Download Oral Hypoglycemics - Bruyere/Primrose Units

Oral Hypoglycemics
Roland Halil, BScPharm, ACPR, PharmD
Clinical Pharmacist, Bruyere Academic Family Health Team
Assistant 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
2-hour
And/or after
OGTT
IFG
6.1-6.9
IFG (isolated)
6.1-6.9
IGT (Isolated)
< 6.1
7.8-11.0
6.1-6.9
7.8-11.0
IFG and IGT
N/A
AND
< 7.8
Can J Diabetes 2003;27(2);S11
Diabetes: complications
MACROvascular
Stroke
Heart disease
&
hypertension
MICROvascular
Diabetic eye
disease
(retinopathy &
cataracts)
Nephropathy
Peripheral
vascular disease
Neuropathy
Foot problems
Foot problems
Kumamoto Study – HbA1c & Complications
• Intensive vs. conventional insulin therapy (N=110)
• Median A1c - 7.1% vs. 9.4%
16
14
Retinopathy
16
14
12
Nephropathy
12
10
10
8
8
6
6
4
2
0
7%
5
6
7
7%
4
2
0
8
9
HbA1c (%)
10 11
5
6
7
8
9
HbA1c (%)
10
11
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 Studies
Study
Drug
DPP
Metformin
850mg BID
2.8
31
STOPNIDDM
Acarbose 100mg
TID
3.3
30
DREAM
Rosiglitazone
8mg daily
3.0
55
Orlistat 120mg
TID
4.0
37
XENDOS
Duration
(years)
RRR (%)
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
Secretagogues
• Metformin
• Glitazones
• Sulfonylureas
– Eg. Glyburide, Gliclazide
• Meglitinides
– Rosiglitazone (AVANDIA)
– Pioglitazone (ACTOS)
– Eg Repaglinide (GLUCONORM)
Other
• Alpha glucosidase inhibitors (Acarbose)
SGLT2 inhibitors (Canagliflozin)(Dapagliflozin )
• DPP4 inhibitors (Gliptins)
Incretin (GLP1) Analogues
• Sitagliptin,
Linagliptin
• Saxagliptin,
Alogliptin
* Liraglutide
(VICTOZA) (sc inj)
* 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 Outcomes
a) Any mortality benefit?
b) Any morbidity benefit?
Then,
2. SURROGATE Outcomes
a) Clinically relevant?
EFFICACY
1. HARD Outcomes
–
Mortality benefit
– Metformin – UKPDS-34 trial
–
Morbidity
– Reduction in microvascular complications (nephropathy,
retinopathy, neuropathy)
2. SURROGATE Outcomes
a) 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?)
EFFICACY
A) Surrogate Outcome - Hgb-A1c
–
~ 1% to 2%
•
•
•
•
•
–
Metformin
Sulfonylureas
Repaglinide
Glitazones (TZDs)
Canagliflozin
(1% - 2%)
(1% - 2%)
(1% - 1.5%)
(0.4% - 1.5%)
(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
–
–
–
–
• Secretatgogues
CHF
Fractures
M.I.
(Sulfonylureas &
Meglitinides)
•
– Severe Hypoglycemia
(rosiglitazone)
Bladder Cancer
•
(pioglitazone)
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/ucm44
6845.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.
Risk Factors - Lactic Acidosis
• Severe renal impairment
– (caution if CrCl < 30ml/min)
and
•
•
•
•
•
•
•
Hepatic disease
alcoholism
CHF
COPD
CRF
Pneumonia
Ongoing acidosis
– Lactic, keto etc.
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 - Bothersome
3) Glitazones:
–
Edema
4) Meglitinides:
–
Hypoglycemia
5) Acarbose:
–
GI upset / diarrhea / bloating
6) Gliptins:
•
GI upset, edema, ?infection
7) Incretin analogues
•
N/V/D, ?infection
8) 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 eformulary
– 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!
www.rxfiles.ca
Individualization of Drug Therapy
Patient Factor
Consider→ Possibly preferred drugs
Renal Failure
Repaglinide, Acarbose, ‘Gliptins
Also: 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 Acarbose
Rapid insulin if PPBG very high
Questions?