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Modern Management Type 2 Diabetes - Oral Agents

Modern Management Type 2 Diabetes - Oral Agents. Janie Thomason Diabetes Lead GP Moray CHP Clinical Assistant Diabetes Dr Grays. Managing Diabetes Mellitus Type 2. From diagnosis, explode the myth! There is no such diagnosis as “mild diabetes” - only well controlled and poorly controlled DM.

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Modern Management Type 2 Diabetes - Oral Agents

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  1. Modern Management Type 2 Diabetes - Oral Agents Janie Thomason Diabetes Lead GP Moray CHP Clinical Assistant Diabetes Dr Grays

  2. Managing Diabetes Mellitus Type 2 • From diagnosis, explode the myth! • There is no such diagnosis as “mild diabetes” - only well controlled and poorly controlled DM. “Diabetes is a state of disordered metabolism which may present with hyperglycaemia if the patient doesn’t first succumb to cardiovascular mortality” BDA Meeting, 1998 2

  3. Two-hour plasma glucose levels are an independent risk indicator for mortality*1 2.5 2.0 1.5 1.0 0.5 0.0 Hazard ratio 11.1  7.8–11.0 Two-hour plasma glucose*(mmol/L) <7.8 <6.1 6.1–6.9 7.0  FPG (mmol/L) Adjusted for age, centre, sex, cholesterol, BMI, SBP, smoking Adapted from DECODE * as measured by an OGTT 1. DECODE study group. Lancet 1999; 354: 617–621.

  4. -16 P=0.052 MI Retinopathy Cataract extraction Microvascular endpoint Albuminuria at 12 years Any diabetes related endpoint -21 P=0.015 -24 P=0.046 -25 P=0.009 -34 P=0.00005 -12 P=0.029 0 -10 -20 -30 -40 -50 % Reduction in Risk Lowering HbA1C Reduces Risk of Complications In intensively-treated patients, HbA1C was 7.0% compared to 7.9% in conventionally treated patients. This 0.9% decrease in HbA1c is associated with a reduction in risk for diabetic complications UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998; 352 (Sept. 12): 837–853.

  5. Glycaemic control and primary prevention of cardiovascular disease • UKPDS demonstrated a 14% reduction in MI with a 1% fall in HbA1C • Metformin reduced HbA1C by 0.6%, but reduced MI by 39% • Benefits of Metformin may relate to improved insulin sensitivity and reduced pro-thrombotic factors 2

  6. Causes of hyperglycaemia in type 2 diabetes Peripheral tissues (muscle) Receptor + post-receptor defect Insulin resistance Glucose Liver Increased glucose production Pancreas Impaired insulin secretion

  7. Extrapolation of the time of deterioration of -cell dysfunction1 100 80 60 ß-cell dysfunction (%) 40 20 0 –12 –10 –8 –6 –4 –2 0 2 4 6 Years from diagnosis Adapted from UKPDS 16. 1. UKPDS 16. Diabetes 1995; 44: 1249–1258.

  8. Loss of early-phase insulin release in type 2 diabetes mellitus1 Pattern of insulin release is altered early in type 2 diabetes Normal Type 2 diabetes 120 100 80 60 40 20 0 120 100 80 60 40 20 0 20gglucose 20g glucose Plasma insulin (µU/ml) Plasmainsulin (µU / ml) –30 0 30 60 90 120 –30 0 30 60 90 120 Time (minutes) Time (minutes) 1. Ward W, et al. Diabetes Care 1984; 7: 491–502.

  9. FPG Gaining control of hyperglycaemia1-3 Insulin signalling defect -cell dysfunction The development of type 2 diabetes is the result of a combination of -cell dysfunction and insulin resistance Loss of early phase insulin release Insulin resistance GLUCOSETOXICITY Postprandial glucose spikes Increased basal glucose levels Hyperglycaemia HbA1c 1. Lebovitz HE. Diabetes Rev 1999; 7: 139–53. 2. Ward W, et al. Diabetes Care 1984; 7: 491–502. 3. Yki-Järvinen H. Endocr Rev 1992; 13: 415–31.

