3THE 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.
4THE NEED FOR COMBINATION Each drug affects one aspect of metabolism (insulin deficiency or insulin resistance).Each drug has side effects.Low doses in combinationhave multi dimensional effect.Less side effects.
5GLITAZONES :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).
6GLITAZONES 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).
7DIABETES 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).
8CVD RISK REDUCTIONInsulin 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).
9CVD RISK REDUCTIONGlitazones 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,2004pio : Tapagi T et al,2003).
10IS 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.
11TRIPLE 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.
12TRIPLE 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%
13TRIPLE 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%.
14TRIPLE 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.
15WE 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.
16Pro active STUDY,2005. 5328 patients Extensive macrovascular disease 1/3 on insulin85% on anti platelet drugs70% on ARB /ACEI43% on statins
17Pro active STUDY,2005. Primary end point disease end points death ,MI ,strokeProcedure end pointscoronary ,leg revasularizationsSecondary end pointdisease end points ONLY
18PRO active NEWS GOOD NEWS in 20 end point by 16% BAD NEWS ↑ body weight 4x↑ edema not attributable to heart failure 4x↑ heart failure 2xNo. in 10 end point↑ Bladder cancer↑ pneumonia
19QUADRUPLE THERAPYAdding 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%
20QUADRUPLE 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/dInsulin freq 2.05 to 1.18 injns/dInsulin stopped in 42.10%Glibenclamide dose by ≥ in 10.52%Pendsey SP et al, 2002.
21LONG TERM BENEFITS β cell preservation. off- loading of β cell. endogenous insulin secretion maintained.porto systemic gradient maintained.glucagon secretion.