Abbotsford feb 26 2014

Even more about diabetes…

Dollars and sensible therapeutics

Sara Stafford MDCM, FRCPC26 February 2014

Abbotsford Regional Hospital

OutlineCase

Guidelines

Hypoglycemia

Driving and Diabetes

Metformin & Combination Tablets: Side Effects & Compliance

CV Risk with Oral Agents

Cost analysis & Pharmacare coverage

CDA Toolkit

Case John is 47yo man with type 2 diabetes, diagnosed 5 years

ago. He is a truck driver, and has private insurance through his work. He has hypertension and dyslipidemia, but no microvascular or macrovascular complications. His work schedule is irregular. He sometimes forgets to take his medication, and find that his metformin bothers his stomach a bit if he misses dinner on the road.

Medications: Metformin 1g bid, perindopril 4mg, atorvastatin 20mg

On examination: BMI 32.1 kg/m2, BP 127/76

Labs: A1c 7.9%, eGFR 72, urine ACR negative

Individualizing A1C Targets

which must be balanced against the risk of hypoglycemia

Consider 7.1-8.5% if:

2013

Start metformin immediately

Consider initial combination with another antihyperglycemic agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5%Symptomatic hyperglycemia with

metabolic decompensationA1C 8.5%

Initiate insulin +/-metformin

If not at glycemic target (2-3 mos)

Start / Increase metformin

If not at glycemic targets

LIFESTYLE

Add an agent best suited to the individual:

Patient CharacteristicsDegree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityComorbidities (renal, cardiac, hepatic)Preferences & access to treatmentOther

See next page…

AT DIAGNOSIS OF TYPE 2 DIABETES

Agent CharacteristicsBG lowering efficacy and durabilityRisk of inducing hypoglycemiaEffect on weightContraindications & side-effectsCost and coverageOther

2013

If not at glycemic target

From prior page…

• Add another agent from a different class• Add/Intensify insulin regimen

Make timely adjustments to attain target A1C within 3-6 months 2013

LIFESTYLE

Hypoglycemia

RISK FACTORS FOR HYPOGLYCEMIA

Risk factors for hypoglycemia1,2,3,4

Older age Renal Impairment Long duration of diabetes treatment Prior episode of severe hypoglycemia Hypoglycemia unawareness, especially during sleep Delayed, smaller, or missed meal Alcohol Recent moderate, or intensive exercise Glucose lowering medications: Secretagogues & Insulin Glycemic control – Inverse? Correlated?

1. CDA. Can J Diabetes 2008; 32:S29–S31. 2. Workgroup on Hypoglycemia, American Diabetes Association. Diabetes Care. 2005;28(5):1245-1249; 3. Frier BM. Diabetes Metab Res Rev. 2008;24(2):87-92; 4. Cryer PE. Diabetes. 2008;57(12):3169-3176.

Hypoglycemia in the Community

Based upon US public health surveillance data, adverse drug events account for 1 in 67 emergency admissions

100 000 emergency hospitalizations for ADE in adults 65+ each year

48.1% of these admissions in adults 80+

65.7% unintentional overdoses

Budnitz et al. 2011. Emergency Hospitalizations for Adverse Drug Events in Older Americans. NEJM. 365(21): 2002-2012

Adverse Drug EventsFour medications classes accounted for 67.0% of

hospitalizations:Warfarin 33.3% Insulin 13.9%Oral antiplatelet agents 13.3%Oral hypoglycemic agents 10.7%

Of hospitalizations related to diabetes medications, 94.6% were for hypoglycemia and 66.6% of these were for severe hypoglycemia (LOC, seizure, altered mental status)

Budnitz et al. 2011. Emergency Hospitalizations for Adverse Drug Events in Older Americans. NEJM. 365(21): 2002-2012

