DIABETES CONTROL The Alphabet Strategy • Advice • Blood pressure • Cholesterol • Diabetes control • Eye examination • Feet examination • Guardian drugs Smoking , diet , exercise < 140/80 TC ≤ 4 , LDL : HDL ≤ 2 HbA1c ≤ 7% Annual examination Annual examination Aspirin, ACEI, statins &c Effect on diabetes complications of HbA1c% reduction Study name DCCT UKPDS Kumamoto Steno-2 HbA1c 2% 0.9% 2% 1.0% Retinopathy 63% 17-21% 69% 58% Nephropathy 54 24-33% 70% 61% Autonomic neuropathy 60% _ _ 63% CVD 41% 16% _ 53% Reductions in HbA1c and corresponding reductions in microvascular and macrovascular complications described in major studies of persons with T1 DM and T2 DM Micro albuminuria cataract Retinal laser MI micro vasculars 0% any diabetes endpoints UKPDS : HbA1c% 7.0% versus 7.9% -5% -10% -15% -20% 12% 16% P=0.052 25% -25% -30% 24% 29% P=0.046 P=0.0099 33% P=0.0031 -35% P<0.001 UKPDS : glycaemic control 9 HbA1c (%) Conventional 8 Intensive 7 6.2% upper limit of normal range 6 0 0 3 6 9 12 Years from randomisation 15 Type 1 diabetes - treatment options Type 1 diabetes - treatment options • Lifestyle • Diet, exercise • Insulin • Islet transplantation Type 1 diabetes Premixed Insulin Basal Bolus Regime Why pre-mixed insulins don’t work Diagrammatic representation of physiological insulin secretion and 30/70 pre-mixed insulin time-action profile Physiological insulin Blood insulin levels Pre-mixed 30/70 regimen 06.00 12.00 Breakfast Lunch 18.00 Dinner 24.00 06.00 Type 2 diabetes - treatment options Type 2 diabetes - treatment options • Lifestyle • Diet, exercise • Oral monotherapy • Oral combination therapy • Insulin (with or without oral agents) Primary sites of action of hypoglycaemic agents -glucosidase inhibitors Stomach Carbohydrate Gut Sulphonylureas Incretin mimetics DPP-IV inhibitors Glucose I I Adipose tissue Insulin Pancreas Insulin acts on all tissues I Liver Muscle Thiazolidinediones Biguanides Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329. Oral hypoglycaemic agents Oral hypoglycaemic agents • • • • • • • Metformin Sulphonylureas Acarbose Guar gum Postprandial glucose regulators Thiazolidinediones Dipeptidyl peptidase-IV inhibitors By injection • Incretin mimetics Metformin : history • French Lilac or Goat’s Rue (Galega officianalis) - a traditional remedy for diabetes - is rich in guanidine Metformin : history • • • • • Used by mediaeval monks 1920s : guanidine derivatives introduced, then forgotten 1957 : metformin, phenformin 1970s : phenformin withdrawn 1994 : metformin obtained FDA approval in USA Metformin : efficacy • FPG 2 - 4, HbA1c 1 - 2% • Effect depends on the presence of insulin • Hypoglycaemia unlikely with monotherapy • Weight neutral • Small improvement in lipid profile • Reduced cardiovascular events UKPDS : metformin in overweight subjects 0 Diabetes-related endpoints Diabetes-related deaths All-cause mortality Myocardial infarction Risk reduction (%) 5 10 15 20 25 30 35 p = 0.0023 p = 0.011 40 45 p = 0.01 p = 0.017 p values in comparison to conventional treatment group United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865. Metformin : use • First – line monotherapy in obese and non• • obese Combination with other oral agents : effects additive Combination with insulin Metformin : contraindications Metformin : contraindications • Impaired renal function • Cardiac or respiratory insufficiency • Liver disease, alcohol abuse • History of metabolic acidosis • Severe sepsis • Use of IV contrast media Metformin : adverse effects Metformin : adverse effects • Lactic acidosis: • • • 0.03 cases / 1000 patient years • 50% mortality GI symptoms B12 malabsorption Sulphonylureas : history • 1940s : sulphonamides noted to cause • • • • • hypoglycaemia. 