70.5 mmol/mol) Sitagliptin BYDUREON, BL=8.5% (69.4 mmol/mol)

30 DURATION-3: BYDUREON vs insulin glargine HbA 1c improvement with BYDUREON vs insulin sustained for 3 years Exenatide QW (n=228) 2 mg once weekly Insulin glargine (n=220) Once daily, variable dose based on treat-totarget algorithm* 8.0 HbA 1c (%) 7.5 Δ % p= Time (weeks) Modified from Diamant M, et al *The daily dose of insulin glargine was based on the INITIATE algorithm (Initiate Insulin by Aggressive Titration and Education) and was individually adjusted to achieve fasting glucose values of mmol/l. In the Insulin glargine arm, from a starting daily insulin dose of 10IU/day, mean dose increased to approximately 31 IU/day at 26 weeks. Background therapy: Metformin with or without sulfonylurea. Reference 1. Diamant M, et al. Lancet Diabetes Endocrinol 2014; 2:

31 Weight in DURATION studies: Overview *1 5 *BYDUREON is not indicated for weight loss. BYDUREON did not meet primary endpoint of non-inferiority vs 1.8mg liraglutide (upper limit of CI <0.25%) in DURATION-6. 4 æ BYDUREON is not indicated for use in combination with TZDs Modified from BergenstalRM, et al Reference 1. Bergenstal RM, et al. Lancet 2010; 376:431-9; 2. Drucker DJ, et al. Lancet 2008; 372: ; 3. Blevins T, et al. J Clin Endocrinol Metab 2011; 96: ; 4. BuseJB, et al. Lancet 2013; 381:117-24; 5. Diamant M, et al. Lancet 2010; 375:

32 DURATION-3: BYDUREON vs insulin glargine Weight change over 3 years 1,2 Treatment with Bydureon resulted in significant weight reduction compared to weight gain with insulin glargine over 3 years 1 * *BYDUREON is not indicated for weight loss. 2 4 Insulin glargine, BL=90.6 kg (n=222) Bydureon, BL=91.2 kg (n=233) Change in bodyweight (kg) Time 2 (weeks) Graph adapted from Diamant M, et al. 2014, showing data for the modified intent-to-treat population as least squares mean ±standard error. 1 *p< BL=baseline. Reference 1. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464 73; 2. BYDUREON Approved Product Information Change from BL: ± 0.28 kg 2.49 ± 0.28 kg*

33 DURATION-2: individual efficacy vs weight change HbA1c HbA1c 7 v 6.5 fbsl Weight HbA1c vs Weight Bergenstal et al. Lancet ;

34 Less nausea with BYDUREON vs. exenatide bd æ1 3 Withdrawal due to nausea or vomiting each occurred in 1% of BYDUREON-treated patients 1 Most episodes of nausea were mild to moderate 1 BYDUREN associated with less nausea compared to exenatide BD or 1.8mg liraglutide æ 1 4 BYDUREON did not meet primary endpoint of non-inferiority vs 1.8mg liraglutide (upper limit of CI <0.25%) in DURATION-6. 4 æ Statistical significance not tested. Patients administered exenatide or liraglutide with background therapy. Adapted from BYDUREON Approved Product Information 1 and Buse et al Reference 1. BYDUREON Approved Product Information. 2. Drucker DJ et al. Lancet 2006; 368: Blevins T et al. DURATION-5. J Clin Endocrinol Metab 2011; 96: Buse JB et al. DURATION-6. Lancet 2013; 381(9861):

35 Injection-site Injection-site reactions Mostly mild to moderate Usually did not lead to withdrawal from studies Injection site reactions were higher in exenatide once weekly treated patients (16%) compared exenatide BD treated patients (2%- 7%): pruritus (8%), erythema (4%), induration (4%) and nodule (3%). Asymptomatic nodule formation (up to 77%). Approximately 73% of the first incidence of treatment emergent injection site reactions resolved within 60 days. Injection-site bumps Small, raised nodules very frequently occur at the injection site Consistent with known properties of poly (D,L-lactide co-glycolide) polymer microsphere technology Size of bump Bump Most individual nodules were asymptomatic and resolved over 4-8 weeks Reference 1. BYDUREON Approved Product Information. 2. DeYoung MB et al. Diabetes Technol Ther 2011; 13:

