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Transcript of Pharmacologic Management T2DM - Province of …€¦ · Pharmacologic Management Type 2 Diabetes...
Pharmacologic Management Pharmacologic Management Type 2 DiabetesType 2 Diabetes
Dr. Sora LudwigMedical Advisor, Chronic Disease Branch, MHHL
Associate ProfessorUniversity of Manitoba
CDENFebruary, 2009
Type 2 Diabetes:Type 2 Diabetes: Pharmacologic Management of DiabetesPharmacologic Management of Diabetes
Outline:•
Pharmacologic management utilizing oral antidiabetic
agents:
–
Classification–
Mechanism of Action
•
Combination oral therapy•
Pharmacologic management utilizing insulin:–
Classification
–
Mechanism of Action•
Combination of insulin with oral agents
•
Insulin regimens
TargetsTargets Glucose levelsGlucose levels
A1C (%) FPGPre-
prandial (mmol/L)
2hr post- prandial
(mmol/L)
Target ≤
7.0 4.0-7.0 5.0-8.0
Normal range
≤
6.0 4.0-6.0 5.0-8.0
GlycemiaGlycemia
MonitoringMonitoring•
A1C:–
Every 3 months
•
SBGM:–
General benefit to monitoring
–
Necessary when taking meds with risk of hypoglycemia
–
Frequency:•
Dependent on treatment regimen
Type 2 diabetes: Type 2 diabetes: Antihyperglycemic agents Antihyperglycemic agents
PrinciplesPrinciplesCombination therapy in sub-maximal dosages:•
Monotherapy
will lower A1C by 0.5-1.5 %
•
Combinations of agents with different mechanisms of action
In presence of “marked”
hyperglycemia (A1C ≥
9%) initial use of 2 or more agents
with serious consideration of insulin
Oral antihyperglycemic agentsOral antihyperglycemic agents
•
Metformin-
in overweight and non-overweight ptes
•
In alphabetical order:–
Alpha-glucosidase
inhibitors
–
GLP-1 analogues/DDP IV inhibitors–
Repaglinide
–
Sulfonylureas–
TZD
Diabetes ManagementDiabetes Management
Initial Assessment:•
History (Hx)
•
Physical (Px)•
Diabetes complications assessment
Diabetes ManagementDiabetes Management
•
Investigations:–
Glycemic control
–
Complications:•
Microvascular:
–
Retinopathy, –
Nephropathy
–
Neuropathy•
Macrovascular:
–
Cardiovascular–
Cerebral vascular
–
Peripheral Vascular
Pathophysiologic Basis of OHA Therapy:Pathophysiologic Basis of OHA Therapy:
•↓
Hepatic Glucose Output•Modulate CHO Absorption•↓
Insulin Resistance
•Muscle & Adipose Tissue•↑
Pancreatic Insulin Secretion
↓
Hepatic Glucose Output: Hepatic Glucose Output: Biguanides: MetforminBiguanides: Metformin
•
Suppresses excessive hepatic glucose production
•
Increases glucose utilization in peripheral tissue to a lesser degree
•
Appropriate for obese Type 2 diabetes–
No weight gain
Metformin:Metformin:••
Dose: Dose: –
start @ 250-500 mg bid ac meals (may give at HS)
–
maximum dose: 850 mg TID••
Duration:Duration:
8 hrs
••
Effects: Effects: –
Contraindicated with renal /hepatic impairment•
CrCl/eGFR< 30ml/min
•
LFT’s
> 3 x ULN–
GI effects alleviated with slow dosing titration
CHO Absorption: CHO Absorption: Alpha 1 Glucosidase InhibitorsAlpha 1 Glucosidase Inhibitors
••
AcarboseAcarbose–
Modulates enzymatic digestion of di/poly/complex saccharides into monosaccharides
–
Effect on post-prandial glucose rise
–
Role in insulin resistance
AcarboseAcarbose••
Dose: Dose: –
Start @ 25 mg with meal
–
Titrate weekly to usual dose of 50- 100 mg/meal
••
Duration:Duration:
post-prandial••
Effects: Effects: –
GI, GI, GI
–
“Beano”
counteracts action–
No hypoglycemia, No weight gain
Insulin Resistance: Muscle & Adipose TissueInsulin Resistance: Muscle & Adipose Tissue ThiazolindinedionesThiazolindinediones: :
MechanismMechanism
•
Binds & activates nuclear transcription factor–
Peroxisome proliferation-activated receptor-gamma (PPAR-γ)
–
PPAR-γ:•
Involved in transcription of insulin-
responsive genes including GLUT 4 transporters and lipogenesis enzymes
•
Present in adipose muscle & liver tissues•
Appears to be ↑
obesity & diabetes
Insulin Resistance:Muscle & Adipose TissueInsulin Resistance:Muscle & Adipose Tissue ThiazolindinedionesThiazolindinediones
••
Rosiglitazone:Rosiglitazone:Dose:
–
Start @ 2 mg OD–
Maximum dosage-
4 mg BID
••
Pioglitazone:Pioglitazone:Dose:
–
Start @ 15 mg/day–
Titrate to 30-
45 mg/day
Insulin Resistance:Muscle & Adipose TissueInsulin Resistance:Muscle & Adipose Tissue ThiazolindinedionesThiazolindinediones
••
Effects:Effects:–
Weight gain:•
↑
plasma volume
•
Shift from visceral to subcutaneous fat
