Diabetes is emerging as the dominant healthcare epidemic Source: Diabetes Atlas 3rd Edition. Last accessed 25 January 2007

The Tale of Two Epidemics SA prevalence Diabetes = 5.5% Direct cause of death = 4.3% Contributory to 14% IHD, 12% hypertensive, 12% renal + 10% stroke deaths Glycemic Control: 37% of patients have HbA levels < 7.0% Metabolic Control: 20% achieve HbA + BP + Lipid targets AIDS RELATED DEATHS (UNAIDS 2010) (SAMJ 2007)

HIV vs DM in SA Absolute No (m) Mortality Rank Mortality Growth Rate ARV vs OHA/Ins (%) VL vs HbA control (%) Medication vintage Advocacy 1 Advocacy 2 6 vs 4 1 vs 6 1 vs 3 37 vs vs vs 1947 TAC vs SA Diabetes Guidelines HIV vs DM

Cost of DM Care US 2006: $1 in $7 / $ 200 billion OPD: 15% / consultations / laboratory / medications In-Patients: 85% / complications / investigations / procedures / medications

Poor Glucose Control in SA Many patients Many undiagnosed Few health personnel Poorly skilled personnel Poorly resourced clinics Reduced patient contact time (40 min per year) Poor uptake / application of lab testing (30 % have regular tests) Delay in treatment change / up-titration Sub-optimal medication

Diabetes “Re-thinking the Failure”

Defining Mental Retardation “ achieve no result, persist in doing the same and expect and different outcome” (Albert Einstein)

UKPDS 35: Higher HbA 1c is associated with increased micro- and macrovascular complications in T2DM Each 1% rise in mean HbA 1c was associated with –21% risk increase for any diabetes endpoint (p<0.0001) –21% risk increase for diabetes-related mortality (p<0.0001) –14% risk increase for myocardial infarction (MI) (p<0.0001) –37% risk increase for microvascular complications (p<0.0001) Stratton IM, et al. BMJ 2000;321:405–12 Any diabetes endpoint Diabetes-related morbidity MI <6% 6  7% 7  8% 8  9% 9  10% ≥10% Mean HbA 1c concentration (%) Adjusted event rate / 1,000 person years Microvascular complications

Diagnosis – Fasting Glucose Insulin Resistance Pre-Diabetes Diabetes > 5.6 mmol/l > 6.0 mmol/l > 7.0 mmol/l

T2 DM and Primary Prevention Parameter Weight Loss Exercise Success Rate < 5 %

ADA CONCENSUS 2007 TREAT PRE-DIABETES (IFG / IGT ) LIFESTYLELIFESTYLE + METFORMIN Age < 60 y Risk Factors (BP, Lipids, BMI) HbAic > 6 % Type 2 Diabetes and Primary Prevention Cost Analysis DPP 10 y FU: Lifestyle vs Metformin:: +$1500 vs -$30 [ADA 71 st 2011]

Years HbA 1c (%) Standard therapy Intensive therapy 8.1% 7.5% 6.4% Effects of intensive glucose lowering in T2DM ACCORD Gerstein et al. N Engl J Med 2008;358:2545–59

Years Patients with events (%) First occurrence of non-fatal MI, non-fatal stroke or CV death HR (CI) 0.90 (0.78, 1.04) p=0.16 HR (CI) 1.22 (1.01, 1.46) p= Death from any cause Effects of intensive glucose lowering in T2DM ACCORD Gerstein et al. N Engl J Med 2008;358:2545–59 Standard therapy Intensive therapy

Side-effects of intensive glucose lowering Hypoglycaemia* N (%) Drug interaction Weight gain >10kg N (%) Standard therapy Intensive therapy p-value Hypothesis: *hypoglycaemia defined as requiring any assistance 261 (5.1)< (14.1)< % of non-insulin-treated and 60% of insulin-treated patients were taking three or more oral antidiabetic drugs at study end 830 (16.2) 1399 (27.8) ACCORD Gerstein et al. N Engl J Med 2008;358:2545–59

Potential mechanisms of hypoglycaemia-induced mortality  Cardiac arrhythmias due to abnormal cardiac repolarisation in high-risk patients (IHD, cardiac autonomic neuropathy)  Increased thrombotic tendency/decreased thrombolysis  Cardiovascular changes induced by catecholamines Increased heart rate Silent myocardial ischaemia Angina and myocardial infarction

GLP 1 Mimetics The Virtuous Therapeutic Cycle GLUCOSE CONTROL WEIGHT LOSS NO HYPOGLYCEMIA HbA = 7 %

Diabetes Therapy - Safety Hypoglycemia Weight gain CVS mortality Cancer

Strategic Rx AE / PEWt GainHypo’sWt LossBPLipids etc Met (3)no yes=no SU (0)yes no Pio (2)yesno yes DPP (3)no yes>no GLP1 (4)no yes ADVERSE POSITIVE

