Medical therapy advances London/Manchester RCP February/June 2016
Advances in medical therapies for diabetes mellitus Duality of interest: The speaker or institutions with which he is associated has received funding from the manufacturers Professor Philip of nearly Home all the new insulin and non-insulin therapies discussed, for his advisory, Newcastle University lecturing and research activities
Baseline adjusted risk factors for IHD in the UKPDS cohort Turner et al, BMJ, 1998 Model position Coronary artery disease n=280 All MI n=192 Fatal MI n=79 variable p variable p variable p 1 LDL chol <0.001 LDL chol 0.002 dbp 0.001 2 HDL chol 0.001 dbp 0.007 LDL chol 0.012 3 HbA 1c 0.002 Smoking 0.025 HbA 1c 0.024 4 sbp 0.007 HDL chol 0.026 5 Smoking 0.056 HbA 1c 0.053 Age/sex adjusted in 2693 whites with Type 2 diabetes Triglycerides and hypertension significant for CAD on univariate analysis Body weight, waist hip ratio, serum insulin, exercise level not predictive on univariate analysis
Areas of care in routine diabetes management Preventing complications Glucose control Blood pressure control Lipids Aspirin Smoking Detecting and managing complications Macrovascular Retinopathy Nephropathy Neuropathy and PAD 2006
Advances in medical therapies for diabetes mellitus Not discussed Lipid modification, BP lowering, anti-platelet therapies Therapies for extant complications (eye, renal, cardiac) Therapeutic education Preventative approaches (metabolic, immunological) Discussed New evidence on recently introduced glucose-lowering therapies oral agents and injectables
CV outcome studies of DPP-4 inhibitors All studies are DPP-4 placebo-blinded, inhibitors prevent with a the standard degradation of care of comparator the Study : gut hormone SAVOR Comparator GLP-1, which is EXAMINE secreted in Stroke TECOS HR (95% CI) response to food, and enhances insulin production medication saxagliptin alogliptin sitagliptin n RECORD 16 metformin/sulfonylurea 492 5380 0 7214 (0 49, 671 1 06) time ADOPT (yr) 1 2.1 glibenclamide (glyburide) 1.5 0.773.0 (0.38, 1.59) or metformin population CV or high risk recent ACS prior CV Early rosiglitazone mixed 0.48 (0.23, 0.98) event studies rate (%/yr) 1 a 3.6 7.9 3.2 MACE PROactive HR (95% 2 CI) 1.00 placebo (0.89,1.12) 0.96 ( b ) 0 81 0.98 (0 61, (0.88,1.09) 1 07) a, contrrol group; b, not given None of these studies establishes the CV safety or efficacy of its studied medication in a population typical of ambulatory diabetes care, and followed for a reasonable number of years Scirica et al, NEJM, 2013; White et al, NEJM, 2013; Green et al, NEJM, 2015 No similar data is available for linagliptin or vildagliptin A weak heart failure signal was found in the SAVOR study, and was not present in the TECOS study
CV outcome studies of GLP-1 receptor agonists No useful GLP-1 data receptor is available agonists for are exenatide injected peptides preparations, liraglutide, which lixisenatide, activate the albiglutide, receptor of the or hormone dulaglutide GLP-1, enhancing insulin production and inducing satiety ELIXA (lixisenatide) (and thus weight MACE loss) results post ACS study (<180 days) placebo/comparator rate 6.3 events/yr 25 months MACE HR 1.02 (0.89, 1.17) This study does not established the CV safety Pfeffer or et efficacy al, N Engl of J M, 2015 lixisenatide (or the GLP-1 receptor agonist class) in a population typical of ambulatory diabetes care, and followed for a reasonable number of years
Cardiovascular outcome (MACE) with liraglutide compared to standard of care % % MACE Death p = Marco et al, NEJM, 2016
CV outcome studies of SGLT-2 blockers No useful data is available for canagliflozin or dapagliflozin SGLT-2 blockers reduce sodium/glucose resorption from the proximal tubule, thus causing urinary glucose loss, and thus glucose-lowering placebo-blinded, standard of care comparator (extra drugs +12 %) and body weight loss n 7020 Consequences include increased genital time (yr) infections and 3.1 an osmotic diuresis / volume population depletion prior CV disease, T2DM event rate (%/yr) 4.0 (MACE, placebo) empagliflozin EMPA-REG-OUTCOME study MACE HR (95% CI) 0.86 (0.74 0.99) MI HR 0.87 (0.70 1.09) Stroke HR 1.18 (0.89 1.56) CV-death HR 0.62 (0.49 0.77) (3.7% vs 5.9%) all death HR 0.68 (0.57 0.82) (5.7% vs 8.3%) heart failure 0.65 (0.50 0.85) (2.7% vs 4.1%) Zinman et al, N Engl J Med, 2015
Kaplan-Meier time to event curve for MACE in the EMPA-REG study Participants with event (%) placebo empagliflozin Time (months) Zinman et al, NEJM, 2015
Kaplan-Meier time to event curve for MACE in the Empagliflozin EMPA-REG EMPA-REG-OUTCOME study conclusion In very high risk people with prior CV disease empagliflozin reduces Participants risk of with heart event failure (%) and death Effects on MI are uncertain, and for stroke there is an adverse signal placebo empagliflozin Time (months) Zinman et al, NEJM, 2015
Renal outcomes in the empagliflozin outcome study egfr (ml/min) Wanner et al, NEJM, 2016
Renal outcomes in the empagliflozin outcome study egfr (ml/min) Wanner et al, NEJM, 2016 The results were the same in those starting with egfr <60 ml/min!
