New frontiers in Diabetes management Diabetes & macrovascular disease: Current views on the role of glucose control Key-slides prepared and presented at CDMC on April 20, 2013 in Hanoi, Vietnam by Mark Cooper, MD Melbourne Australia

Improvement in risk associated with a 1% reduction in HbA1c from 10 to 9%, and from 7 to 6%

Relative Risk Reduction Each 1% reduction in HbA1c was associated with: 22% ↓ in risk of macrovascular event 26% ↓ in risk of microvascular event 22% ↓ in risk of death

UKPDS: Aggregate endpoints by treatments Endpoint Intensive Conventional RR for Intensive Treatment (N=2729) (N=1138) Any diabetes endpoint 963 438 0.88 (0.79-0.99) Diabetes-related death 285 129 0.90 (0.73-1.11) All-cause mortality 489 213 0.94 (0.8-1.10) MI 387 186 0.84 (0.71-1.00) Stroke 148 55 1.11 (0.81-1.51) Amputation/ PVD death 29 18 0.65 (0.36-1.18) Microvascular 225 121 0.75 (0.60-0.93) UKPDS Group, Lancet 1998

A factorial randomized trial of blood pressure lowering and intensive glucose control in 11,140 patients with type 2 diabetes

Irrespective of the level of hemoglobin A1c or blood pressure at entry Hypotheses: Among individuals with type 2 diabetes, the risks of major microvascular and macrovascular events will be reduced by: Intensive glucose control with a sulfonylurea (gliclazide-MR) based regimen targeting a hemoglobin A1c of 6.5% of less Routine BP lowering with a fixed combination of an ACE inhibitor (perindopril) and a diuretic (indapamide) Irrespective of the level of hemoglobin A1c or blood pressure at entry

Relative risk reduction All-cause mortality 25 Standard Intensive Relative risk reduction 7%: 95% CI -6 to 17% p=0.28 20 15 Cumulative incidence (%) 10 5 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months)

Major macrovascular events 25 Standard Intensive Relative risk reduction 6%: 95% CI: -6 to 16% p=0.32 20 15 Cumulative incidence (%) 10 5 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months)

Average glucose control (HbA1c) is associated with CVD Every 1% higher HbA1c above 7% is associated with a 38% higher risk of macrovascular events Intensive All Standard Mean HbA1c during follow-up (%) Zoungas et al. Diabetologia 2012

Hospitalisation for CHF VADT1 (n=1700) ACCORD2 (n=10,250) ADVANCE3 (n=11,140) HbA1c at end of follow up: standard vs intensive 8.4 vs 6.9 7.5 vs 6.4 7.3 vs 6.5 Primary endpoint Non-fatal MI Non-fatal stroke CVD death Hospitalisation for CHF Revascularisation Hazard ratio for primary outcome (95% CI) 0.87 (0.730 – 1.04) 0.90 (0.78 – 1.04) 0.94 (0.84 – 1.06) Hazard ratio for mortality (95% CI) 1.065 (0.801 – 1.416) 1.22 (1.01 – 1.46) 0.93 (0.83 – 1.06) * *p=0.04 1 Duckworth W et al for the VADT Investigators. N Engl J Med 2009; 360: 129–39. 2The ACCORD Study Group N Engl J Med 2008;358:2545-2559; 3The ADVANCE Collaborative Group N Engl J Med 2008,358:2560-2572

Mortality (meta-analysis) Hazard ratio (95% CI) UKPDS 0.94 ( 0.80 , 1.10 ) ADVANCE 0.93 ( 0.83 , 1.06 ) VADT 1.07 ( 0.80 , 1.40 ) ACCORD 1.22 ( 1.01 , 1.46 ) Overall 0.5 1 2 Risk ratio (95% CI) Favors intensive glucose control Favors standard glucose control

No mortality benefit and at what cost? 140 +40%* Intensive control 120 100 Standard control 80 Events per 100 patient years 60 40 +87%* 20 0.7 0.4 Minor hypoglycaemia Severe hypoglycaemia *p<0.001

Hypoglycaemia and CVD Hypoglycaemia is an independent risk factor for serious cardiovascular events Triggers paroxysmal neurohormonal surges Higher frequency of ischemic ECG changes when glucose levels fall < 4 mM Increases in the corrected QT interval Cause for autonomic neuropathy ? Prothrombotic The risks of recurrent or severe hypoglycemia sometimes supersede the CV benefits of improved glycemic control.

