EARLY COMBINATION THERAPY IN DIABETES MELLITUS:EFFECT ON LONG

TERM CONTROL

Dr. SANJAY KALRA

Bharti Hospital,Karnal

COMBINATION THERAPY

INSULIN Basal 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 2xNo. 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.