–
↑
plasma volume ⇒ ↓
HCT•
Edema
–
Exacerbation CHF–
? ↑
risk CVD/MI
Risk of CVD with Risk of CVD with ThiazolindinedionesThiazolindinediones ((TZDTZD’’ss))
•
DREAM trial•
Diabetes Reduction Assessment with Ramipril
and
Rosiglitazone
Medication
•
Non-significant trend towards increased incidence of CVD death, MI or CVA (1.2% vs
0.9%, p=0.2
MetaMeta--analysisanalysis
NissenNissen, , WolskiWolski--
NEJM2007;356:2457NEJM2007;356:2457
•
Results:–
Odds ratio for MI was 1.43
(95% CI, 1.03-1.98; P= 0.03)–
Odds ratio for death from CVD cause was 1.64
(95% CI. 0.98-2.74; P=0.06)
•
Limitations:–
Results based on relatively small number of events, resulting OR that could be affected by small changes in the adjudication/classification of events –
hence the
wide CI–
Heterogenous
studies-
pooled small trials not designed
to look at CVD outcomes–
Small observations vs
classification
–
Accessible data
LongLong--term Risk of term Risk of Cardiovascular Events with Cardiovascular Events with RosiglitazoneRosiglitazone
A MetaA Meta--analysisanalysis
Singh S, Singh S, LokeLoke
TK, TK, FurbergFurberg
CD. JAMA, Sept.12,2007CD. JAMA, Sept.12,2007--Vol298,No.10Vol298,No.10
•
Risk of MI:–
RR: 1.42;95% CI, 1.06-1.91; P=0.02–
No evidence of substantial heterongeneiy
amongst trials–
42% increased risk of MI-from 31% (without any effect on CVD mortality)
•
Risk of CHF:–
RR: 2.09; 95% CI, 1.52-2.88; p < 0.001–
No evidence of substantial heterongeneity
amongst trials–
Doubling risk•
CVD mortality:–
Compared with control-
no increased risk with rosiglitazone
•
NNH for MI with rosiglitazone: without previous hx
of MI–
220/yr•
NNH for CHF with rosiglitazone: without previous hx
of CHF•
30/yr
PioglitazonePioglitazone
and Risk of Cardiovascular Events in patients with and Risk of Cardiovascular Events in patients with Type 2 DMType 2 DM
a Metaa Meta--analysis of Randomized Trialsanalysis of Randomized Trials
Lincoff
AM, Wolski
K, Nicholls SJ, Nissen
SE. JAMA Sept. 2007-Vl.298
•
Criteria:–
RCT’s
–
Composite end=point:•
Death from any cause
•
Nonfatal MI•
Nonfatal CVA
–
19 eligible–
16,390 ptes
↑↑Pancreatic Insulin SecretionPancreatic Insulin Secretion
•
Stimulation of pancreatic insulin secretion––
SulfonylureasSulfonylureas•
Glyburide
•
Gliclazide•
Glimiperide
––
MeglitinidesMeglitinides•
Repaglinide
↑↑Pancreatic Insulin Secretion:Pancreatic Insulin Secretion: SulfonylureasSulfonylureas
••
GlyburideGlyburide–
↑Pancreatic insulin secretion
––
DoseDose::•
start @ 2.5-5 mg OD/BID ac meals
•
Maximum dose: 10 mg BID––
Duration:Duration:
16-24 hrs
––
Effects: Effects: •
Promotes weight gain
•
Hypoglycemia
↑Pancreatic Insulin Secretion: Pancreatic Insulin Secretion: SulfonylureasSulfonylureas
••
GliclazideGliclazide–
↑Pancreatic insulin secretion
––
Dose:Dose:•
start @ 80 mg OD/BID ac meals
•
Maximum dose: 160 mg BID•
Gliclazide
MR: 30-120 mg OD
––
Duration:Duration:
8-16 hrs––
Effects:Effects:•
Causes less hypoglycemia
↑↑Pancreatic Insulin Secretion: Pancreatic Insulin Secretion: SulfonylureasSulfonylureas
••
GlimepirideGlimepiride–
Improves overall glucose control without increasing c-peptide levels as much as glyburide
–
Binds to a different B-cell site than Glyburide–
Lower insulin concentration
–
24-hour control with once-daily dosing ( 1-8 mg)
–
Approval as sulfonylurea to be used in conjunction with insulin
↑↑Pancreatic Insulin Secretion:Pancreatic Insulin Secretion: ShortShort--acting Insulinotropic Agentacting Insulinotropic Agent
••
Meglitinides:Meglitinides:–
Repaglinide
Non-sulfonylurea agents
–
Short-acting–
Causes less hypoglycemia
–
Selectively targets post-prandial hyperglycemia without affecting FBS
•
Provides flexibility in mealtimes & quantity
RepaglinideRepaglinide
••
Dose: Dose: –
Start @ 0.5 mg shortly before each meal
–
Titrate dosage from 0.5-
2(4) mg/meal –
Titrate according to CHO intake
••
Duration:Duration:
post-prandial••
Effects:Effects:–
may cause hypoglycemia
–
Appears safe in mild/moderate CRF
New Agents New Agents IncretinsIncretins--
GLPGLP--11’’ss
GLP-1’s•
Hormones produced from the gastrointestinal tract that enhance the normal release of insulin after the oral ingestion of carbohydrates
•
Slow the gastric absorption of nutrients and act to promote a feeling of satiety –
that can lead to weight loss in overweight individuals.
