Oral Hypoglycemic Agents H.Rezvanian.MD Objectives 1.List oral hypoglycemic agents currently on the...

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Transcript of Oral Hypoglycemic Agents H.Rezvanian.MD Objectives 1.List oral hypoglycemic agents currently on the...

Oral Hypoglycemic

AgentsH.Rezvanian.MD

Objectives

1. List oral hypoglycemic agents currently on the market

2. Classify oral hypoglycemic agents based on their mechanism, onset, duration, and place in therapy

3. Describe pros and cons of the different oral hypoglycemic agents available

4. Summarize limitations and contraindications of oral hypoglycemic agents

Classification and Diagnosis

Diagnostic Criteria

Fasting Glucose mg/dL

2-h OGTT mg/dL

Random Glucosemg/dL

A1c

Normal <100 <140 <200 <5.7%

Prediabetes 100-125(IFG)

140-199(IGT)

5.7-6.4%

Diabetes ≥ 126 ≥ 200 ≥ 200 ≥ 6.5%

ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.

Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing.

Prevention, Prevention, Prevention!

Refer patients with IGT, IFG, or A1C 5.7–6.4% to ongoing support program Target weight loss = 7% of total body weight Minimum of 150 min/week of moderate physical activity

Follow-up counseling important for success

Based on cost-effectiveness of diabetes prevention, third-party payers should cover such programs

In those with pre-diabetes, monitor for development of diabetes annually

ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16

Prevention, Prevention, Prevention!

Medications shown to delay progression of IGT/IFG to T2DM Metformin (US DPP, NEJM 2002) Acarbose (STOP-NIDDM, Lancet 2002) Pioglitazone (ACT NOW, presentation 2008)

Consider metformin for prevention of type 2 diabetes if IGT, IFG, or A1C 5.7–6.4% Especially for those with BMI >35 kg/m2, age <60 years, and

women with prior GDM

None are FDA approved for Diabetes Prevention

ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16

A1c Monitoring

Twice Yearly in those who have stable glycemic control and no therapy changes

Quarterly in patients whose therapy has changed or who are not meeting glycemic goals

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18.

A1C CorrelationMean plasma glucose

A1C (%) mg/dL mmol/L

6 126 7.0

7 154 8.6

8 183 10.2

9 212 11.8

10 240 13.4

11 269 14.9

12 298 16.5

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18. Table 8.

Easy A1c Correlation

NOTE: This is an estimate only

(A1C -2) x 30 i.e. A1C= 7%; (7-2) x30 = 150mg/dL

Goals

Glycemic Recommendations

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S20. Table 9.

*Individualize goals based on these values.†Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes

Target Treatment

Goal

AACE/ACE 2011

ADA 2012

A1c ≤6.5% <7%

Fasting Glucose FPG <110 mg/dl Preprandial PG 70-130mg/dl

Postprandial Glucose

2-hr postprandial <140mg/dl

Peak <180mg/dl

Goals: A1c

Goal: <7% Lowering A1c <7% has been shown to reduce microvascular

complications and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease More stringent goals (i.e. 6.5%)are reasonable in patients if

it can be achieved without significant hypoglycemia or side effect New diagnosis of diabetes, long life expectancy and no

significant CVD

Less stringent goals (i.e. 8%) may be reasonable for those who have experienced severe hypoglycemia, limited life expectancy, advanced complications, or extensive comorbidities.

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18-19.

Oral Hypoglycemic Treatment

Non-Insulin Hypoglycemic Agents

OralBiguanidesSulfonylureasMeglitinidesThiazolidinedionesAlpha Glucosidase inhibitorsIncretin Enhancers (DPP-IV inhibitors)Resin binder.SGLT2 inhibitors

Parenteral Amylin analogs Incretin mimetics

Pharmacology - Biguanides

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University

Class Biguanides

Compound Metformin

Mechanism Activates AMP-kinase

Action(s) • Hepatic glucose production • Intestinal glucose absorption • Insulin action

Glucose Lowering Effect

• Fasting• Post Prandial

Advantages • No weight gain• No hypoglycemia• Reduction in cardiovascular events and mortality (UKPDS

f/u)

Disadvantages • Gastrointestinal side effects (diarrhea, abdominal cramping)

• Lactic acidosis (rare)• Vitamin B12 deficiency• Contraindications: reduced kidney function

Cost Low – free at Marsh

Pharmacology - Sulfonylureas

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.

