Stephen Leow Disclosures I have received honoraria, sat on the advisory boards or received grants from Novo Nordisk, Sanofi Aventis, Eli Lilly, Boehringer Ingleheim, Jansenn Cilag, Mundipharma, BioCSL, Rickett Benkiser, AstraZeneca, GlaxoSmithKlein, Pfizer, Takeda and Grunenthal T2 Diabetes in 216 Exciting new era Or More of the same Agenda Why do we treat diabetes? Why do we treat glycaemia? Do we treat to target? Is aggressive treatment always good? The case for early vs late treatment Beyond Glycaemia EMPHA-REG LEADER More tools for our toolbox Is it to prevent complications? Nephropathy Neuropathy Retinopathy Is it to increase lifespan? What do diabetics die from? Association between mean HbA 1c and complications: UKPDS Targets What are HbA1c targets in 216? Is it 7% (53 mmol/mol)? Is lower better? Is lower always better? Adapted from Stratton IM et al. on behalf of the UK Prospective Diabetes Study Group. BMJ 2; 321:5 12. 1
ADS recommended targets for HbA 1c Are we doing enough already? *Achievement of HbA 1c targets must be balanced against risk of severe hypoglycaemia, especially among older people. In an older adult, long duration might be considered to be >1 2 years, but for a person who develops type 2 diabetes at a young age, it may be considerably longer. Examples of major comorbidities include chronic medical conditions, such as chronic kidney disease stages or 5; heart failure stages III or IV (New York Heart Association grading); incurable malignancy; and moderate to severe dementia. Where practical, suggest blood glucose target level <15 mmol/l to help minimise risk of infection. Adapted from Cheung NW et al. Med J Aust 29; 191: 339. Early intensive multifactorial therapy: STENO-2 Does glycaemic control alone save lives? Adapted from Gaede PG et al. N Engl J Med 29; 358: 58-91. The argument for early aggressive treatment Early intensive glycaemic control: UKPDS The Legacy Effect UKPDS Trial showed the advantage of treating glycaemia After the trial, the HbA1c of the control group and the intervention group were the same In the1 year follow up of the trial, the benefits of the intervention group continued, despite the glycaemic control being the same Adapted from UKPDS Group Lancet 1998; 352: 837 53. Holman RR et al. N Engl J Med 28; 359: 1577 89. 2
Is glucose lowering always a good thing? Intensive versus standard glucose control: VADT, ACCORD, ADVANCE There is an established benefit to treating Blood Glucose early How about treating Blood Glucose later on in the progression of the disease? Should we treat all diabetic patients aggressively? If achievable, are lower targets always better? Duckworth W et al. for the VADT investigators. N Engl J Med 29; 36: 129 39. The ADVANCE Study Group. N Engl J Med 28; 358: 256 72. The ACCORD Study Group. N Engl J Med 28; 358: 255 59. CVD: cardiovascular disease. MI: myocardial infarction. CHF: coronary heart failure. In the light of the ACCORD Trial, the ADS HbA1c targets are different for early and late stage diabetes How do you treat diabetes? *Achievement of HbA 1c targets must be balanced against risk of severe hypoglycaemia, especially among older people. In an older adult, long duration might be considered to be >1 2 years, but for a person who develops type 2 diabetes at a young age, it may be considerably longer. Examples of major comorbidities include chronic medical conditions, such as chronic kidney disease stages or 5; heart failure stages III or IV (New York Heart Association grading); incurable malignancy; and moderate to severe dementia. Where practical, suggest blood glucose target level <15 mmol/l to help minimise risk of infection. First line Second line Third line Adapted from Cheung NW et al. Med J Aust 29; 191: 339. Wonderful Metformin Lowers BGLs Few hypos Weight loss Lower rates of cancer 1 st line treatment in most, if not all, guidelines 3
Rosiglitazone, the game changer In 27, Steve Nissen published a metanalysis showing that Rosiglitazone was associated with increased myocardial infarctions This caused a lot of controversy, with GSK defending Rosiglitazone in the ADOPT trial This resulted in the FDA mandating a Black Box warning on Rosiglitazone The Black Box warning was removed after publication of the RECORD trail in 28 Cardiovascular Outcomes Since Rosiglitazone, the FDA has mandated that all new diabetes medication undergo cardiovascular safety trials There are many cardiovascular trials currently underway All are powered to show non inferiority ie no cardiovascular risk However, the Holy Grail with these trials is to show cardiovascular benefit Most trials prior to 215 have showed no cardiovascular risk Do you expect there to be better cardiovascular outcomes with hypoglycaemics? All the FDA mandated trials are powered to show NON INFERIORITY If a drug actually showed a cardiovascular benefit beyond glycaemic control In Stockholm, on September 215, the game changed Would this be a game changer?
