EARLY COMBINATION THERAPY IN DIABETES MELLITUS:EFFECT ON LONG TERM CONTROL Dr. SANJAY KALRA Bharti...
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Transcript of EARLY COMBINATION THERAPY IN DIABETES MELLITUS:EFFECT ON LONG TERM CONTROL Dr. SANJAY KALRA Bharti...
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.