Cardiovascular outcomes in insulin- and noninsulin-treated participants a in the ORIGIN study glargine b comparator c (rate per 100-person-yr -1 ) HR (95% CI) MACE 2.94 2.85 1.02 (0.94 to 1.11) MACE+ 5.52 5.28 1.04 (0.97 to 1.11) MACE+ includes revascularization and hospitalized HF a, 88 % T2DM, 59 % prior CV event b, dose 0.31 U/kg at 1 yr, 0.40 U/kg at 6 yr n=12 537; follow-up 6.2 yr c, excess comparator usage +28 % two or three agents, +22 % sulfonylurea, +13 % metformin, and others ORIGIN Trial Investigators, NEJM, 2012
Current areas of advances in insulin therapy new basal insulins: degludec and glargine 300 U/ml biosimilar insulin glargine fixed and flexible combination with GLP-1 receptor agonists fixed combination of insulins aspart and degludec fasting-acting insulin aspart glucose-sensitive ('smart') insulins closed loop insulin pump therapy regenerative medicine, encapsulated islets
Injectable therapy contrasts type 2 diabetes GLP-1 Insulin receptor agonists therapy Glucose-lowering ++ +++ (islet cell independent) Hypoglycaemia ± ++ Body weight change ++
Change in HbA 1c when exenatide twice daily is added to insulin glargine in people with Type 2 diabetes Time (weeks) 0 10 20 30 Δ HbA 1c (%) 0.0 0.5 1.0 1.5 n=259; mean (SE) baseline HbA 1c 8.4 % glargine + placebo difference 0.7 ( 0.9 to 0.5) % 2.0 glargine + exenatide 10 μg bd 2.5 insulin dose difference: 6.5 ( 12.3 to 0.8) U/day Buse et al, Ann Int Med, 2011
Effect of fixed-ratio combination degludec+liraglutide vs components in insulin naïve type 2 diabetes Therapy HbA 1c Hypoglycaemia Body weight (%; mmol/mol) (event/person-yr) (kg) lira+degludec -1.9; -21*** 1.8-0.5*** liraglutide -1.3; -14 0.2-3.0 degludec -1.4; -15 2.6 +1.6 n=1663; 26 weeks ***, p<0.001 vs single agent Gough et al, Lancet Diabetes Endocrinol, 2014
Cumulative confirmed hypoglycaemia with insulin degludec and insulin glargine in type 1 diabetes Events/person any time Events/person nocturnal Rate ratio 1 07 (0 89 1 28) Rate ratio 0 75 (0 59 0 96) Time (weeks) Time (weeks) Heller et al, Lancet, 2012
Confirmed nocturnal hypoglycaemia events with insulin glargine 300 U/ml in obese people with type 2 diabetes Cumulative events/person 3.0 prior basal + meal-time 3.0 prior basal only 2.5 RR 0.78 (0.68 to 0.89) 2.5 RR 0.71 (0.58 to 0.86) 2.0 1.5 glargine U100 2.2 1.6 2.0 1.5 glargine U100 2.0 1.0 0.5 0.0 glargine U300 1.0 0.5 1.0 glargine U300 0 4 8 12 16 20 24 0.0 28 0 4 8 12 16 20 24 28 Time (weeks) Riddle et al, Diabetes Care, 2014; Yki-Järvinen et al, Diabetes Care, 2014 FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY DO NOT DISTRIBUTE
Hypoglycaemia composite analysis in the type 2 diabetes from the EDITION studies people with event (%) Gla-300 Gla-100 relative risk (95% CI) nocturnal 30.0 39.8 0.75 (0.68, 0.83) any-time 65.5 72.0 0.91 (0.87, 0.96) composite of EDITION 1, 2, and 3 Severe hypoglycaemia was rare in both treatment groups (2.3% with Gla- 300 vs 2.6% with Gla-100) Ritzel et al, DGIM, 2014
CGM profiles in type 1 diabetes with Gla-300 and Gla-100 morning and evening Gla-300 mean±se Supports: Gla-100 Once daily dosing in all Flexibility in timing of injection Any time of day injection Bergenstal et al, EASD, 2014
Comparison of fixed-ratio combination of insulins degludec+aspart vs glargine 100 U/ml in insulin naïve type 2 diabetes in Japan Endpoint (actual and/or difference) Insulin dose (U/kg) +0.41 vs +0.41 HbA 1c (%) 0.28 ( 0.46, 0.10) (to 7.0 vs 7.3) (mmol/mol) 3 ( 5, 1) (to 53 vs 56) Fasting plasma glucose (mmol/l) 0.15 ( 0.29; 0.60) Hypoglycaemia (rate ratio (95% CI)) overall 0.73 (0.50; 1.08) nocturnal 0.75 (0.34; 1.64) Body weight (kg) +0.7 vs +0.7 n=296; 26 weeks Onish et al, Diabetes Obes Metabol, 2013
Current areas of advances in insulin therapy: brief conclusions Many of the CV outcomes studies of the past 5 years only address safety and in limited populations The reductions demonstrated for CV death (empagliflozin) and MACE (liraglutide) are very welcome but apply only to populations with prior CV events The reduction (cessation) of rate of decline in egfr with SGLT2-blockers is also welcome The new insulins show useful reductions in nocturnal hypoglycaemia, and work well combination GLP-1RAs, and as a premix (insulin degludec)
Thank you for listening Placeholder for thank you picture JBN: 194,119.011 Date of Prep: June 2014