DIABETES MELLITUS

1. STATUS OF FIXED DOSE DRUG COMBINATIONS IN ANTIDIABETIC DRUG THERAPYbyProf. P.L. Sharma, M.D., Ph.D.(Lond.), FAMS1. Director, Clinical Research, ISF College of Pharmacy, Moga-142001, Punjab2. Emeritus Professor, PGIMER, Chandigarh-160012

2. DIABETES MELLITUS • Multifactorial in origin, has a variable and progressive course, requires attention to attendant risk factors and co-morbidities on long term basis. • Each antihyperglycemic drug has advantages and disadvantages. eg. degree of blood glucose control, risk of hypoglycemia and nonglycemic benefits/risk. • Tight glycemic control improves outcomes, usually not achieved with monotherapy, without unacceptable adverse effects. There is progressive requirement for multiple drug therapy. (UKPDS-49) Turner et al(1999) Against this background, coadministered combination therapies have become common place. Also, fixed dose combinations of drugs have emerged to facilitate regimens of multiple therapies.

3. Treatment of Diabetes Mellitus Pharmacological treatment regimen should be Individualized (Fit the drug(s) to the patient) Factors to be taken into account Degree of hyperglycemia Properties of Antihyperglycemic drugs - effectiveness in lowering blood sugar - durability of glycemic control - side effects profile - contraindications - risk of hypoglycemia - patient Preferences 3. Co-morbidities

4. Drug combinations for treatment of Diabetes Mellitus: Type 1 diabetes mellitus • Basal insulin+ Rapid acting insulin. Type 2 diabetes mellitus • Secretagogues: sulphonylureas, meglitinides. • Insulin sensitizers: metformin, glitazones.

5. Type 1 Diabetes: Premixed Insulins • Fixed dose combination of a rapid acting insulin (aspart or lispro) and basal insulin are better than regular insulin to, • Improve glycemic control • Minimize occurrence of hypoglycemia • Achieve postprandial glucose targets • These are not generally suitable for initial intensive glycemic control because patients require frequent changes in the individual components of their insulin regimens.

6. Premix fixed-dose insulin's for treatment of type 1 diabetes • Premixed regular – NPH (Humulin 30/70) • Novolin g 30/70, 40/60, 50/50 • Biphasic insulin aspart (Novomix 30) • Insulin lispro/ lisproprotamine (Humalog Mix 25, Mix 50)

7. Type-2 Diabetes mellitus: Limitations of long term Monotherapy Target end point: HbA1C level < 7 mg % (UKPDS-49) Monotherapy for 3 years = Success rates 50% Monotherapy for 9 years = Success rates 30% (Turner et al.,1999) Patients not achieving or maintaining the target would be candidates for multiple oral antidiabetic therapy and/or intensified insulin treatment. (Bailey, 2010) Also, early use of two oral antidiabetic drugs is now considered as an opportunity to achieve glycemic control earlier and for a longer period.

8. Type-2 Diabetes: • Monotherapy v/s Combination Treatment • Monotherapy affects only one metabolic abnormality (Insulin deficiency or insulin resistance) • Each drug has side effects. • 1. Lower dose of each drug used in combination treatment . • Covers both metabolic abnormalities. • Have fewer side effects. 2. Combination treatment with full dose of each drug. • Tight glycemic control achieved rapidly and is maintained. • Without significant increase in clinically important side effects.

9. Diabetes Mellitus: Need for combination treatment • Many patient do not achieve adequate glycemic control with monotherapy. Koro et al. (2004) • Gradual deterioration of glycemic control occurs with time in most patients. UK PDS , (1998) • Tight glycemic control significantly improves outcomes. Not safely achievable with monotherapy.

10. Type-2 Diabetes mellitus : Combination Treatment Severe hyperglycemia (HbA1C > 9%) • Usually requires combination of antihyperglycemic agents. • Goal to attain target HbA1C level(< 7 mg %) in 6-12 months.

11. Type-2 Diabetes mellitus : Combination Treatment The initial use of combination of submaximal doses of antihyperglycemic drugs produces more rapid and improved glycemic control and is better tolerated, as compared to monotherapy at maximal doses.