RELATIONSHIP BETWEEN SEVERE HYPOGLYCEMIA AND HbA1c

Inci

dence

per

10

0 p

ers

on-y

ears

Updated average HbA1c

6

5

4

3

2

1

0

6.0 7.0 8.0 9.0

Severe hypoglycemia correlated to poor control in intensively treated patients

HYPOGLYCEMIA UNAWARENESS IS ASSOCIATED WITH A HIGHER RATE OF SEVERE

HYPOGLYCEMIA

12

Severe

hypogly

cem

ia*

(epis

odes/

pati

en

t/year)

0

0.5

1.0

1.5

2.0

2.5

9-fold higher rate of severe hypoglycemia

0.22

2.15

Normalawareness

(n=144)

Impairedawareness

(n=13)

Severe hypoglycemia was defined as an episode requiring external assistance for recovery. Subjective changes in hypoglycemia symptom intensity were recorded by the participants based on a hypoglycemia awareness scale of 1 to 7, where 1 equals always aware and 7 equals never aware and a score of 4 or more correlates with impaired awareness.

* Based on data from a retrospective survey of 215 patients with T2DM treated with ≥2 injections of insulin daily for ≥1 year. Henderson et al. Diabetes Med. 2003;20(12):1016-21.

SEVERE HYPOGLYCEMIA INCREASES THE RISK FOR ADVERSE OUTCOMES

13

*Severe hypoglycemia is defined as blood glucose <2.8 mmol per litre with transient dysfunction of the CNS, without other apparent cause, during which the patient was unable to administer treatment (requiring help from another person).†Adjusted for multiple covariates: sex, duration of diabetes, treatment assignment, presence or absence of a history of macrovascular disease, presence or absence of a history of microvascular disease, and smoking status at baseline. Time-dependent covariates during follow-up included age; level of glycated hemoglobin; body mass index; creatinine level; ratio of urinary albumin to creatinine; systolic blood pressure; use or nonuse of sulfonylurea, metformin, thiazolidinedione, insulin, or any other diabetes drug; and use or nonuse of antihypertensive agents.‡p<0.001. CI=confidence interval. Zoungas S. N Engl J Med. 2010;363(15):1410-18.

Clinical Outcome and Interval After Hypoglycemia

Hazard Ratio(95% CI)†

Microvascular events 2.07 (1.32-3.26)‡

Macrovascular events 3.45 (2.34-5.08)‡

Death from any cause 3.30 (2.31-4.72)‡

Death from non-CV cause 2.86 (1.67-4.90)‡

Death from CV cause 3.78 (2.34-6.11)‡

Hazard ratios represent the risk of an adverse cardiovascular outcome or death among patients reporting severe hypoglycemia (<2.8 mmol/L)* as

compared with those not reporting severe hypoglycemia

Hypoglycemia & Sulphonylureas

Hypoglycemia in Patients with Antihyperglycemic Therapy

15AHA = antihyperglycemic agent; CI = confidence interval; DPP-4 = dipeptidyl peptidase 4; OR = odds ratioAdapted from: Tschöpe D et al. Cardiovasc Diabetol 2011; 10:66.

MetforminSulfonylureasGlucosidase inhibitorsGlinidesThiazolidinedionesDPP-4 inhibitorsAHA monotherapyAHA dual combination therapy

SulfonylureasGlucosidase inhibitorsGlinidesThiazolidinedionesDPP-4 inhibitors

0.64 (0.50–0.82)2.16 (1.75–2.67)0.41 (0.17–1.02)1.29 (0.82–2.02)0.87 (0.56–1.36)0.60 (0.34–1.07)0.72 (0.58–0.89)1.39 (1.13–1.72)

2.08 (1.44–2.99)0.22 (0.03–1.60)0.87 (0.46–1.63)0.50 (0.28–0.89)0.34 (0.16–0.72)

1.0 10.00.10.01

OR (95% CI)

Add-o

n t

o

metf

orm

in

Less frequent More frequent

Monoth

era

py

Meta-analysis of Hypoglycemia:

Glyburide vs. Other Secretagogues

16CI = confidence interval; RR = relative riskAdapted from: Gangji AS et al. Diabetes Care 2007; 30(2):389-94.

