Oral Hypoglycemics

Roland Halil, BScPharm, ACPR, PharmDClinical Pharmacist, Bruyere Academic Family Health TeamAssistant Professor, Dept of Family Medicine, U of Ottawa

July 2015

Objectives• List the classes of oral antihyperglycemic agents and

understand their place in therapy.– Determine the relative efficacy, toxicity, cost and

convenience of these agents before choosing therapy– Rationalize prescribing of oral hypoglycemics

• Describe the current approach to pharmacologic management of type 2 diabetes.

Diagnosis of IFG, IGT

Category FPG And/or2-hour after OGTT

IFG 6.1-6.9 N/A

IFG (isolated) 6.1-6.9 AND < 7.8

IGT (Isolated) < 6.1 7.8-11.0

IFG and IGT 6.1-6.9 7.8-11.0Can J Diabetes 2003;27(2);S11

MACROvascular MICROvascularStroke

Heart disease &

hypertension

Foot problems

Diabetic eye disease(retinopathy & cataracts)

Nephropathy

Neuropathy

Foot problems

Diabetes: complications

Peripheral vascular disease

Kumamoto Study – HbA1c & Complications

5 6 7 8 9 10 11 111098765

HbA1c (%) HbA1c (%)

Rat

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er p

atie

nt-

y ea r

s

Ra t

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atie

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• Intensive vs. conventional insulin therapy (N=110)• Median A1c - 7.1% vs. 9.4%

0246

86

10

121416

10

1614

12

8

420

7% 7%

Retinopathy Nephropathy

Prevention of Diabetes in IGT

• Lifestyle modification – (see Finnish Diabetes Trial)– Moderate weight loss (5%) (esp. abd fat)– Regular physical activity

• > 150 minutes per week– 58% RRR for type 2 Diabetes at four years

• Pharmacotherapy– Multiple effective trials

• Eg. LIFE trial - Losartan onset of new DM2

Can J Diabetes 2003;27(2);S12

Pharmacological Prevention StudiesStudy Drug Duration

(years)RRR (%)

DPP Metformin850mg BID 2.8 31

STOP-NIDDM

Acarbose 100mg TID 3.3 30

DREAM Rosiglitazone8mg daily 3.0 55

XENDOS Orlistat 120mg TID 4.0 37

Non-Pharmacologic Tx

Mainstay of therapy!

• Nutrition therapy– ↓ A1c 1-2%– CDA recommends counseling by a dietician for

all type 2 diabetics– www.cvtoolbox.com diet for Type 2 diabetes

Can J Diabetes 2003;27(2);S27

Pharmacotherapy

Comparison of antihyperglycemics

Drug Classes

Sensitizers Secretagogues

Other

Drug Classes

Sensitizers• Metformin• Glitazones

– Rosiglitazone (AVANDIA)– Pioglitazone (ACTOS)

Secretagogues• Sulfonylureas

– Eg. Glyburide, Gliclazide• Meglitinides

– Eg Repaglinide (GLUCONORM)

Other• Alpha glucosidase inhibitors (Acarbose) SGLT2 inhibitors (Canagliflozin)(Dapagliflozin )

• DPP4 inhibitors (Gliptins) Incretin (GLP1) Analogues

• Sitagliptin, Linagliptin * Liraglutide (VICTOZA) (sc inj)

• Saxagliptin, Alogliptin * Exenatide (BYETTA) (sc inj)

Drug Classes

Sensitizers• Metformin• Glitazones

– Rosiglitazone (AVANDIA)– Pioglitazone (ACTOS)

• Sensitizers – reduce insulin resistance

• Increase glucose uptake & utilization in muscle and adipose tissue

• Reduce hepatic glucose output

Drug Classes• ↑Basal & prandial insulin

secretion, ↓hepatic gluconeogenesis

• Doesn’t correct impaired 1st phase insulin secretion; primarily affects 2nd phase

• Beta-cell sensitizer – primes glucose mediated insulin secretion (1st phase)

