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Treating Earlier and Effectively with Combination Therapies.

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Presentation on theme: "Treating Earlier and Effectively with Combination Therapies."— Presentation transcript:

1 Treating Earlier and Effectively with Combination Therapies

2 Aim Provide practical guidance on improving diabetes care through highlighting the need for: a sense of urgency in treating to target earlier introduction of combination therapy consideration of patient profile use of combinations of drugs with complementary mechanisms of action

3 At diagnosis of type 2 diabetes: 50% of patients already have complications 1 up to 50% of  -cell function has already been lost 2 Current management: two-thirds of patients do not achieve target HbA 1c 3,4 majority require polypharmacy to meet glycemic goals over time 5 Need for an early and intensive approach to type 2 diabetes management 1 UKPDS Group. Diabetologia 1991; 34:877–890. 2 Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3 Saydah SH, et al. JAMA 2004; 291:335–342. 4 Liebl A, et al. Diabetologia 2002; 45:S23–S28. 5 Turner RC, et al. JAMA 1999; 281:2005–2012.

4 Barriers to achieving good glycemic control Limitations of reactive, stepwise treatment Therapy not matched to the individual Conservative prescribing of antidiabetic agents

5 Limitations of reactive, stepwise treatment

6 7 6 9 8 HbA 1c (%) 10 OAD* monotherapy Diet and exercise OAD combination OAD + basal insulin OAD monotherapy up-titration Duration of diabetes OAD + multiple daily insulin injections Conservative management of glycemia: traditional stepwise approach HbA 1c = 6.5% Campbell IW. Br J Cardiol 2000; 7:625–631. HbA 1c = 7% *OAD = oral antidiabetic

7 Drawbacks of the stepwise approach Even short periods of hyperglycemia increase risk of complications 1–3 A proactive approach is required to get patients to achieve their glycemic goals sooner Microvascular complications Myocardial infarction Incidence per 1000 patient-years Updated mean HbA 1c (%) 20 40 60 80 567891011 0 0 Normal HbA 1c levels 1 EDIC Group. JAMA 2003; 290:2159–2167. 2 EDIC Group. JAMA 2002; 287:2563–2569. 3 Nathan DM, et al. N Engl J Med 2003; 348:2294–2303.

8 Diet and exercise are beneficial to good glycemic control Lifestyle changes can have beneficial outcomes 1,2 Patients may require motivation to encourage them to follow a healthy diet and take exercise 1 Levy J, et al. Diabet Med 1998; 15:290–296. 2 Macauley KA, et al. Diabetes Care 2002; 25:442–452.

9 Benefits of diet and exercise may be difficult to maintain in the long term Stepwise treatment may lead to delays Pharmacological therapy should be introduced in tandem with lifestyle changes

10 Delays often occur between stepping up from monotherapy to combination therapy 0 5 10 15 20 25 Months Metformin only n = 513 14.5 months Sulfonylurea only n = 3394 20.5 months Length of time between first monotherapy HbA 1c > 8.0% and switch/addition in therapy (months) Brown, JB et al. Diabetes Care 2004; 27:1535–1540.

11 Up-titrating monotherapy to the maximum recommended dose may not provide benefit Gastrointestinal side effects Patients stopping treatment (%) 0 2 4 6 8 10 5001000150020002500 Metformin dosage (mg) HbA 1c -2.5 -2 -1.5 -0.5 5001000150020002500 Change in HbA 1c from placebo (%) 0 Metformin dosage (mg) Garber AJ, et al. Am J Med 1997; 103:491–497.

12 OAD + basal insulin OAD + multiple daily insulin injections Diet and exercise OAD* monotherapy OAD combinations OAD up-titration Duration of diabetes 7 6 9 8 HbA 1c (%) 10 ACTION POINT: HbA 1c = 7% HbA 1c = 6.5% Proactive management of glycemia: early combination approach *OAD = oral antidiabetic

13 Earlier achievement of therapeutic goals Potential reduction in risk of side effects if you combine drugs at lower doses versus up-titration of single dose Opportunity to combine oral antidiabetic drugs with complementary modes of action Potential to delay disease progression Potential advantages of early combination therapy

14 Benefits of adding TZD to sub-maximal sulfonylurea compared with up-titration 0 10 20 30 40 50 60 Patients achieving HbA 1c < 7% (%) Up-titrated SU + PBO 22% RSG + SU 50% Rosenstock J, et al. Diabetes Obes Metab 2005; [In press]. Abbreviations: PBO, placebo; RSG, rosiglitazone; SU, sulfonylurea; TZD, thiazolidinediones.

15 Benefits of adding TZD to sub-maximal metformin compared with up-titration 0 2 4 6 8 10 12 Patients discontinuing due to GI disturbances (%) MET 1 g/day + MET 1 g/day 7% MET 1 g/day + RSG 8 mg/day 3% Gastrointestinal side effects 0 10 20 30 40 50 60 Patients achieving HbA 1c < 7% (%) MET 1 g/day + MET 1 g/day 48% MET 1 g/day + RSG 8 mg/day 58% HbA 1c Rosenstock J, et al. Diabetes 2004; 53 (Suppl. 2):A144. Abbreviations: MET, metformin; RSG, rosiglitazone; TZD, thiazolidinediones.