  10. Historic therapeutic options for Type 2 diabetes

  11. New drugs in the real World…Opportunities in Type 2 Diabetes to: • To provide better glycaemic control with less adverse side-effects • To tailor both tablets and insulins according to the patient’s lifestyle and circumstances • To (hopefully) reduce cardiovascular disease and microvascular complications

  12. HbA1c in Diet Treated Patients: Effects of Various Medications(Difference From Placebo. Different studies) HbA1c (%) Troglita-zone Acarbose Glipizide -GITS Metformin Repaglinide

  13. ‘Achieving’ Glycaemic Targets in the UKPDS (2): HbA1C <7.0%

  14. Glycaemic control with Diet, Sulphonylurea, Metformin, or Insulin in Patients with Type 2 Diabetes Progressive requirement for multiple therapies (UKPDS 49) JAMA 1999; 281: 2005-2012

  15. Selecting an oral hypoglycaemic agent • Sulphonylurea first choice if BMI < 25 kg/m2 • Action - potentiates pancreatic beta cell insulin release • Gliclazide 40-320mg / 24hr • or as Gliclazide MR (Diamcron MR) 30-120mg • Glimepiride 2-6mg (od advantage) • Glipizide 2.5-20mg / 24hr • (consider tolbutamide in renal impairment) Remember - discuss risk of hypoglycaemia - remind patient to inform DVLA of treatment

  16. New Sulphonylureas: Glimepiride and Gliclazide MR (2) • Consider switching from Gliclazide if compliance difficulties (i.e. 1 tablet daily, rather than 4) • Although reduced hypoglycaemia, can still cause severe hypoglycaemia (NB, caution in the elderly, and patients with renal impairment) • Lack of long-term data (NB, likewise generic Gliclazide!)

  17. Selecting an oral hypoglycaemic agent • Metformin • Action - reduces insulin resistance • Primary drug of treatment if overweight; adjunct to insulin • Dose 500mg - 3g / 24hrs • commence 500mg od with/after food, increasing in 500mg increments at 2 week intervals • side effects often limit dose. (diarrhoea; lethargy; anorexia; malabsorption of B12 and folate) • CI in renal failure (creatinine > 150), liver disease and alcoholism

  18. The need for new therapy options in Type 2 Diabetes • Patients prefer tablets to injections • Ideally, a tablet providing sustained glycaemic control over years, rather than months • Such a tablet needs to address both progressive beta cell loss (insulin deficiency) and insulin resistance

  19. New Oral Hypoglycaemic Agents • The PPAR gamma agonists (TZDs): Rosiglitazone (Avandia) Pioglitazone (Actos) • Newer Sulphonylurea agents: Glimepiride (Amaryl) Gliclazide MR (Diamicron MR) • Prandial glucose regulators: Repaglinide (Novonorm) Nateglinide (Starlix)

  20. Selecting an oral hypoglycaemic agent • Rosiglitazone(Avandia); Pioglitazone (Actos) • Action: thiazolidindione acting at the level of the PPAR-gamma receptor to improve insulin resistance • Dose - 4 to 8mg /24 hrs Rosiglitazone 15 to 45mg/24 hrs Pioglitazone • Licensed as add-on to either metformin or sulphonylurea or recently as monotherapy; recently available as triple therapy • CI if hepatic impairment (AAT x2 normal at baseline) or cardiac failure • Does require commitment to monitoring LFT’s – suggest baseline and 6 monthly (current research looking at use in IGT and reducing cardiovascular mortality)

  21. Clinical Effectiveness of Rosiglitazone after 9 months (n=23)

  22. Baseline 6 months P value HbA1C (%) 10.0(+/- 1.7) 8.4 (+/- 2.0) P <0.01 Weight (kg) 85.9 (+/- 24.0) 87.5 (+/- 22.9) ns Chol (mmol/l) 6.2 (+/- 3.6) 6.4 (+/- 2.8) ns HDL (mmol/l) 1.1 (+/- 0.4) 1.2 (+/- 0.4) ns Trig (mmol/l) 7.7 (+/- 17.2) 7.2 (+/- 15.1) ns Systolic BP 141 (+/- 18) 140 (+/- 22) ns Diastolic BP 79 (+/- 11) 75 (+/- 21) ns Clinical Effectiveness of Pioglitazone after 6 months (n=23)