36 BYDUREON: Summary of safety and tolerability profile As with other GLP-1 receptor agonists, 1 4 the most frequent adverse drug reactions ( 5% of patients treated with BYDUREON) were mainly gastrointestinalrelated (nausea, vomiting, diarrhoea and constipation) In addition, injection-site reactions (pruritus, nodules, erythema,induration), hypoglycaemia (with a SU) and headache occurred 1 Most adverse reactions associated with BYDUREON were mild to moderate in intensity 1 There have been rare, spontaneously reported events of acute pancreatitis and renal failure. If pancreatitis is suspected, BYDUREON should be discontinued 1 Data source comprises 5 trials comparing 2 mg exenatide once weekly to either 10 μg exenatide twice daily (a 30 week study), sitagliptin and pioglitazone (a 26 week study), and insulin glargine (a 26 week study). Background therapies included diet and exercise and oral antidiabetic agents. BD=twice daily; SU=sulphonylurea; TZD=thiazolidinedione. Reference 1. BYDUREON Approved product Information. 2. BYETTA Approved product Information. 3. VICTOZA Approved product Information. 4. LYXUMIA Approved product Information.

37 PBS listing Dual combination therapy with metformin OR a sulfonylurea Authority Required (STREAMLINED) 6354 Clinical Criteria: The treatment must be in combination with metformin; OR the treatment must be in combination with a sulfonylurea AND Patient must have a contraindication to a combination of metformin and a sulfonylurea; OR patient must not have tolerated a combination of metformin and a sulfonylurea AND Patient must have, or have had, a HbA1c measurement greater than 7% prior to the initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon-like-peptide-1 or a sodium-glucose co-transporter 2 (SGLT2) inhibitor despite treatment with either metformin or a sulfonylurea. Triple combination therapy with metformin AND a sulfonylurea Authority Required (STREAMLINED) 6339 Clinical Criteria: The treatment must be in combination with metformin AND The treatment must be in combination with a sulfonylurea AND Patient must have, or have had, a HbA1c measurement greater than 7% prior to the initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagonlike-peptide-1 or a sodium-glucose co-transporter 2 (SGLT2) inhibitor despite treatment with maximally tolerated doses of metformin and a sulfonylurea.

38 BYDUREON PEN: SUMMARY BYDUREON is the first approved once weekly GLP-1 receptor agonist HbA 1c reductions are sustained for up to 6 years vs baseline 2 Potential for weight reduction over 6 years vs baseline * and low risk of hypoglycaemia 1,2 Most common adverse events: gastrointestinal (nausea, diarrhoea, vomiting, constipation), nasopharyngitis, hypoglycaemia, injection site reactions (pruritus, nodules, erythema, induration) 1 Open-label, uncontrolled extension study in patients administered BYDUREON with background therapy. 43% of patients remained in the study at Year 6. *BYDUREON is not indicated for weight loss. 1 SUs are associated with an increased risk of hypoglycaemia. When BYDUREON is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia. 1 Reference 1. BYDUREON Approved Product Information. 2. Henry RH, et al. Poster presented at ADA P

39 Swedish Registry outcome data: GLP1a best All cause All CVD GLP1a CHD CCF DPP4i & TZD GLP1a GLP1a N = 20, 442, Ekstrom Diab Obes Metab 2016

40 GLP1 analogue & CV outcome RCT N = 9340, >50yr & CV factor, 3.8yr f/up, no DPP4i Primary EP = 3-pt MACE: 13.0 vs 14.9%, HR 0.87, p<0.001 Marso, NEJM 2016

41 New arrivals

42 Sodium glucose co-transporter (SGLT2) inhibitors Induce prox tubular glycosuria Benefits: reduce HbA1c 1% with few or no hypo s used alone lower weight & BP Risks: dehydration (esp if on diuretics) hypo s with SU or insulin UTIs, vulvovaginitis, balanitis Cefalu, Lancet Sept 2013

43 GFR retention but efficacy AUC 20mg 1 week 50mg stat ugluc loss 20mg 1 week Kasichayanulaet al, Dapagliflozin pharmacokinetics in moderate and severe CKD, BJCP 2012

44 SGLT2i & CKD: wt, BP, GFR & uacr Wt GFR BP uacr Yale et al. doi: /dom.12348

45 Gliflozin guidelines 20% reduction in insulin/ SU if tight control 50% reduction in BP Rx/diuretic if tight control Daily BP, weight, BSL Daily groin/apron wash, dry, baby powder Zinc/castor oil if red, clotrimazole if thrush MSU pot & cephalexin, pre-emptive Rx if dysuria Hold SGLT2i if too symptomatic, try alternate daily Watch for DKA in long-standing T2DM

