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

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

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.

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.

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).

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).

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).

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).

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).

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.

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 : 1.0 -2.5 g/d. Glitazone : max/2 to max dose. HbA1c  -1.31% in G group,  - 0.33 % in P group. FBG  - 37.4 mg% in G group.  - 3.5 mg% in P group. Roberts Vl et al ,2005.

TRIPLE THERAPY GLITAZONE ADDED TO MET + SU Bell DS, Ovalle F (2002) Sustained  HbA1c over 3 years. Orbay E et al (2004)  HbA1c - 0.97 %  FPG – 33.70 % after 26 weeks. Dailey GE et al (2004)  HbA1c – 1.0%  FPG - 48 mg%

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%.

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.

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, 2003- nurse – directed care. Fanning EL et al, 2004- treatment algorithms.

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

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

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

QUADRUPLE THERAPY Adding proglitazone to insulin + glibenclamide + metformin in patients with uncontrolled type 2 diabetes. 57 patients 56.84 u BMI 26.30 pro 30 mg + met 1 g/d x 6 mths. HbA1c  8.15% to 7.17% FPG  209.3 mg% to 115.14 mg%

QUADRUPLE THERAPY body weight  2.43 kg BMI ↑ 0.64 kg m-2 edema 33.33% mild hypoglycemia 22.80% Severe hypoglycemia 2/52 (3.84%) Insulin dose  33.51 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.

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