Class Sulfonylureas (2nd generation)

Compound • Glibenclamide/Glyburide• Glipizide• Gliclazide• Glimepiride

Mechanism Closes KATP channels on β-cell plasma membranes

Action(s) Insulin secretion

Advantages • Generally well tolerated• Reduction in cardiovascular events and mortality

(UKPDS f/u)

Disadvantages • Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death

• Weight gain• Primary and secondary failure

Cost Low – free at Marsh

Pharmacology – Meglitinides

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.

Class Meglitinides

Compound • Repaglinide (Prandin®)• Nateglinide (Starlix®)

Mechanism Closes KATP channels on β-cell plasma membranes

Action(s) Insulin secretion

Advantages Accentuated effects around meal ingestion

Disadvantages • Hypoglycemia, weight gain• Dosing frequency

Cost Medium

Pharmacology – Thiazolidinediones (TZD)

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.

Class Thiazolidinediones (Glitazones)

Compound Pioglitazone (Actos®)

Mechanism Activates the nuclear transcription factor PPAR-

Action(s) Peripheral insulin sensitivity

Advantages • No hypoglycemia• HDL cholesterol • Triglycerides

Disadvantages • Weight gain• Edema• Heart failure (CI with stage III and IV)• Bone fractures

Cost High

Pharmacology – Thiazolidinediones (TZD)

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.

Class Thiazolidinediones (Glitazones)

Compound Rosiglitazone (Avandia®)

Mechanism Activates the nuclear transcription factor PPAR-

Action(s) Peripheral insulin sensitivity

Advantages No hypoglycemia

Disadvantages • LDL cholesterol • Weight gain• Edema• Heart failure (CI with stages III and IV)• Bone fractures• Increased cardiovascular events (mixed evidence)• FDA warnings on cardiovascular safety

Cost High

TZDs and the FDA

Rosiglitazone Restricted by FDA – can only be used by patients

currently benefiting from therapy or do not get adequate DM treatment from other agents and not willing to use pioglitazone

1-800-AVANDIA

Pioglitazone FDA alert – ongoing analysis of risk of bladder

cancer (with prolonged use >12 months) Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1].

Pharmacology – Alpha-Glucosidase Inhibitors

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.

Class α-Glucosidase inhibitors

Compound • Acarbose• Miglitol

Mechanism Inhibits intestinal α-glucosidase

Action(s) Intestinal carbohydrate digestion and absorption slowed

Advantages • Nonsystemic medication• Postprandial glucose

Disadvantages • Gastrointestinal side effects (gas, flatulence, diarrhea)

• Dosing frequency

Cost Medium

Pharmacology – Incretin Mimetics

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.Adapted with permission from Silvio Inzucchi, Yale University.

Class GLP-1 receptor agonists (incretin mimetics)

Compound • Exenatide (Byetta®)• Liraglutide (Victoza®)

Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas; brain/autonomous nervous system

Action(s) • Insulin secretion (glucose-dependent)• Glucagon secretion (glucose-dependent)• Slows gastric emptying• Satiety

Advantages • Weight reduction• Potential for improved β-cell mass/function

Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea)• Cases of acute pancreatitis observed• C-cell hyperplasia/medullary thyroid tumors in animals

(liraglutide)• Injectable• Long-term safety unknown

Cost High

Pharmacology – Incretin Enhancers

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.Adapted with permission from Silvio Inzucchi, Yale University.

Class DPP-4 inhibitors (incretin enhancers)

Compound • Sitagliptin (Januvia®)• Vildagliptin (available in Europe)• Saxagliptin (Onglza®)• Linagliptin (Tradjenta®)

Mechanism Inhibits DPP-4 activity, prolongs survival of endogenously released incretin hormones

Action(s) • Active GLP-1 concentration • Insulin secretion • Glucagon secretion

Advantages • No hypoglycemia• Weight “neutrality”

Disadvantages • Occasional reports of urticaria/angioedema• Cases of pancreatitis observed• Long-term safety unknown (cancer ?)

Cost High

Pharmacology – Amylin Analog

Class Antihyperglycemic Synthetic Analog

Compound • Pramlintide (Symilin®)

Mechanism • Amylinomimetic

Action(s) • Glucagon secretion (glucose-dependent)• Slows gastric emptying• Satiety

Advantages • Potential weight loss

Disadvantages • Meal time injections• Nausea• Hypoglycemia in combination with insulin

Cost High

Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1].

Pharmacology – Bile Acid Sequestrants

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.Adapted with permission from Silvio Inzucchi, Yale University.