Secretagogues

• Sulfonylureas– Eg. Glyburide, Gliclazide

• Meglitinides– Eg Repaglinide

(GLUCONORM)

Drug Classes: Other• Alpha glucosidase inhibitors (Acarbose)

• Competitive inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases, resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose; Dose-dependent reduction in postprandial serum insulin and glucose peaks; inhibits the metabolism of sucrose to glucose and fructose

• SGLT2 inhibitors (Canagliflozin, Dapagliflozin)

– Inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, reducing reabsorption of filtered glucose from the tubular lumen and lowering the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

• DPP4 inhibitors (Gliptins) – (Sitagliptin, Lingliptin, Saxagliptin, Alogliptin)

• Prolongs the action of endogenous incretin hormones by blocking their breakdown by the enzyme, dipeptidyl peptidase-4 (DPP-4). This leads to more insulin release after eating.

• Incretin (GLP1) Analogues – (Liraglutide (Victoza®), Exenatide (Byetta®))

– sc injection

– mimic endogenous incretin hormones

Rational Prescribing

• FOUR steps to Rational Prescribing:1. EFFICACY

2. TOXICITY

3. COST

4. CONVENIENCE

EFFICACY – Ask…

1. HARD Outcomesa) Any mortality benefit? b) Any morbidity benefit?

Then,

2. SURROGATE Outcomesa) Clinically relevant?

EFFICACY

1. HARD Outcomes– Mortality benefit

– MetforminMetformin – UKPDS-34 trial– Morbidity

– Reduction in microvascular complications (nephropathy, retinopathy, neuropathy)

2. SURROGATE Outcomesa) Hgb-A1c reduction

• Blood glucose level reduction– Fasting or Prandial

b) Insulin Sparing Effects

Effect of Metformin on Event Rates in the UKPDS

• Diabetes-related endpoint 32% p=0.002 • All-cause mortality 36% p=0.011

MI / CVA

• Diabetes-related death 42% p=0.017 – But.. When added early to sulfonylurea

risk of DM-related death (?statistical anomaly?)

EFFICACYA) Surrogate Outcome - Hgb-A1c

– ~ 1% to 2%• Metformin (1% - 2%)

• Sulfonylureas (1% - 2%)

• Repaglinide (1% - 1.5%)

• Glitazones (TZDs) (0.4% - 1.5%)

• Canagliflozin (0.8 – 1%)

– ~ 0.5% to 0.8%• Acarbose• DPP4 inhibitors (‘Gliptins)• Nateglinide• Dapagliflozin

Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.

EFFICACY

B) Surrogate Outcome - Insulin Sparing Effect– METFORMIN– ACARBOSE– TZD’s (GLITAZONE’s)– DPP4 inh (‘gliptins)– Incretin Analogues (Liraglutide, Exenatide)

– SGLT2 inh (Canagliflozin, Dapagliflozin)

= Weight neutral or weight negative= Reduction of hyperinsulinemia

TOXICITY – Ask…

1. Serious / Fatal Side Effects

2. Bothersome / Common s.e.

3. Age? • Newer agents = Less Safety Data• Older agents = More Safety Data

TOXICITY – Serious / Fatal

• Glitazones– CHF– Fractures– M.I.

• (rosiglitazone)– Bladder Cancer

• (pioglitazone)

• Secretatgogues (Sulfonylureas &Meglitinides)

– Severe Hypoglycemia

TOXICITY – Serious / Fatal

• SGLT2 inhibitors (Canagliflozin) (Dapagliflozin)

– ?DKA• “March 2013 to June 6, 2014,

20 cases of acidosis — diabetic ketoacidosis, ketoacidosis or ketosis — were recorded in the FDA Adverse Event Reporting System in patients treated with SGLT2 inhibitors. All patients required emergency room visits or hospitalization to treat the ketoacidosis.”