Baba 1983Dills 1996Draeger 1996Haider 1976Hamblin 1970Harrower 1994Landgraf 1999Mafauzy 2002Marbury 1999Rosenstock 1993UKPDS 13 1995Wolffenbuttel 1999

Total (95% CI)

GliclazideGlimipirideGlimipirideChlorpropamideChlorpropamideGliclazideRepaglinideRepaglinideRepaglinideGlipizideChlorpropamideRepaglinide

1.08–4.590.94–2.130.90–1.710.26–07.810.72–15.050.77–16.760.39–2.240.66–2.310.86–1.810.32–27.741.78–3.200.55–1.94

1.21–1.92

2.231.421.245.263.293.580.931.231.252.962.391.03

1.52

RR, 95% CI RR (95% CI)

Glyburide more

Secretogogue more

Test for heterogeneity I2 = 42.1% 0.1 0.2 0.5 1 2 5 10

R

Proportion of patients experiencing minor hypoglycemia at study end

0%

5%

10%

15%

20%

25%

30%

35%

8.9%10.1%

3.3%

29.0%

4.5% 5.3% 5.3%

0.6%2.8%

0.8%2.5% 2.5%

16.9%

Prop

ortio

n of

Pati

ents

(%)

SAXAn=191

PBOn=179

SITAn=979

SUn=748

EXE 5 μgn=110

EXE 10 μgn=113

PBOn=113

LIRA 1.2 mgn=240

LIRA 1.8 mgn=242

PBOn=121

SUn=242

Saxagliptin 5 mg QD + MET

Sitagliptin 100 mg QD + MET

Exenatide 5 μg BID + METExenatide 10 μg BID + METLiraglutide 1.2 mg QD + METLiraglutide 1.8 mg QD + METSulphonylurea + METPlacebo + MET

Linagliptin 5 mg QD + MET

LINAn=523

PBOn=177

SU=sulphonylurea; MET=Metformin. Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2013; Sitagliptin Canadian Product Monograph, Merck Frosst, 2013.; Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2013; Exenatide Canadian Product Monograph, Bristol Myers Squibb, 2013. Linagliptin

Canadian Product Monograph. Boehringher Ingelheim (Canada) Ltd. 2012. Pratley R et al. Lancet 2010;375:1447-56.

Sitagliptin 100 mg QDGlipizide

Proportion of patients achieving HbA1c goal of <7% after 52 weeks

30.0

70.0

40.0

50.0

20.0

60.0

% o

f pat

ient

s to

HbA

1c g

oal

62.8%

58.9%

HbA1c <7% at 52 weeks

Nauck MA, et al. Diabetes Obes Metab. 2007;9:194–205.

Add on to metformin: Sitagliptin Was Noninferior to Sulphonylureas in

Reducing HbA1c

0 12 24 38 52 60 78 91 104

HbA

1c (%

)

Weeks

Glipizide (up to 20 mg/d; mean 9.5 mg/d)+metformin (n=256)Sitagliptin (100 mg/day)+metformin (n=248)

5.8

6.2

6.6

7.0

7.4

7.8

CI=confidence interval; LS=least-squares; SD=standard deviation.SE=standard error.

Difference in LS Mean HbA1c= -0.03(95% CI: –0.13, 0.07)

Per-Protocol PopulationLS mean change from baseline at 30 weeks

(for both groups): –0.5%

1. Seck T, et al; Sitagliptin Study 024 Group. Int J Clin Pract. 2010;64(5):562-576.2. Arechavaleta R, et al. Diabetes Obes Metab. 2011;13(2):160-168.

