Professor Rudy Bilous James Cook University Hospital

Professor Rudy Bilous James Cook University Hospital

Rate per 100 patient years Rate per 100 patient years 16 Risk of retinopathy progression 16 Risk of developing microalbuminuria 12 12 8 8 4 0 0 5 6 7 8 9 10 11 12 4 0 0 5 6 7 8 9 10 11 12 HbA 1c (%) DCCT: N Engl J Med 1993;329:977 86

Cumulative incidence of retinopathy progression 0.4 DCCT Intensive DCCT Conventional 0.3 0.2 0.1 0 DCCT end 1 2 3 4 5 6 7 Years of follow-up (EDIC) Adapted from: JAMA 2002287:2563 9

DN defined as : AER > 300 mg/d and/or Serum Creatinine > 176 mmol/l and/or Dialysis/Transplantation CONVENTIONAL 25% INTENSIVE 9% Dialysis and/or Transplantation CONVENTIONAL 16 INTENSIVE 8

Effect of glycaemic control on combined microvascular endpoints in UKPDS

Metabolic memory and the UKPDS

Meta-analysis of intensive glucose lowering in T2DM

Glucose control is important to avoid complications of diabetes Macrovascular and Microvascular Type1 and Type2 diabetes Important both Now and For the Future Balance benefit against risk of hypoglycaemia DO NOT FORGET OTHER RISK FACTORS ( BP & CHOLESTEROL)

Eating alone will not keep a man well; he must also take exercise. Hippocrates, Regimen. 5 th century BC

Cumulative Incidence of Diabetes According to Study Group Diabetes Prevention Program Research Group,. N Engl J Med 2002;346:393-403

Interventional arm 16 one to one tutorials with trained educators Monthly sessions during trial some individual some group 7% reduction in body weight 150 mins exercise per week

Metformin decreases insulin resistance Sulfonylureas insulin secretagogue Alpha glucosidase inhibitors Glitinides insulin secretagogue Thiazolidinediones PPARg agonists Incretin agonists DPP4 inhibitors Insulin SGLT2 antagonists (Bile acid sequestrants / Dopamine Agonists)

Metformin Metformin Metformin

Cheap 500 mg tds 1.53 per month Reduces hepatic glucose output Precise mode of action unclear Weight neutral or losing Main problem is GI side effects Vitamin B12 deficiency with long term use

Reduces vascular disease mortality Reduces cancer Reduces weight Restores fertility Kills 99% of household germs! But - restrictions for those with egfr < 30 ml/min

Cheap gliclazide 80 mg bd 1.49 per month Insulin secretagogues Close Potassium ATP channels Possible excess CV mortality (not UKPDS) Weight gain Main side effect hypoglycaemia

UK Hypoglycaemia Study Group Diabetologia (2007) 50:1140 1147

Prevent breakdown of disaccharides in gut Weight neutral / losing GI side effects No long term outcome studies Cheap 50 mg tds 7.35 per month

Work in same way as sulfonylureas - shorter acting Main problem hypoglycaemia No long term studies Cheap Repaglinide 500mg tds 3.95 per month Expensive Nateglanide 60 mg tds 22.91 per mth

PPARg agonists nuclear transcription Weight gain Evidence of long term CV benefit PROACTIVE Multiple side effects Fluid retention and heart failure Fractures Bladder cancer Expensive Pioglitazone 30 mg/d 35.89 per mth

Plasma glucose (mmol/l) C-peptide (nmol/l) Oral glucose (50 g) Isoglycaemic intravenous (IV) glucose 12 Plasma glucose (mmol/l) 2.0 C-peptide (nmol/l) * 10 8 6 1.5 1.0 * * * Incretin Effect * * 4 2 0.5 * 0 0.0 0 60 120 180 Time (min) 0 60 120 180 Time (min) Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492 498. Plasma glucose values converted to mmol/l from mg/dl using conversion factor of 0.0555; C-peptide values converted to nmol/l from ng/ml using conversion factor 0.333.