• http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm

– Unknown – too new

• Incretin Analogues – (Liraglutide, Exenatide (sc inj))

&• DPP4 inhibitors

(‘gliptins)– ?Heart failure

• http://www.medscape.com/viewarticle/839315

– ?Pancreatitis• http://www.ncbi.nlm.nih.gov/pubmed/24352344

– Unknown - too new

TOXICITY – Serious / Fatal

• Metformin • ?Risk of Lactic Acidosis

– 0.03 cases / 1000 pt-yrs– ~ 50% fatal– When implicated:

• Metformin plasma levels are usually >5 μg/mL• Cases - primarily diabetics w/ significant renal

insufficiency, both intrinsic renal disease and renal hypoperfusion, w/ multiple medical/surgical problems and multiple medications.

Metformin Dosing• Dosing recommendations with renal insufficiency:

– (CONTROVERSIAL)• CrCl 60ml/min→

– 1700 mg/day (Rxfiles)– 2.5g/day (Roland)

• CrCl 30ml/min→ – 850mg/day (Rxfiles)– 2.5g/day (Roland)

• CrCl < 30ml/min→– Contraindicated (Rxfiles)– 1g/day (>20mL/min) (Roland) If NO other risk factors, else D/C.

– Take home: assess OTHER RISK FACTORS for L.A.

• Severe renal impairment – (caution if CrCl < 30ml/min)

and• Hepatic disease • alcoholism• CHF• COPD• CRF • Pneumonia• Ongoing acidosis

– Lactic, keto etc.

Risk Factors - Lactic Acidosis

TOXICITY - Bothersome

1) METFORMIN– GI upset / diarrhea – Start low, go slow!

• Initial dose 250mg QDaily to BID– B12 / folate deficiency / anemia (6 - 8/100)

• Reduced absorption – so, supplement– Anorexia – usually transient– Metallic taste

TOXICITY - Bothersome

2) Sulfonylureas:– Sulfa skin reactions

• Rash / photosensitivity ~1%– Weight gain (2-3kg)– Mild Hypoglycemia:

• Most with glyburide. Least w/ glimepiride & gliclazide• Requires consistent food intake• Major episodes 1-2% (esp. in elderly)

TOXICITY - Bothersome3) Glitazones:

– Edema4) Meglitinides:

– Hypoglycemia5) Acarbose:

– GI upset / diarrhea / bloating6) Gliptins:

• GI upset, edema, ?infection7) Incretin analogues

• N/V/D, ?infection8) SGLT2 inhibitors

HyperK+, ARF, GU infection

Cost – Ask…

• Patient cost vs societal cost

• Rx cost?• ODB coverage? • Covered under other plans?

Cost• From Rxfiles May 2013

– (N.B. June 2015 costs ~ same)• Cost per 100 days therapy

(in Sask.)

• Alternatively, check ODB e-formulary– N.B. Not true pt costs– Comparative costs

http://www.rxfiles.ca/rxfiles/uploads/documents/members/cht-diabetes.pdf

Convenience

• PO vs IV?• QD vs QID?

Convenience

• Gliptin’s - QD• Glitazones - QD• SGLT2 inh - QD• Sulfonylureas – QD to BID• Metformin - QD to TID• Meglitinides – QD to TID with meals• Acarbose – QD to TID

• 1st line – METFORMIN • 2nd line - SULFONYLUREA or INSULIN

– Meglitinide – if poor CrCL or irregular eating

• 3rd line – any other hypoglycemic if patients absolutely REFUSE insulin

NEVER USE GLITAZONEs!Did I say, never? I meant NEVER!

Individualization of Drug TherapyPatient Factor Consider→ Possibly preferred drugs

Renal Failure Repaglinide, Acarbose, ‘GliptinsAlso: insulin

Hepatic Disease Insulin, repaglinide, acarbose, Caution: glyburide, metformin, glitazones

Hyoglycemia Metformin, Acarbose, (DPP4 inh),(SGLT2 inh)Also, repaglinide, gliclazide

Obese Metformin, Acarbose

Irregular Mealtimes Repaglinide (may be preferred over SU)

PPBG >10mmol/L and FBG minimally ↑’d

Repaglinide or AcarboseRapid insulin if PPBG very high

www.rxfiles.ca

Questions?