HbA

1c (%

)

0 6 12 18 24 306.0

6.4

6.8

7.2

7.6

8.0

Glimepiride (up to 6 mg/d; mean 2.1 mg/d)+metformin (n=436)Sitagliptin (100 mg/d)+metformin (n=443)

Weeks

Hypoglycemia Over 30 WeeksBetween groups difference =

–15.0%

Hypoglycemia over 104 weeks

Between-groups difference = –28.8%

0

10

20

30

40

50

系列 1

0

10

20

30

40

50

系列 1

APaT=all-patients-as-treated; CI=confidence interval; LS=least-squares.

1. Seck T, et al; Sitagliptin Study 024 Group. Int J Clin Pract. 2010;64(5):562-576.2. Arechavaleta R, et al. Diabetes Obes Metab. 2011;13(2):160-168.

Despite Similar Glycemic Efficacy to Sulphonylureas, Sitagliptin are Associated

with a Lower Risk of Hypoglycaemia

P<0.001

P<0.001

Network meta-analysis comparing antihyperglycemic drugs as add-on to metformin

Mean difference from placebo

*All statistically significant vs. placebo. TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4. 1. Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820.

A1C reductions with antihyperglycemic agents

AGIs DPP-4i GLP-1 RABasalinsulin

PremixedinsulinMeglitinides SUs TZDs

21

Network meta-analysis comparing antihyperglycemic drugs as add-on to metformin

Odds ratio vs. placebo

*Statistically significant vs. placebo. TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4. 1. Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820.

Overall risk of hypoglycemia

AGIsDPP-4i GLP-1 RABasalinsulin

Premixedinsulin

Meglitinides SUs TZDsPlacebo (Ref)

22

Hypoglycemia & Driving in BC: OSMV Regulations

Drivers who have a medical condition that has the potential to affect their fitness to drive may be required to have their doctor complete a Driver’s Medical Examination Report (DMER)

The type and frequency of assessment varies by the class of licence, as well as the type and control of diabetes

Class 5-8 Licences

Type 2 Not Treated with Insulin or Secretagogues

DMER required

Report to OSMV if beginning insulin

Remain under medical supervision to monitor for progression or complications

Reassess q5y, or if starting insulin or secretagogues

Type 2 Treated with Secretagogues

DMER Required

Fit to drive if: Good understanding of diabetes Follow medical care & supervision

Report if: begin insulin, episode of severe hypoglycemia

Stop driving if hypoglycemia suspected

Not drive for at least 45min after treating BG 2.5-4.0mM

Reassess q5y unless unstable or insulin initiated

Diabetes treated with insulin (Type 1 or 2)

DMER Required

Fit to drive if: Understand diabetes, follow medical care and supervision

Report if episode of severe hypoglycemia or hypoglycemia unawareness

On long drives: check BG before driving and q4h Carry carbohydrates not drive if BG <4.0 prophylactically treat if BG 4.0-5.0 not drive for 45 min after treating BG 2.5-4.0

Reassess q5y if stable

Drivers with an episode of severe hypoglycemia

DMER required

Report to OSMV if episode of severe hypoglycemia

For next 6m, test BG immediately before driving and q1h

For next 6m, not drive if BG <6.0mM

Once no episodes of severe hypoglycemia for 6 months, regular guidelines

Class 1-4 Licences

Type 2 Diabetes – Not Treated with insulin or

secretagoguesDMER required

Report if beginning insulin

Remain under medical supervision to monitor for progression or complications

Reassess q5y, or if insulin or secretagogue therapy initiated

Type 2 treated with secretagogues

DMER required

Fit to drive if good understanding of diabetes, and following instructions, remain under medical supervision

Report if beginning insulin, experience severe hypoglycemia

Stop driving if hypoglycemia suspected

Do not drive for at least 45 min after treating BG 2.5-4.0mM

Reassess q1y or if initiating insulin

Diabetes treated with insulin (type 1 or 2)

Diabetic Package: DMER (MD), Diabetic Driver Report (MD), Driver’s Diabetes Questionnaire (patient), Exam of Visual Function (optho or opto)