OHA and CV Protection Metformin (UKPDS) Rosi / TZD (RECORD) Tolbu / SU (UGDP) MI reduction 39% (vs insulin / chlor / gliben MI increased (OR 1.43) CV mortality increased by 30%

SU vs Met (Schramm T et al, Eur Heart J, April 2011) SUIncrease All- Cause Mortality Increase MI, All CVD, Stroke Glimiperide32 %21 % Glibenclamide19 %12 % Glipizide27 %17 % Tolbutamide28 %27 % [Conclusion: Metformin = protective? vs some SU bad?]

DM and Cancer Medications for DM can affect cancer risk and outcome - ? Insulin ? Pioglitazone Metformin reduces cancer risk Sulfonylurea: probably no effect GLP-1 agonists: currently unknown but seemingly safe

GLP-1 and DPP-4 1 CL=clearance rate; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; IV=intravenously. 1. Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88(1):220–224 Plasma t ½ = 1–2 min (IV) CL = 5–10 L/min HisAlaGluGlyThrPheThrSerAsp Val Ser TyrLeuGluGlyGlnAla Lys Glu Phe IleAlaTrpLeuValLysGlyAla NH DPP-4

Incretin Therapy DPP 4 Sitagliptin ^ Vildagliptin* Alogliptin Saxagliptin GLP1 Exenatide* Liraglutide ^ Exenatide LAR Albuglutide Taspoglutide [*Available / ^ Imminent in SA]

Incretin - GLP 1 Therapy Stimulates insulin secretion Insulin secretion is glucose dependent Inhibits glucagon secretion Increases beta cell mass Delays gastric emptying Inhibits appetite Secretogogue No hypoglycemia Reduces meal-related glucose peaks Maintains beta cell reserve Reduces meal-related peaks; reduces weight Reduces weight

Liraglutide in combination with metformin presents a low risk of hypoglycaemia Minor hypoglycaemic events are at the placebo level (LEAD 2, above) There is a small but increased risk of minor hypoglycaemia when combined with SUs (1.0 events per subject every second year; LEAD 1) Minor hypos/patient/year Liraglutide 1.2 mg PlaceboGlimepiride Liraglutide 1.8 mg Nauck et al, Diabetes Care, published online /dc (LEAD 2) and Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1).

A quarter of patients lose an average of 7.7 kg with liraglutide Weight change (kg) 0–Q1: mean weight change for the 25% of subjects who had the largest weight loss Q1–Q2: mean weight change for the 25–50% weight loss quartile Q2–Q3: mean weight change for the 50–75% weight loss quartile Q3–Q4: mean weight change for the 75–100% weight loss quartile, that is, the 25% who had the smallest weight loss Liraglutide 1.8 mg + met Q3-Q4 Nauck et al, Diabetes Care, published online /dc (LEAD 2).

Sustained weight reduction over 52 weeks with liraglutide Liraglutide 1.8 mg/day Liraglutide 1.2 mg/day Glimepiride 8 mg/day Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg Waist circumference increased by 0.4 cm with glimepiride (p<0.0001) *** ***p< for change from baseline 52 Garber et al, The Lancet, early online publication, 25 Sept 2008 (LEAD 3).

Liraglutide reduces visceral body fat Change in body fat DEXA scan Change in body fat, kg (%) Two thirds of weight lost was fat tissue (liraglutide 1.8 mg) Liraglutide 1.2 mg + met Glimepiride + met -1.6* (-1.1%*) -2.4* (-1.2%*) +1.1 kg (+0.4%) Liraglutide 1.8 mg + met Visceral vs. subcutaneous fat CT scan VisceralSubcutaneous Change in percentage fat (%) * -8.5* +3.4 Data are mean±SEM; *p<0.05 vs. glim+met; n=160. LEAD 2 substudy, originally presented as Jendle et al. Diabetes 2008;57(Suppl. 1):A32.

Liraglutide improves beta-cell function as measured by HOMA-B and proinsulin:insulin ratio 56.4%70.6%56.3%45.5%Baseline p= p= HOMA (%) Change in proinsulin:insulin Liraglutide 1.8 mg Liraglutide 1.2 mg Rosi- glitazone PlaceboLiraglutide 1.8 mg Liraglutide 1.2 mg Rosi- glitazone Placebo Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1). Data are mean±2SE.

Diabetes Care – Future? 1)Pre-Diabetes 2)CVD Protection 3)Cancer 4)Hypoglycemia 5)Weight 6)Disease Modifying Metformin Metformin, TZD, GLP1 Metformin Metformin, TZD, GLP1 Metformin, GLP1 GLP1