1950s : carbutamide, tolbutamide 1960s : tolazamide, chlorpropamide 1970s : ? detrimental cardiovascular effects 1970s – 1980s : glibenclamide, glipizide, gliclazide 1990s : glimepiride Sulphonylureas : efficacy • FPG 2 - 4, HbA1c 1 - 2% • Only effective if beta-cell still functioning. • Can initiate insulin release when plasma • glucose < 5. Maximum glucose lowering effect may be achieved below maximum permitted dose. Sulphonylureas : use • Not preferred in obese subjects • Monotherapy • Combination with other oral agents : effects • additive ? Combination with insulin Sulphonylureas : adverse effects Sulphonylureas : adverse effects • Hypoglycaemia • Weight gain : 1 - 4 KGm in 6 months • Sensitivity reactions Postprandial glucose regulators • Nateglinide, repaglinide • Reduce postprandial glucose spikes by • • • • • • restoring early phase insulin release Reduce HbA1c% by 0.5-2.0% Main use in combination with metformin Meal time flexibility ? Less weight gain than with sulphonylureas Gastrointestinal side-effects, hypoglycaemia No outcome data Glitazones : history • 1980s : effect first described • 1997 : troglitazone introduced – and • • • withdrawn 1999 : rosiglitazone (Avandia , GSK) and pioglitazone (Actos , Takeda) introduced. 2005 : PROactive Study – small reduction in CV events with pioglitazone. 2007 : does rosiglitazone increase CV events? Glitazones : efficacy • FPG 2 - 3, HbA1c around 1 % • Effect depends on the presence of insulin • Full expression of dose may not be apparent • for 3 months Not all patients respond Glitazones : adverse effects Glitazones : adverse effects • Fluid retention : oedema , heart failure , • • • anaemia Weight gain : 1 – 4 KGm in 6 months Hypoglycaemia in combination with other oral agents ? Unforeseen chronic effects Glitazones : contraindications Glitazones : contraindications • Heart failure • Oedema • Anaemia • ? Insulin therapy • ? Impaired liver function New agents for T2D • CB1 receptor antagonist • Rimonabant • Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics) • Exenatide • Liraglutide • Dipeptidyl peptidase-4 (DPP-4) inhibitors (incretin enhancers) • Sitagliptin • Vildagliptin UKPDS : glycaemic control 9 HbA1c (%) Conventional 8 Intensive 7 6.2% upper limit of normal range 6 0 0 3 6 9 12 Years from randomisation 15 UKPDS : decline of -cell function over time -cell function (%) 100 Start of treatment 80 60 40 20 0 –10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6 Time from diagnosis (years) HOMA model, diet-treated n = 376 Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25. Insulin : history • 1921 • 1940s • 1980s • 1990s : Banting and Best : protamine and zinc : human insulin : insulin analogues Insulin : mechanisms Increases : Reduces : • • • • • • • • • • Glucose uptake by cells Glycogen synthesis Fatty acid synthesis Cholesterol & LDL synthesis Amino acid transport Protein synthesis Glycogen breakdown Gluconeogenesis Lipolysis Protein breakdown Insulin : use Insulin : use • Type 1 diabetes • Improved metabolic control in type 2 diabetes • Oral therapies contraindicated or not tolerated • Post-myocardial infarction (DIGAMI) • Severe intercurrent illness , surgery • Gestational diabetes not controlled by diet Insulin : adverse effects Insulin : adverse effects • Hypoglycaemia • Weight gain • Allergy • Lipohypertrophy and lipoatrophy • Transient deterioration of retinopathy • Insulin neuritis Control versus hypos : DCCT Weight gain with insulin : UKPDS Change in weight (kg) 10.0 7.5 Intensive (Insulin) 5.0 2.5 Conventional 0 0 3 6 9 Years from randomisation 12 15 Insulin preparations Short acting onset 30 mins peak 2-4 hours duration 8 hours Humulin S Actrapid Intermediate onset 1-2 hours peak 4-12 hours duration 16-24 hours Insulatard Humulin I Long acting onset 1-2 hours peak 4-12 hours duration 20-35 hours Human Ultratard Humulin Zn Analogue onset 0-15mins peak 1-2 hours duration 4-6 hours Humalog (Lispro) Novorapid (Aspart) duration 24 hours Glargine , Levemir How many do you need ? How many do you need ? • Novorapid • NPH • Glargine • Detemir • Novomix 30 Insulin regimes • Twice daily mixture • Once daily long acting • Basal - plus • Four times a day basal bolus • ? Inhaled insulin • Continuous Subcutaneous Insulin Infusion Basal insulin* & oral combination therapy in insulin naïve T2DM Mean A1C level during study N=756 Mean A1C (%; ± SE) 9 8.6 8.5 8 7.5 7.5 7.1 6.9* 7 6.5 0.5 0 8 Time (weeks) * Basal insulin therapy studied was either Lantus (n=367) or NPH (n=389) 12 18 Basal bolus regime Insulin : combination therapies • Metformin • Sulphonylureas • Glitazones EASD/ADA Algorithm (2006) Bailey C et al (2006) Br J Diab Vasc Dis 6: 147