12. Desirable Attributes Of A Good Fixed Dose Drug Combination: Different mechanism of action of each ingredient. Submaximal dose, if feasible, of each ingredient. Ingredients with similar t1/2. Different ADR profile of each ingredieent. FDC should be cheaper.

13. Type-2 Diabetes: Fixed Dose Combination Therapy (FDCT) Stated Objectives:- To improve tight glycemic control To reduce “Pill Burden” and, thereby, improve adherence to treatment To decrease the incidence/severity of Adverse Drug Reactions To delay the need for insulin therapy. Caution:- Do not combine drugs from different classes, but with the same mechanism of action e.g. sulphonylureas and meglitinides.

14. Combination of antidiabetic drugs: Effect on adherence to treatment over 1 year period • Sulphonylureas- 31% • Metformin- 34% • Sulphonylureas + Metformin- 13% (co-administration) • Donan et al. (2002) • FDC Rosiglitazone + Metformin- 78% Zinman et al. (2010) • FDC, ease the pill burden and significantly improve adherence to treatment and tight glycemic control, as compared to monotherapy or co-administration of ingredient drugs.

15. Reterospective analysis of rosiglitazone – metformin:co administration or administrated as FDC Type 2 diabetes, n=16928. Duration of study- 1 year End-point of interest: Adherence to medication. Conclusion: Medication with FDC resulted in significant improvement in medication adherence rates, compared with co administered regime. (Vanderpoel et al, 2007)

16. Advantages of Combination Treatment in Type-2 diabetes Drug HbA1c Weight gain Hypoglycemia Risk Glyburide ++ + Significant Glipizide ++ + Moderate Gliclazide ++ + Moderate Glimiperide ++ + Moderate Repaglinide ++ + Minimal Metformin ++ 0,- Minimal Rosiglitazone ++ + Moderate Pioglitazone ++ + Moderate Sitagliptin +± 0 Negligible

17. Advantages of Combination Treatment in Type-2 Diabetes Drugs HbA1c Wt.gain Hypo.Risk Metformin+Glyburide +++ ± Significant Metformin+Rosiglitazone +++ 0,± Moderate Metformin+Pioglitazone +++ 0,± Moderate Metformin+Gliclazide +++ 0,± Moderate Metformin+Glipizide +++ 0,± Moderate Metformin+Glimipiride +++ 0,± Moderate Metformin+Repaglinide ++ 0,± Minimal Glimipiride+Rosiglitazone +++ 0,± Moderate

18. Type- 2 Diabetes: FDC studies • Metformin + Glyburide better than monotherapy with either drug. • Garben et al, 2002 • Metformin + Rosiglitazone better than monotherapy with either drug . Rosenstock et al, 2006; Bailey, 2004 • Metformin + Repaglinide better than monotherapy with either drug. • Metformin + Pioglitazone • Rendell et al, 2003; Derosa et al, 2007 • Metformin + Glipizide better than monotherapy with either drug. • Rosiglitazone+ Glimepiride is better than monotherapy with either drug. McChiskey et al, 2006

19. FDC’s of oral anti diabetic drugs available in Indian Market • FDC Dose-Strength (mg) Number of Brands • Metformin + Glyburide 250-1.25; 500-2.5; 500-5 36 • Metformin + Glipizide 250-2.5; 500-2.5; 500-5 25 • Metformin + Rosiglitazone 500-1; 500-2;500-1;1000-2 17 • Metformin + Pioglitazone 500-1; 500-2; 500-1; 100-2 35 • Metformin + Repaglinide 500-1;500-2 1 • Metformin + Gliclazide 500-80 57 • Glimiperide + Pioglitazone 23 • Metformin + Glimiperide 500-1; 500-2 49 • Three Drug FDC’s • Metformin + Pioglitazone + Glimiperide 500-15-1 & 2 3 • Metformin + Pioglitazone + Glibenclamide 500-15-5 1

20. Therapeutic use of Fixed Dose drug combinations: The Rational Procedure Step 1- Use co-administration of two separate insulin preparations (Type-1 diabetes) or separate tablets of two drugs (Type-2 diabetes). Work out suitable dose proportion in each patient. Step 2- Switch over to FDC, that is close to dose proportion determined in step 1. Limitations:- 1. FDC’s marketed in limited dose-proportions. 2.Not all marketed dose-proportions are available in all the countries.