16 Benefits of glyburide/metformin versus monotherapy as initial pharmacotherapy 0 10 20 30 40 50 60 70 80 GLYMETGLY/MET Patients achieving HbA 1c < 7% (%) Patients achieving HbA 1c < 7% Garber AJ, et al. J Clin Endocrinol Metab 2003; 88:3598–3604. Abbreviations: GLY, glyburide; MET, metformin.

17 How quickly should patients be reaching HbA 1c targets? The Global Partnership recommends: Treat patients intensively so as to achieve target HbA 1c < 6.5%* within 6 months of diagnosis *Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA 1c is not possible < 6.5% Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

18 When should combination therapy be introduced? *Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA 1c is not possible After 3 months, if patients are not at target HbA 1c < 6.5%,* consider combination therapy The Global Partnership recommends: Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

19 Therapy not matched to the individual

20 Individuals with high baseline HbA 1c require more intensive treatment Risk of complications increases with HbA 1c Individuals with high baseline values require particularly urgent and intensive treatment Monotherapy is often insufficient in these individuals and combination therapy should be initiated earlier Stratton IM, et al. BMJ 2000; 321:405–412.

21 How should patients with high baseline HbA 1c be managed? Initiate combination therapy or insulin immediately for all patients with HbA 1c  9% at diagnosis The Global Partnership recommends: Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

22 Inappropriate prescribing of antidiabetic agents

23 Reasons for conservative prescribing patterns Familiarity with traditional agents Concerns regarding safety of newer agents Perceived lack of efficacy of antidiabetic agents

24 Treatment options for type 2 diabetes Sulfonylureas –1st generation e.g. chlorpropamide, tolbutamide –2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone –3rd generation e.g. glimepiride –Modified release Glinides/meglitinides –Non-sulfonylureic e.g. repaglinide –Amino acid derivatives e.g. nateglinide Biguanides –e.g. metformin Thiazolidinediones –e.g. rosiglitazone, pioglitazone  -glucosidase inhibitors –e.g. acarbose Insulin –regular –intermediate/long acting –pre-mixed –analogs  rapid acting  long acting Fixed-dose oral antidiabetic drug combinations –e.g. glyburide/metformin, glipizide/metformin, rosiglitazone/metformin

25 Choosing antidiabetic agents: efficacy = reduced levels= increased levels = no significant effect Insulin secretagogues MetforminTZDs* Effect on FPG/HbA 1c 1 Effect on plasma insulin 1,2 – Effect on insulin resistance 3 – Effect on insulin secretion 4 EFFICACY Insulin ANTIDIABETIC AGENTS α-glucosidase inhibitors 1 DeFronzo RA. Ann Intern Med 1999; 131:281–303. 2 Lebovitz HE. Endocrinol Metab Clin North Am 2001; 30:909–933. 3 Matthaei S, et al. Endocrine Reviews 2000; 21:585–618. 4 Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol; 2001; 109 (Suppl. 2):S265–S287. *TZDs = thiazolidinediones –

26 = not commonly seen in monotherapy Choosing antidiabetic agents: safety and tolerability = treatment-related adverse event SAFETY AND TOLERABILITY Risk of hypoglycemia 1,2 Weight gain 1,2 Gastrointestinal side effects 1 Lactic acidosis 1 Edema 3 ANTIDIABETIC AGENTS α-glucosidase Insulin secretagogues Metformin inhibitors TZDs* Insulin 1 DeFronzo RA. Ann Intern Med 1999; 131:281–303. 2 UKPDS. Lancet 1998; 352:837–853. 3 Nesto RW, et al. Circulation 2003; 108:2941–2948. *TZDs = thiazolidinediones

27 Choosing oral antidiabetic agents: mechanism of action  Glucose output  Insulin resistance Biguanides  Insulin secretion Sulfonylureas/ meglitinides  Carbohydrate breakdown/ absorption  -glucosidase inhibitors  Insulin resistance Thiazolidinediones 1 Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. 2 Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

28 What are the ideal components for combination therapy? The Global Partnership recommends: Agent B Agent A Use combinations of oral antidiabetic agents with complementary mechanisms of action Improved glycemic control Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

29 Paradigm for early combination treatment If HbA 1c > 6.5%* at 3 months Initiate combination therapy † in parallel with diet/exercise If HbA 1c  9% at diagnosis Initiate combination therapy † or insulin in parallel with diet/exercise 0123456 If HbA 1c < 9% at diagnosis Initiate monotherapy in parallel with diet/exercise Months from diagnosis Treat to goal of HbA 1c < 6.5%* by 6 months *Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA 1c is not possible † Combination therapy should include agents with complementary mechanisms of action Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.


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