1. Dr. SANJAY KALRA Bharti Hospital,Karnal
EARLY COMBINATION THERAPY IN DIABETES MELLITUS:EFFECT ON LONG TERM CONTROL
Dr. SANJAY KALRA
Bharti Hospital,Karnal

2. COMBINATION THERAPY OHAs INSULIN Basal SECRETAGOGUES Pre-Mixed
Intensive
3 dose
4 dose
OHAs
SECRETAGOGUES
sulfonylureas
meglitinides
SENSITIZERS
metformin
thiazolidinediones

3. THE NEED FOR COMBINATION
Many patients do not achieve adequate control. (Koro CE et al,2004).
Gradual deterioration in control occurs with time(UPKDS,1998).
Poor control leads to complications.
Good control can prevent complications.

4. THE NEED FOR COMBINATION
Each drug affects one aspect of metabolism (insulin deficiency or insulin resistance).
Each drug has side effects.
Low doses in combination
have multi dimensional effect.
Less side effects.

5. GLITAZONES :PLEIOTROPIC EFFECTS
Glucose control.
Diabetes prevention.
Improvement in CVD risk factors (TG,HDL,LDL particle size).
Fall in BP.
Decrease in markers of endothelial inflammation (CRP, wbc count, fibrinogen,MMP-9,TNFα).
Decrease in markers of elevated thrombotic risk (PAI-1,platelet aggregation).

6. GLITAZONES Target insulin resistance.
Achieve stable control over ≥ 2 years (Tan MH et al,2005).
Improve β cell secretory function (Matsui J et al,2004).
reduce FFA levels.
correct lipotoxicity.
improve β cell secretory function.
Improve β cell mass.
(Kendall MD, 2006).

7. DIABETES PRVENTION Metformin ~ 30% RR (DPP; 2002)
Glitazones > 50% RR (DPP;2005)
Metformin masks hyperglycemia by early treatment (DPP).
GLitazones delay diabetes onset if given before onset if given before onset of IGT (TRIPOD) (Buchanan TA et al,2002).

8. CVD RISK REDUCTION
Insulin resistance/ hyperglycemia both increase the risk of CVD.
Meformin reduces CV risk in obese patients with diabetes (UKPDS,1998).
Insulin reduces mortality after MI(DIGAMI,1997).

9. CVD RISK REDUCTION
Glitazones improve risk factors (goldberg RB et al,2005).
PIoglitazone reduces cholesterol (goldberg Rb et al,2005).
Glitazones reduces restenosis rate after stent implantation (rosi : Choi D et al,2004
pio : Tapagi T et al,2003).

10. IS INSULIN USEFUL?
Insulin is usually started after secondary OHA failure.
Patients, physicians usually do not have time required to effectively use insulin.
Intensive insulin management is costly, and needs more resources(Hayward RA et al,1997).
Patient compliance is significantly less with insulin than with OHAs.

11. TRIPLE THERAPY GLIMEPERIDE ADDED TO M + GLITAZONE
Multicentre, randomized, double blind, placebo – controlled study x 26 weeks.
Diabetes x ≥ 1 year.
Glimeperide : 2-8 mg/d.
Metformin : g/d.
Glitazone : max/2 to max dose.
HbA1c  -1.31% in G group,
 % in P group.
FBG  mg% in G group.
 mg% in P group.
Roberts Vl et al ,2005.

12. TRIPLE THERAPY GLITAZONE ADDED TO MET + SU
Bell DS, Ovalle F (2002)
Sustained  HbA1c over 3 years.
Orbay E et al (2004)
 HbA1c %
 FPG – %
after 26 weeks.
Dailey GE et al (2004)
 HbA1c – 1.0%
 FPG mg%

13. TRIPLE TEHRAPY INSULIN + METFORMIN + TROGLITAZONES
Strowg SM et al,2004.
Adding metformin to patients well-controlled on insulin > 30 units/day+ troglitazone improved control even further : 6.2 to 5.8%.
Adding troglitazone to patients on insulin + metformin improved HbA1c : 7.0 to 6.1%.

14. TRIPLE TEHRAPY INSULIN + METFORMIN + TROGLITAZONES
There is no right way to treat type 2 diabetes.
The goal is to achieve evidence-based targets .
No studies directly compare different therapeutic approaches along to progressive continuum of type 2 diabetes.
Davidson MB,2004.

15. WE CAN IF WE TRY!
One can achieve HbA1c ~ 7.0% in properly educated, minority populations.
Progressive increase in dose of met/SU q 2 wks until goal is achieved.
Add next medication if maximal dose is reached.
All can achieve similar outcomes.
Davidson MB, nurse – directed care.
Fanning EL et al, treatment algorithms.

16. Pro active STUDY,2005. 5328 patients Extensive macrovascular disease
1/3 on insulin
85% on anti platelet drugs
70% on ARB /ACEI
43% on statins

17. Pro active STUDY,2005. Primary end point disease end points
death ,MI ,stroke
Procedure end points
coronary ,leg revasularizations
Secondary end point
disease end points ONLY

18. PRO active NEWS GOOD NEWS  in 20 end point by 16% BAD NEWS
↑ body weight 4x
↑ edema not attributable to heart failure 4x
↑ heart failure 2x
No.  in 10 end point
↑ Bladder cancer
↑ pneumonia

19. QUADRUPLE THERAPY
Adding proglitazone to insulin + glibenclamide + metformin in patients with uncontrolled type 2 diabetes.
57 patients u BMI pro 30 mg + met 1 g/d x 6 mths.
HbA1c  8.15% to 7.17%
FPG  mg% to mg%

20. QUADRUPLE THERAPY body weight  2.43 kg BMI ↑ 0.64 kg m-2 edema 33.33%
mild hypoglycemia %
Severe hypoglycemia 2/52 (3.84%)
Insulin dose  to 20.0 u/d
Insulin freq  2.05 to 1.18 injns/d
Insulin stopped in 42.10%
Glibenclamide dose  by ≥ in 10.52%
Pendsey SP et al, 2002.

21. LONG TERM BENEFITS β cell preservation. off- loading of β cell.
endogenous insulin secretion maintained.
porto systemic gradient maintained.
glucagon secretion.