Oral Hypoglycemics

1
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

2
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.

3
Diagnosis of IFG, IGT
Category FPG And/or 2-hour after OGTT
IFG 6.1-6.9 N/A
IFG (isolated) 6.1-6.9 AND lt 7.8
IGT (Isolated) lt 6.1 7.8-11.0
IFG and IGT 6.1-6.9 7.8-11.0
Can J Diabetes 200327(2)S11
4
Diabetes complications
MACROvascular
MICROvascular
Diabetic eye disease (retinopathy cataracts)
Stroke
Heart disease hypertension
Nephropathy
Peripheral vascular disease
Neuropathy
Foot problems
Foot problems
5
Kumamoto Study HbA1c Complications

• Intensive vs. conventional insulin therapy
  (N110)
• Median A1c - 7.1 vs. 9.4

16
Retinopathy
Nephropathy
16
14
14
12
12
Rate per patient-years
Rate per patient-years
10
10
8
8
6
6
7
7
4
4
2
2
0
0
11
10
9
8
7
6
5
5
6
7
8
9
10
11
HbA1c ()
HbA1c ()
6
Prevention of Diabetes in IGT

• Lifestyle modification
• (see Finnish Diabetes Trial)
• Moderate weight loss (5) (esp. abd fat)
• Regular physical activity
• gt 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 200327(2)S12
7
Pharmacological Prevention Studies
Study Drug Duration (years) RRR ()
DPP Metformin 850mg BID 2.8 31
STOP-NIDDM Acarbose 100mg TID 3.3 30
DREAM Rosiglitazone 8mg daily 3.0 55
XENDOS Orlistat 120mg TID 4.0 37
8
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 200327(2)S27
9
Pharmacotherapy

• Comparison of antihyperglycemics

10
Drug Classes

• Sensitizers

• Secretagogues

• Other

11
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)

12
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

13
Drug Classes

• ?Basal prandial insulin secretion, ?hepatic
  gluconeogenesis
• Doesnt 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)

14
Drug Classes Other

• Alpha glucosidase inhibitors (Acarbose)
• Competitive inhibitor of pancreatic a-amylase
  and intestinal brush border a-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

15
Rational Prescribing

• FOUR steps to Rational Prescribing
• EFFICACY
• TOXICITY
• COST
• CONVENIENCE

16
EFFICACY Ask

• HARD Outcomes
• Any mortality benefit?
• Any morbidity benefit?
• Then,
• SURROGATE Outcomes
• Clinically relevant?

17
EFFICACY

• HARD Outcomes
• Mortality benefit
• Metformin UKPDS-34 trial
• Morbidity
• Reduction in microvascular complications
  (nephropathy, retinopathy, neuropathy)
• SURROGATE Outcomes
• Hgb-A1c reduction
• Blood glucose level reduction
• Fasting or Prandial
• Insulin Sparing Effects

18
Effect of Metformin on Event Rates in the UKPDS

• Diabetes-related endpoint ?32 p0.002
• All-cause mortality ? 36 p0.011
• ? MI / CVA
• Diabetes-related death ? 42 p0.017
• But.. When added early to sulfonylurea
• ? risk of DM-related death (?statistical
  anomaly?)

19
EFFICACY

• A) 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)311-11.
20
EFFICACY

• B) Surrogate Outcome - Insulin Sparing Effect
• METFORMIN
• ACARBOSE
• TZDs (GLITAZONEs)
• DPP4 inh (gliptins)
• Incretin Analogues (Liraglutide, Exenatide)
• SGLT2 inh (Canagliflozin, Dapagliflozin)
• Weight neutral or weight negative
• Reduction of hyperinsulinemia

21
TOXICITY Ask

• Serious / Fatal Side Effects
• Bothersome / Common s.e.
• Age?
• Newer agents Less Safety Data
• Older agents More Safety Data

22
TOXICITY Serious / Fatal

• Glitazones
• CHF
• Fractures
• M.I.
• (rosiglitazone)
• Bladder Cancer
• (pioglitazone)

• Secretatgogues
• (Sulfonylureas
• Meglitinides)
• Severe Hypoglycemia

23
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

24
TOXICITY Serious / Fatal

• Metformin
• ?Risk of Lactic Acidosis
• 0.03 cases / 1000 pt-yrs
• 50 fatal
• When implicated
• Metformin plasma levels are usually gt5 µg/mL
• Cases - primarily diabetics w/ significant renal
  insufficiency, both intrinsic renal disease and
  renal hypoperfusion, w/ multiple medical/surgical
  problems and multiple medications.

25
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 lt 30ml/min?
• Contraindicated (Rxfiles)
• 1g/day (gt20mL/min) (Roland) If NO other risk
  factors, else D/C.
• Take home assess OTHER RISK FACTORS for L.A.

26
Risk Factors - Lactic Acidosis

• Severe renal impairment
• (caution if CrCl lt 30ml/min)
• and
• Hepatic disease
• alcoholism
• CHF
• COPD
• CRF
• Pneumonia
• Ongoing acidosis
• Lactic, keto etc.

27
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

28
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)

29
TOXICITY - Bothersome

• 3) Glitazones
• Edema
• 4) Meglitinides
• Hypoglycemia
• 5) Acarbose
• GI upset / diarrhea / bloating
• Gliptins
• GI upset, edema, ?infection
• Incretin analogues
• N/V/D, ?infection
• 8) SGLT2 inhibitors
• HyperK, ARF, GU infection

30
Cost Ask

• Patient cost vs societal cost
• Rx cost?
• ODB coverage?
• Covered under other plans?

31
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/me
mbers/cht-diabetes.pdf
32
Convenience

• PO vs IV?
• QD vs QID?

33
Convenience

• Gliptins - QD
• Glitazones - QD
• SGLT2 inh - QD
• Sulfonylureas QD to BID
• Metformin - QD to TID
• Meglitinides QD to TID with meals
• Acarbose QD to TID

34
(No Transcript)
35

• 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!

36
Individualization of Drug Therapy
www.rxfiles.ca
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 gt10mmol/L and FBG minimally ?d Repaglinide or Acarbose Rapid insulin if PPBG very high
37
Questions?