  23. The Role of the TZDs, 2006 • Add-on therapy to Metformin in the overweight and obese patient with Type 2 Diabetes • Maybe a better choice than a sulphonylurea in many patients (no problems with hypos / improved cardiovascular surrogate markers) • Sulphonylureas produce a more rapid improvement in glycaemic control, and are the best option in symptomatic patients but increasing concerns with increased mortality

  24. The Role of the TZDs, 2006 • An alternative to Metformin in the sulphonylurea treated patient who is intolerant of Metformin, or has renal impairment • Sulphonylurea monotherapy is usually in normal weight patients, and UKPDS demonstrated excellent long-term control reducing microvascular complications but not macrovascular • Combination with sulphonylurea should be the rarer use of dual therapy with a glitazone

  25. When not to use the TZDs? • As a substitute for insulin (osmotic symptoms and weight loss = lifelong insulin) • Cardiac failure or fluid retention • Significant liver disease • Woman of child-bearing age planning pregnancy

  26. TZDs and the future... • Long-term cardiovascular and mortality end-point studies are ongoing. Evidence gathering eg Proactive study • A first-line role can only be justified when ‘hard end-point’ data is available • They are most likely to be of benefit earlier in the course of Type 2 Diabetes

  27. Selecting an oral hypoglycaemic agent • Acarbose • Action : alpha-glucosidase inhibitor which slows digestion and absorption of carbohydrates • used as adjunct to other agents or insulin • dose 50 - 300mg / 24 hrs as tolerated (increment slowly) _ No effect on mortality and morbidity • safety point - if patient also on insulin or SU, hypo must be treated with dextrose/glucose

  28. Selecting an oral hypoglycaemic agent • Nateglinide (Starlix): Repaglinide (Novonorm) • Action:improve beta cell insulin release in response to post-prandial hyperglycaemia • Novonorm licensed for monotherapy or with Metformin; Starlix licensed for use as adjunct to Metformin alone • Novonorm 500mcg initially before meals (max 16 mg/24 hrs); Starlix 60mg-120mg before meals • Glucose sensitive - apparently low risk of hypoglycaemia even if meal omitted • May be improved cardiovascular mortality - data not yet available • “Niche” drug – useful if sensitive to SU

  29. Clinical Experience with Repaglinide • Patients being troubled by hypoglycaemia caused by sulphonylureas (e.g., the elderly and patients with renal impairment) • Patients with ‘flexible lifestyles’ or ‘erratic eaters’ (CF, basal bolus insulin regimes with rapid acting analogues) • Patients who fast

  30. Hospitalisation with Hypoglycaemia • The Leicester Royal Infirmary, April 1997 to March 1999 • 83 patients, the notes of 75 patients being reviewed (90%) • 38 patients (51%) had Type 2 Diabetes • 50% male, and patients aged 51 to 92 years (mean 76 years)

  31. Hypoglycaemia in the elderly with Type 2 Diabetes • High risk, and sulphonylureas should be avoided • Metformin is the safest choice, assuming no contra-indication (i.e., renal impairment) • TZD monotherapy will be an option in the near future (need to ensure no overt cardiac failure) • Repaglinide has been a useful option in monotherapy during recent years

  32. Indo-Asian people with Type 2 Diabetes • One quarter of Indo-Asian people over 60 years have Type 2 Diabetes • High prevalence of cardiovascular disease and diabetic nephropathy • Fasting seasons / days for both Muslim and Hindu people, and problems with sulphonylureas • After Metformin monotherapy, TZDs and prandial glucose regulators maybe the best options

  33. CONCLUSIONS • TREATMENT improves outcomes SAVES lives • RANGE of treatments available • EVIDENCE available to help chose the most suitable option • One Size Fits All - NOT AVAILABLE • DIET & LIFESTYLE are at least as important perhaps more so than the type of OHA or insulin used

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