46 SGLT2i: CV benefit data CV CCF Zinman, NEJM, Sept 2015

47 SGLT2i: CKD benefit data Wanner, NEJM, June 2016

48 Turning lemonade into Gatorade

49 SGLT2i class efficacy & safety Less CV Less CCF More stroke N= 37,525, 6 regulatory submissions, 7 drugs Wu, Lancet Diab Endocrin 2016

50 Therapy PRO CON Metformin Experience / Proven outcomes / Cost GI symptoms/ CKD Sulfonylurea Experience / Cost Hypo s/ Wt. gain / CKD DPP4-i (gliptin) TZD (glitazone) SGLT2-i (gliflozin) Acarbose GLP-1 (incretin analogue) Wt. neutral / Low risk of hypo s Low risk of hypo s Wt. loss / SBP reduction / Low risk of hypo s Low risk of hypo / Wt. neutral / Cost Wt. loss / Low risk of hypoglycaemia Cost / CCF (saxa, not sita) / CKD (except lina) / LFT s (vilda) Cost / Fluid retention / Wt. gain / Fracture risk /?Bladder ca (pio) New / Dehydration / DKA $ / UTI & thrush / CKD inefficacy Limited efficacy / GI tolerability Cost / Injection / GI symptoms Insulin Experience / Effective Injection / Wt. gain / Hypo s 50

51 Therapy PRO CON Metformin Experience / Proven outcomes / Cost BASELINE GI symptoms/ CKD Sulfonylurea Experience / Cost Hypo s/ Wt. gain / CKD DPP4-i (gliptin) Wt. neutral / Low risk of hypo s Cost / CCF (saxa, not sita) / CKD (except lina) / LFT s (vilda) TZD (glitazone) Low risk of hypo s TOO RISKY Fluid retention / Wt. gain / Fracture risk /?Bladder ca (pio) SGLT2-i (gliflozin) Wt. loss / SBP reduction / Low risk of hypo New / Dehydration / DKA $ / UTI & thrush / CKD inefficacy Acarbose GLP-1 (incretin analogue) Low risk of hypo / Wt. neutral / Cost Wt. loss / Low risk of hypoglycaemia TOO WEAK Limited efficacy / GI tolerability Cost / Injection / GI symptoms Insulin Experience / Effective Injection / Wt. gain / Hypo s 51

52 Therapy PRO CON Metformin Experience / Proven outcomes / Cost BASELINE GI symptoms/ CKD HYPOs/WT GAIN Sulfonylurea Experience / Cost Hypo s/ Wt. gain / CKD DPP4-i (gliptin) Wt. neutral / Low risk of hypo s Cost / CCF (saxa, not sita) / CKD (except lina) / LFT s (vilda) SGLT2-i (gliflozin) Wt. loss / SBP reduction / Low risk of hypo New / Dehydration / DKA $ / UTI & thrush / CKD inefficacy GLP-1 (incretin analogue) Wt. loss / Low risk of hypoglycaemia HYPOs/WT GAIN Cost / Injection / GI symptoms Insulin Experience / Effective Injection / Wt. gain / Hypo s 52

53 Homeward bound

54 Organ-specific effects of obesity Depression, fatigue, isolation, low self-esteem CVA, dementia, carpal tunnel, benign intracranial HTN Dyspnoea, asthma, sleep apnoea, PE Glomerulosclerosis, renal calculi, urine incontinence Cancer: breast, uterus, cervix, oesophagus, colon, pancreas, kidney, prostate Osteoarthritis, gout, flat feet, plantar fasciitis Male: erectile dysfn. Female: irregular periods, polycystic ovary, infertility HTN, angina, CCF, varicose veins Gallstones, gastric reflux, fatty liver, cirrhosis, pancreatitis Insulin resistance, lipids & BSL Skin Candida, acanthosis, hirsutism, stretch,

55 Mediterranean diet Alcohol moderation Physical activity Non-smoking Healthy lifestyle Reduced all-cause mortality by 65% Koops, JAMA 2004

56 Lean Weight: Rule of Thumb Height (cm) Weight (kg) BMI = Max lean weight (kg) = Ht (cm) - 100

57 Praise the positive

58 Quantity, quality & value Eat right Pre-meal vinegar as anorectic Eat like a hippie, not like a truckie Make food crunchy and colourful Traffic light detox drink

59 Move well Motivation: age 20 vs 50 vs 80 Purpose: fit, strong, flexible, stable Bird-rocket half-squats Seven

60 Stay calm Friends & family Pets & plants Movement, music & massage CRUfAD.org This Way Up

61 Stay connected