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 2-hour after OGTT And/or IFG
N/A
IFG (isolated)
AND
< 7.8
IGT (Isolated)
< 6.1
IFG and IGT
If FPG + risk factor for diabetes/IGT order a 2hPG in a 75-OGTT.
If and no risk factor then IFG.
Can J Diabetes 2003;27(2);S11

4. Diabetes: complications
MACROvascular
MICROvascular
Stroke
Diabetic eye
disease
(retinopathy & cataracts)
Heart disease & hypertension
Nephropathy
Peripheral vascular disease
Neuropathy
Foot problems
Foot problems

5. Kumamoto Study – HbA1c & Complications
Intensive vs. conventional insulin therapy (N=110)
Median A1c % vs. 9.4%
Retinopathy 16
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 5 6 7 8 9 10 11 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
> 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
***Based on the Finnish Diabetes Prevention Study and the Diabetes Prevention Program.
Can J Diabetes 2003;27(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
DPP
Diabetes Prevention Program
Metformin was more effective in younger more obese subjects and less effective among older, thinner people.
STOP-NIDDM
- Study to Prevent Non-Insulin Dependent Diabetes Mellitus
TRIPOD
Troglitazone in Prevention of Diabetes
This glitazone was withdrawn from the market and was never availabe in Canada
XENDOS
Xenical in the prevention of diabetes in obese swedish subjects
Prouded an average weight loss of 5.8 kg
DREAM
Published Sept 2006.
Included patients with IFG or IGT or both.

8. Non-Pharmacologic Tx Mainstay of therapy! Nutrition therapy ↓ A1c 1-2%
CDA recommends counseling by a dietician for all type 2 diabetics
diet for Type 2 diabetes
Can J Diabetes 2003;27(2);S27

9. Comparison of antihyperglycemics
Pharmacotherapy
Comparison of antihyperglycemics

10. Drug Classes
Sensitizers
Secretagogues
Other

11. Drug Classes Sensitizers Secretagogues Other 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 Sensitizers – reduce insulin resistance
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 Secretagogues
↑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)

14. 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

15. Rational Prescribing FOUR steps to Rational Prescribing: EFFICACY
TOXICITY
COST
CONVENIENCE

16. EFFICACY – Ask… HARD Outcomes SURROGATE Outcomes
Any mortality benefit?
Any morbidity benefit?
Then,
SURROGATE Outcomes
Clinically relevant?

17. EFFICACY HARD Outcomes SURROGATE Outcomes Mortality benefit Morbidity
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% 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?)

19. EFFICACY A) Surrogate Outcome - Hgb-A1c ~ 1% to 2% ~ 0.5% to 0.8%
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.

20. 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

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.”
Unknown – too new
Incretin Analogues – (Liraglutide, Exenatide (sc inj))
&
DPP4 inhibitors (‘gliptins)
?Heart failure
?Pancreatitis
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 >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.

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)
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.

26. 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.

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: 4) Meglitinides: 5) Acarbose:
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 Cost per 100 days therapy (in Sask.)
(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

32. Convenience
PO vs IV?
QD vs QID?

33. 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

35. Did I say, never? I meant NEVER!
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
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

37. Questions?