Class Bile acid sequestrants

Compound Colesevelam (Welchol®)

Mechanism Binds bile acids/cholesterol

Action(s) Bile acids stimulate receptor on liver to produce glucose

Results • Lowers fasting and post prandial glucose

Advantages • No hypoglycemia• LDL cholesterol

Disadvantages • Constipation• Triglycerides • May interfere with absorption of other

medications

Cost High

The Role of SGLT-2 Inhibitors in the Management of Patients

with Type 2 Diabetes

Normal Renal Glucose Physiology• 180 g of glucose is filtered each day

• Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation

• SGLT2 reabsorbs about 90% of the glucose

• SGLT1 reabsorbs about 10% of the glucose

• Virtually no glucose excreted in urine

The Kidneys Play an Important Role in Glucose Control

Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Targeting the Kidney

Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

Renal Glucose Transport

Sodium- Glucose Cotransporters

SGLT1 SGLT2

Site Mostly intestine with some kidney

Almost exclusively kidney

Sugar Specificity Glucose or galactose Glucose

Affinity for glucose HighKm= 0.4 Mm

Low Km = 2 Mm

Capacity for glucose transport

Low High

Role Dietary glucose absorptionRenal glucose reabsorption

Renal glucose reabsorption

Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition

Familial Renal Glucosuria

Presentation• Glucosuria: 1-170 g/day• Asymptomatic

Blood• Normal glucose concentration• No hypoglycemia or hypovolemia

Kidney / bladder• No tubular dysfunction• Normal histology and function

Complications

• No increased incidence of– Chronic kidney disease– Diabetes– Urinary tract infection

Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882;Wright EM, et al. J Intern Med. 2007;261:32-43.

Altered Renal Glucose Control in Diabetes

Gluconeogenesis is increased in postprandial and postabsorptive states in patients with Type 2 DM Renal contribution to hyperglycemia 3-fold increase relative to patients without diabetes

Glucose reabsorption Increased SGLT-2 expression and activity in renal

epithelial cells from patients with diabetes vs. normoglycemic individuals Marsenic O. Am J Kidney Dis. 2009;53:875-883.

Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277. Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434.

SGLT2 Inhibitors in Phase 3 Development

• Empagliflozin

• Canagliflozin

• Dapagliflozin

• Ipragliflozin

Typical A1c ReductionsMonotherapy Route of

AdministrationA1c (%) Reduction

Sulfonylurea PO 1.5-2.0

Metformin PO 1.5

Glitazones PO 1.0-1.5

Meglitinides PO 0.5-2.0

α-glucosidase inhibitors

PO 0.5-1.0

DPP-4 PO 0.5-0.7

GLP-1 agonists Injectable 0.8-1.5

Amylin analogs Injectable 0.6

Insulin Injectable Open to target

Unger J et al. Postgrad Med 2010; 122: 145-57

Drug PearlsMedication PRO CONMetformin Low cost, A1c lowering, +

CV effects, weight loss, PCOS

Renal or hepatic impairment

Sulfonylurea Low cost, A1c lowering Hypoglycemia, treatment failure

Meglitinides Erratic meals, renal insufficiency

Hypoglycemia, treatment failure

Pioglitazone Insulin resistance, decrease in adipose tissue, TG reduction

Edema, wt gain, CI with HF class III and IV

α-glucosidase inhibitors Patients with constipation Long duration of T2DM, patients with GI problems

DPP-4 Well tolerated ? long term safety

GLP-1 agonists Obese patients GI side effects

Amylin analogs Poor PPG control despite insulin therapy

GI side effects

Insulin Flexible treatment (basal, basal bolus, etc)

Hypoglycemia, weight gain

Fasting vs. Postprandial Effect

Mostly targets FASTING hyperglycemia

Mostly targets POSPRANDIAL hyperglycemia

Insulin (long and intermediate action)

Insulin (regular, rapid-action)

Colesevelam α-glucosidase inhibitors

Sulfonylureas Meglitinides

TZD Pramlinitide

Metformin DPP-4 inhibitors

GLP-1 agonist

Considerations When Selecting Therapy

How long has the patient had diabetes (duration of disease – preservation of β-cell function)?

Which blood glucose level is not at target (fasting, postprandial, or both)?

Patient preference for route of administration (oral, injection)?

The degree of A1c lowering effect required to achieve goal?

Side effect profile and the patients tolerability? Co – existing conditions ( CVD, osteoporosis, obesity,

etc)?

Glycemic Control Algorithm

Algorithm for Adding/Intensifying Insulin

QUESTIONS