Download STATUS OF FIXED DOSE DRUG COMBINATION IN ANTIDIABETIC DRUG

STATUS OF FIXED DOSE DRUG
COMBINATIONS IN
ANTIDIABETIC DRUG
THERAPY
by
Prof. P.L. Sharma, M.D., Ph.D.(Lond.), FAMS
1. Director, Clinical Research, ISF College of Pharmacy,
Moga-142001, Punjab
2. Emeritus Professor, PGIMER, Chandigarh-160012
DIABETES MELLITUS
• Multifactorial in origin, has a variable and progressive
course, requires attention to attendant risk factors and comorbidities 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.
Treatment of Diabetes Mellitus
Pharmacological treatment regimen should be
Individualized (Fit the drug(s) to the patient)
Factors to be taken into account
1. Degree of hyperglycemia
2. 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
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.
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,
i. Improve glycemic control
ii. Minimize occurrence of hypoglycemia
iii. 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.
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)
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.
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.
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.
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 612 months.
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.
Desirable Attributes Of A Good Fixed
Dose Drug Combination:
1. Different mechanism of action of each
ingredient.
2. Submaximal dose, if feasible, of each
ingredient.
3. Ingredients with similar t1/2.
4. Different ADR profile of each ingredieent.
5. FDC should be cheaper.
Type-2 Diabetes: Fixed Dose Combination
Therapy (FDCT)
Stated Objectives:1. To improve tight glycemic control
2. To reduce “Pill Burden” and, thereby, improve
adherence to treatment
3. To decrease the incidence/severity of Adverse
Drug Reactions
4. 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.
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.
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)
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
Advantages of Combination Treatment in Type-2 Diabetes
Drugs
HbA1c
Metformin+Glyburide
+++
Metformin+Rosiglitazone +++
Metformin+Pioglitazone +++
Metformin+Gliclazide
+++
Metformin+Glipizide
+++
Metformin+Glimipiride
+++
Metformin+Repaglinide
++
Glimipiride+Rosiglitazone +++
Wt.gain
±
0,±
0,±
0,±
0,±
0,±
0,±
0,±
Hypo.Risk
Significant
Moderate
Moderate
Moderate
Moderate
Moderate
Minimal
Moderate
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
FDC’s of oral anti diabetic drugs
available in Indian Market
•
•
•
•
•
•
•
•
FDC
Metformin + Glyburide
Metformin + Glipizide
Metformin + Rosiglitazone
Metformin + Pioglitazone
Metformin + Repaglinide
Metformin + Gliclazide
Glimiperide + Pioglitazone
Metformin + Glimiperide
Dose-Strength (mg)
250-1.25; 500-2.5; 500-5
250-2.5; 500-2.5; 500-5
500-1; 500-2;500-1;1000-2
500-1; 500-2; 500-1; 100-2
500-1;500-2
500-80
500-1; 500-2
Number of Brands
36
25
17
35
1
57
23
49
Three Drug FDC’s
•
•
Metformin + Pioglitazone + Glimiperide
500-15-1 & 2
Metformin + Pioglitazone + Glibenclamide 500-15-5
3
1
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.