Adjusted mean (SE) change from baseline in HbA 1c (%) Adjusted mean (SE) change from baseline in HbA 1c (%) 22-Sep-16 Change in HbA 1c, in patients with good control (HbA 1c <8%; post-hoc analysis) Change in HbA 1c, in patients with poor control (HbA 1c > 8%; post-hoc analysis).2.1 -.1 -.2 -.3 -. -.5 -.6 -.7 (n=131).6 Empagliflozin 1 mg (n=12).39 p<.1 25 mg (n=136).52 p<.1 Mean baseline Sitagliptin (n=129).55 p<.1 7.37 7.33 7.32 7.31 Comparison with sitagliptin.17 (95% CI,.2,.35) p=.88. (95% CI,.15,.22) p=.7118 EMPA-REG MONO: study 125.2.2 -.2 -. -.6 -.8-1 -1.2-1. (n=97).6 Empagliflozin 1 mg (n=82) 25 mg (n=88) 1.13 1.16 Mean baseline Sitagliptin (n=9).78 8.65 8.83 8.7 8.6 Comparison with sitagliptin.35 (95% CI,.58,.12) p=.31.38 (95% CI,.61,.15) p=.1 EMPA-REG MONO: study 125.2 EMPHA-REG Myocardial Infarcts EMPHA-REG Heart Failure In New Orleans, LEADER added more fuel to the fire LEADER Large clinical trial looking at the cardiovascular safety of (Victoza) Coincidentally, has been released as an a weight loss medication under the trade name SAXENDA 5
Patients with an event (%) Patients with an event (%) Patients with an event (%) Patients with an event (%). 5 1 1. 5 22-Sep-16 CV death Non-fatal myocardial infarction 8 8 6 6 HR=.78 2 95% CI (.66 ;.93) p=.7 6 1 2 1 8 2 3 3 6 2 8 5 Patients at risk 668 61 599 558 55 5 382 322 1723 8 672 68 61 56 79 7 338 267 179 65 2 HR=.88 95% CI (.75 ; 1.3) p=.11 6 1 2 1 8 2 3 3 6 2 8 5 Patients at risk 668 69 531 5 359 263 181 12 1619 672 613 513 7 31 22 13 2 159 2 The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 5 months, because less than 1% of the patients had an observation time beyond 5 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 5 months, because less than 1% of the patients had an observation time beyond 5 months. CI, confidence interval; HR, hazard ratio. Non-fatal stroke Individual components of the primary endpoint 5 Hazard ratio (95% CI) p-value N % R N % R 3 Number of patients 668 1. 672 1. 2 HR=.89 1 95% CI (.72 ; 1.11) p=.3 6 1 2 1 8 2 3 3 6 2 8 5 Patients at risk 668 62 56 5 26 351 269 19 1662 65 672 622 558 8 5 31 228 11 168 5 The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 5 months, because less than 1% of the patients had an observation time beyond 5 months. CI, confidence interval; HR, hazard ratio. CV death.78 (.66 ;.93).7 219.7 1.2 278 6. 1.6 Non-fatal MI.88 (.75 ; 1.3).11 281 6. 1.6 317 6.8 1.8 Non-fatal stroke.89 (.72 ; 1.11).3 159 3..9 177 3.8 1. Hazard ratio (95% CI) Favours Favours Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. %, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 1 patient-years of observation. All-cause death All-cause, CV and non-cv death 2 2 15 1 5 HR=.85 95% CI (.7 ;.97) p=.2 Hazard ratio (95% CI) p-value N % R N % R 1 1 5 Number of patients 668 1. 672 1. All-cause death.85 (.7 ;.97).2 381 8.2 2.1 7 9.6 2.5 CV death.78 (.66 ;.93).7 219.7 1.2 278 6. 1.6 6 12 1 2 18 2 2 3 3 36 2 2 8 8 5 Patients at risk 668 61 599 558 55 5 382 322 1723 8 672 68 61 56 79 7 338 268 179 65 The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 5 months, because less than 1% of the patients had an observation time beyond 5 months. CI, confidence interval; HR, hazard ratio. Non-CV death.95 (.76 ; 1.18).66 162 3.5.9 169 3.6 1.. 5 1 1. 5 Favours Hazard ratio (95% CI) Favours Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. %, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 1 patient-years of exposure. 6