GLP-1 secreted upon the ingestion of food 5.Brain: Promotes satiety and reduces appetite 4,5 2.α-cell: Suppresses postprandial glucagon secretion 1 1. -cell: Enhances glucose-dependent insulin secretion in the pancreas 1 3.Liver: reduces hepatic glucose output 2 4.Stomach: slows the rate of gastric emptying 3 Adapted from 1 Nauck MA, et al. Diabetologia 1993;36:741 744; 2 Larsson H, et al. Acta Physiol Scand 1997;160:413 422; 3 Nauck MA, et al. Diabetologia 1996;39:1546 1553; 4 Flint A, et al. J Clin Invest 1998;101:515 520; 5 Zander et al. Lancet 2002;359:824 830.

No long term outcome studies Weight losing 2.3 5.5kg HbA1c reduction ~ 11 mmol/mol (1%) over 6mo Exenetide bd equivalent to insulin Exenetide wkly and Liraglutide 1.8mg/d better GI side effects possible pancreatitis

Once weekly injection 2mg Can be used in triple therapy (dual if intolerant of DPP 4, TZD, SU or Metformin) if BMI > 35 kg/m 2 or insulin undesirable (TA 258) Have to demonstrate improvement in HbA1c > 11 mmol/mol (1%) and / or 3% reduction in body weight at 6 months (as for other preparations) 73.36 per month (Exenetide 10 mg 68.24, Liraglutide 1.2 mg 78.48 per month) Lixisenetide and others coming

Action Selective inhibitor of dipeptidyl peptidase -4 (DPP-4) Increases GLP-1 levels 2-3 fold Enhanced insulin secretion, reduced glucagon levels DPP-4 I DPP-4 X His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Trp Gly Lys Val Leu Arg Ala

Meta analysis of 53 trials, 20312 patients Weight neutral HbA1c reduction 7 mmol/mol (0.7 %) No long term outcome studies but possible CV benefit ( OR for MACE 0.69 (0.53-0.90; p 0.006) Expensive 33-40 per month

Phung et al JAMA 2010; 303: 1410-18

SGLT2 sodium glucose co-transporters Two main types SGLT1 in intestine and distal proximal tubule in nephron SGLT2 in proximal tubule (possibly muscle and brain) SGLT2 responsible for glucose reabsorption Inhibition results in glucose loss in urine

Misra, J; J Pharmacy & Pharmacol;2012

Dapagliflozin about to be licensed, 9 more in pipeline Meta analysis of 39 studies most short term 7 mmol/mol (0.7%) improved HbA1c vs placebo 2 mmol/mol (0.2%) improved HbA1c with add on No difference with active comparators Reductions in body weight and BP (-4/-2 mmhg) Reductions in plasma uric acid Possible more durable effect than gliptins

Urogenital infections Relative risk 1.3 for UTI Relative risk 5.5 for genital infections Urinary frequency and nocturia Dehydration Possible effects on bone Possible cancer risk bladder and breast Possible liver toxicity Adverse lipid profiles increased LDL cholesterol Cost?

Human or Analogue? Basal or Prandial? Premix?

Three-arm trial in 708 patients with type 2 diabetes from 58 UK and Irish centres Three different analogue insulin regimens to dual oral antidiabetic therapy Open-label randomisation to: Twice a day biphasic insulin (NovoMix 30) Three times a day prandial insulin (NovoRapid) Once a day basal insulin (Levemir) before bed, with a morning injection added if necessary

Changes from Baseline to 3 Years in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight and the Rate of Hypoglycemia Holman RR et al. N Engl J Med 2009;361:1736-1747

Conclusion from 4T Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin but less good glycaemic control Implication for metabolic memory?

6 trials NPH vs Glargine; 2 vs Detemir Weight gain less with Detemir than Glargine Hypoglycaemia less with Glargine & Detemir Nocturnal OR 0.46 (0.38 0.55; p<0.01) Symptomatic OR 0.69 (0.60 0.80; p<0.01) Severe OR o.80 (0.45 1.40; p NS) Expensive NPH 39; Glargine 53; Detemir 80 pm Analogue premixes more expensive 10 extra pm Newer analogues coming Degludec and Lilly Horvath Cochrane Library 2009; Waugh HTA 2010

Incretin mimetic

Incretin mimetic