Hypoglycaemia and CVD “ Since hypoglycemia may exacerbate myocardial ischemia and may cause dysrhythmias, it follows that those medications that predispose patients to this adverse event should be avoided if possible (in patients with or at risk of CVD)” Joint ADA and EASD position statement 2012 Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

Cardiovascular Events Non-Fatal MI, Stroke or CVD Death 0.12 0.10 Risk reduction 57% 95% CI: 12, 79 Log-rank P = 0.018 0.08 Cumulative Incidence 0.06 Conventional 0.04 0.02 Intensive 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years from Study Entry Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96 DCCT/EDIC Study Research Group, NEJM 2005

Pharmacological treatment of hyperglycaemia - overweight or obese person

Metformin as First Line Therapy Evidence-informed Consensus Effective Favourable effect on weight, low risk of hypoglycaemia, and low cost Caution with renal insufficiency presents a major implementation challenge in many parts of the world Possible CVD benefit

STOP-NIDDM trial: Lower incidence of cardiovascular events in acarbose treated patients JL, Josse RG, Gomis R, et al. STOP-NIDDM trial. JAMA 2003; 290: 486–494

New over last few years DPP-4 inhibitors GLP-1 analogues HbA1c for diagnosis of diabetes Community diabetes prevention programs Available new therapies DPP-4 inhibitors GLP-1 analogues TZDs less favoured Multi-factorial interventions Large scale clinical trials

Disappointment of glucose lowering studies Turnbull et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52, 2288-98, 2009

Time to Onset of First Primary Major Adverse Cardiovascular Event (MACE) Controlled Phase 2b/3 Pooled Population 5 4 3 Percentage With First Adverse Event Control 2 All Saxagliptin 1 Reference Frederich R et al. Postgrad Med. 2010;122:16-27. Key Point The time to onset of the first primary MACE was delayed in saxagliptin patients versus controls. The Kaplan-Meier curves diverged within the first few weeks of treatment. Additional Details Primary MACE was defined as myocardial infarction, stroke, or CV-death (defined using a MedDRA (Medical Dictionary for Regulatory Activities, version 11.0) preferred term list selective for these events and supplemented by clinical review of all deaths). BL 24 37 50 63 76 89 102 115 128 Patients at Risk Control 1251 935 860 774 545 288 144 123 102 57 All Saxagliptin 3356 2615 2419 2209 1638 994 498 436 373 197 Weeks Frederich R et al. Postgrad Med. 2010;122:16-27.

EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) CAROLINA : An Active Comparator (glimepiride) CARdiOvascular Outcome Study of the DPP-4 Inhibitor LINAgliptin in Patients with Type 2 Diabetes at High Cardiovascular Risk Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study

Interventions within the incretin axis Analogs Ingestion of food GI tract GLP1 GIP Promotes insulin secretion Retards glucagon release Beta cell proliferation Slows gastric emptying Reduces appetite DPP4 + - L-cells GLP-R Note: slide builds to show actions Key points Incretins (GLP-1 and GIP) are intestinal hormones involved in regulating glucose homeostasis – their effects are glucose dependent. Incretins are released by the intestine throughout the day and levels increase after meals. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic β cells by intracellular signalling pathways involving cyclic AMP. Enhanced tissue glucose uptake occurs with higher insulin levels GLP-1 also lowers glucagon secretion from pancreatic α-cells Decreased glucagon levels, along with higher insulin levels, lead to less hepatic glucose production and a decrease in fasting and postprandial blood glucose levels. Reference Drucker DJ. Cell Metab. 2006;3:153-65. Ludwig DS. JAMA. 2002;287:2414-23. DPP4 DPP4 + Gliptins 23