•
Therefore, these agents work to lower glucose levels in a glucose-dependent fashion without causing hypoglycemia
•
Preserved response in T2 Diabetes
GLPGLP--11••
GLPGLP--1 agonist: 1 agonist: –
Stimulates insulin secretion/Suppresses glucagon secretion
–
Inhibits gastric empting–
Inhibits food intake/weight gain
(central effect)–
Hypoglycemia unlikely as response occurs in presence of hyperglycemia only
••
DPP IV inhibitor:DPP IV inhibitor:–
Reduces metabolism of GLP-1
Incretins:Incretins: Therapies for T2 DMTherapies for T2 DM
GLPGLP--1 agonists1 agonists•
Exenatide
•
Liraglutide
•
Injection •
Potent glucose-
lowering•
Longer-acting
•
Nausea & vomiting
DPPDPP--IV IV ihibitorsihibitors•
Vildagliptin
•
Sitagliptin
•
Oral•
Less potent
•
Shorter-acting•
Less adverse effects
Applications:Applications: EfficacyEfficacy
•
Immediate potency: glucose toxicity–
Sulfonylureas
•
Obesity/insulin resistance:–
Metformin
–
GLP-1/DPP-IV–
TZD’s
–
Acarbose
Applications:Applications: EfficacyEfficacy
•
Monotherapy:
–
All have similar efficacy
–
At 6-12 months-
↓
Hgb A1c= 1-2%
Insulin:Insulin:RapidRapid--acting:acting:
Lispro = Humalog®Aspart = Novo-rapid®Glulisine= Apidra®
ShortShort--acting:acting:
Regular, Toronto®
IntermediateIntermediate--acting:acting:NPH
LongLong--acting:acting:Glargine
= Lantus®
Detemir
= Levemir®
Insulin Action CurvesInsulin Action Curves
InsulinInsulin
Insulin/OHA combinations:HS (bedtime) insulin with OHA’s during the day
Daytime insulin with insulin sensitizer or meglitinides (or glimepiride)
Insulin: Insulin: DayDay--time insulin time insulin Basal/bolusBasal/bolus--
TID/QIDTID/QID
BasalBasal-
long/intermediate-acting:Once or twice/day~ 50% total daily dose
BolusBolus-
rapid-acting:MealsDosage dependent on CHO intake
Split/mixed: NPH & Regular2/3 amac1/3 pmac
Pre-mixes:Mix 25-
NPL & lispro
Novo Mix-
NPA & apsart
Insulin:Insulin: How to StartHow to Start
••
Basal/Bolus:Basal/Bolus:––
Basal:Basal:
By Size:
•
Lean-
5u hs, Insulin-resistant-
10u hs
––
Bolus:Bolus:•
CHO Counting (rapid-acting insulin only):
Start 1 unit / 15 gm CHO•
Algorithm for blood glucose correction
Insulin:Insulin: How to StartHow to Start
•
By Insulin Requirements:–
24 hr insulin infusion requirements= TDD
•
By weight:–
TDD-
0.2-0.5 units/kg
Marilyn
Marilyn is a 49 yr. old woman, presenting as a new patient for a complete assessment:
•
She has no specific complaints other than she would like to lose weight
•
She smokes 1/2 pack/day•
FHx:–
Sister with type 2 DM
–
Brother with hypertension and CAD
MarilynPx:•
BMI: 30
• BP-
140/90
• Rest is unremarkable
1.
Should Marilyn be screened for diabetes?
2.
Why? 3.
How would you screen Marilyn for diabetes?
4.
Who should be screened for diabetes?
MarilynMarilyn’s lab results:FPG-
6.8 mmol/L
1.
What are the diagnostic criteria for diabetes?
2.
What is the diagnosis?3.
What do you do?
Marilyn
Marilyn’s lab results:FPG-
7.8 mmol/L
1.
What are the diagnostic criteria for diabetes?
2.
What is the diagnosis?3.
What do you do?
Marilyn
Marilyn’s lab results:FPG -
10.8 mmol/L
1.
What are the diagnostic criteria for diabetes?
2.
What is the diagnosis?3.
What do you do?
Marilyn
Marilyn’s lab results:FPG -
18.8 mmol/L
1.
What are the diagnostic criteria for diabetes?
2.
What is the diagnosis?3.
What do you do?