Blood pressure (mmhg) HbA 1c (%) HbA 1c (mmol/mol) Body weight (kg) Body weight (lb) 22-Sep-16 HbA 1c Body weight 7 5 9 6 2 9. 7 9 2 2 8. 6 5 6 9 2 2 5 5 9 1 9 8 7. 5 6. ETD at month 36: -.% 95% CI (-.5 ; -.3) 5 3 5 8 8 8 6 ETD at month 36: -2.3 kg 95% CI (-2.5 ; -2.) 1 9 6 1 9 5. 3 8 1 9 2 3 6 1 2 1 8 2 3 3 6 2 8 5 E O T Number of patients at each visit 6 1 2 2 3 6 8 E O T Number of patients at each visit 668 2 355 672 13 355 295 235 135 3 3 395 3877 372 381 36 239 233 89 756 11 87 375 3561 667 671 3 23 32 285 88 397 3835 368 82 766 378 3555 Data are estimated mean values from randomisation to EOT. CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; HbA 1c, glycosylated haemoglobin. Data are estimated mean values from randomisation to EOT. CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference. Blood pressure Hypoglycemia 1 Number of patients at each visit 1 3 5 1 3 8 7 5 7 668 672 5 35 332 295 17 3975 Data are estimated mean values from randomisation to EOT; *EOT may be any time from month 2 onwards. CI, confidence interval; DBP, diastolic blood pressure; EOT, end of trial; ETD, estimated treatment difference; SBP, systolic blood pressure. Marso SP et al. N Engl J Med 216. In press. 3859 3699 P l a c e b o L i r a g l u t i d e L i r a g l u t i d e P l a c e b o 6 12 2 36 8 EEOT* O T * 6 1 2 Time from 2randomisation 3(months) 6 8 823 767 3722 357 SBP ETD at month 36: 1.2 mmhg 95% CI (1.9 ;.5) DBP ETD at month 36:.6 mmhg 95% CI (.2 ; 1.) Confirmed hypoglycemia Severe hypoglycemia. 5 1 1. 5 Hazard ratio (95% CI) Favours Favours Rate ratio (95% CI) p-value.8 (.7 ;.88).69 (.51 ;.93) N % N % <.1 239 3.7 213 5.6.16 11 2. 153 3.3 Confirmed hypoglycaemia was defined as plasma glucose level of less than 56 mg per decilitre (3.1 mmol per litre) or a severe event. Severe hypoglycaemia was defined as hypoglycaemia for which the patient required assistance from a third party. Analysed using a negative binomial regression model. CI, confidence interval. Summary EMPHA-REG 38% Relative Risk Reduction for Myocardial Infarcts 35% Relative Risk Reduction for Hospitalisation for Heart Failure LEADER 22% Risk Reduction for Myocardial Infarcts 11% Risk Reduction for Non Fatal Strokes But theres more Both these agents areasspciated with Weight Loss Bith these agents have low rates of hypoglycaemia Class Effect or Unique Actions? Do all SGLT2 inhibitors have the same effect? Do all GLP1 agonists have the same effect? 7
Not to forget that some old trials have shown cardiovascular benefit Pioglitazone Thought to be due to the positive benefit on lipids Acarbose Thought to be due to the effect on post prandial hyperglycaemia Metformin Teasers New Oral FDCs Smart Insulin Closed loop CGM/Pumps Flash Glucometer Nano technology Insulin/GLP1 FDC High concentration basal insulin SGLT2/DPPi combination Closed Loop Insulin Pump Freestyle Libre Flash Glucometer 8
Insulin Nanotechnology Insulin/GLP1 combo High concentration Basal Insulin Summary Early aggressive treatment benefits our patients Late aggressive treatment may be detrimental The RACGP STOP Rule helps us implement this Certain medications confer cardiovascular benefits beyond glucose lowering The End Any Questions? Will this change the way you treat diabetes? 9