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?