Log of BG performed at least twice daily

Fit to drive if: Certificate of competence from DEC MD has approved work schedule as compatible with your insulin

regimen No uncontrolled diabetes (A1c >12% or >10% of BG < 4.0mM) No significant changes to insulin therapy No indication of lack of compliance

Must carry supplies (monitor, CHO) when driving

Test BG <1h before driving and q4h while driving, not drive if BG falls below 6.0mM

Drivers who have had severe hypoglycemia

DMER Required

Fit to drive if: Log of BG at least 4/d, less than 5% below 4.0mM Re-established stable glycemic control

Report to OSMV if episode of severe hypoglycemia

For the next 6m, test BG immediately before driving and q1h while driving

Not drive or stop if BG <6.0mM

Reassess q1y

Side Effects & Compliance

MetforminMetformin remains first-line therapy for type 2

diabetes

Standard dosing is 1g po bid

Higher doses (e.g. 1g/500mg/1g) do not improve glycemic control but are associated with more gastrointestinal side effects and reduced compliance (tid dosing)

Metformin Dose-Response

0

20

40

60

80

100

0

0.5

1

1.5

2

2.5

3

500 1000 1500 2000 2500

Dec

reas

e in

FP

G f

rom

Pla

ceb

o [m

g/d

l]

DE

CR

EA

SE

IN H

BA

1C FR

OM

P

LA

CE

BO

[%]

Dose [mg/d]Garber et al. Am J Med 1997; 102:491

Metformin Dose-Response Curve

30

20

10

0 500 1000 1500 2000 25000

0,5

1,0

1,5

2,0

Dose

Red

ucti

on

in

A1

C (

%)

% o

f pts

with

gastro

inte

stin

al c

om

pla

ints

Riddle M. Am J Med. 2000;108(6A):15S-22S

Starting metforminStart with metformin 250mg once daily with

largest meal

Ask patient to slowly increase dosing in 250mg increments 250mg bid500mg AC-B, 250mg AC-S500mg bid

…

Target 1g bid

Metformin XRStandard, immediate release metformin is

limited by:

Bid or tid dosing leading to poor complianceParticularly problematic for patients on multiple

different medications

GI symptoms affecting up to 25% of patients, leading to cessation of drug in 5-10% of patients

Adapted from Levy J et al. Diabetol Metab Syndr 2010, 2:161- Garber AJ et al. Am J Med 1997; 103: 491.

Metformin XR – Equivalent Efficacy to Standard Metformin

Adapted from Schwartz S et al. Diabetes Care. 2006 Apr;29(4):759-64.

Randomized, double blind, active-controlled study. *Significant change from baseline within each treatment group (P < 0.001), intent-to-treat population. N = 706 T2DM, A1c ~8.4%, Age ~54years, ~54% Male, BMI~33, ~48% Drug Naïve, Diabetes Duration ~4.2 years † 500 mg in the morning and 1,000 mg in the evening

Treatment Week

0 4 8 12

16

20

24

5

6

7

8

9

10

Hb

A1

c

(%)

Metformin XR 1500 mg QD

Metformin XR 1500 mg (AM/PM) †

Metformin XR 2000 mg QD

Metformin IR 1500 mg (AM/PM) †

** *

0 4 8 12

16

20

24Treatment

Week

5.6

6.7

7.8

8.9

10

11.1

12.2

Fasti

ng

Pla

sm

a

Glu

cose (

mm

ol/

L)

**

* * * * * *

Metformin XR – Improved Tolerability

Adapted from Schwartz S et al. Diabetes Care. 2006 Apr;29(4):759-64.

Any gastroin-testinal event

Diarrhea Nausea0

5

10

15

20

25

18.9

6.9

2.9

15.5

8.3

3.9

20.7

8.9

2.4

19.3

10.5

8.2*

Extended-Release Metformin

Randomized, double blind, active-controlled study. N = 706 T2DM, A1c ~8.4%, Age ~54years, ~54% Male, BMI~33, ~48% Drug Naïve, Diabetes Duration ~4.2 years, † 500 mg in the morning and 1,000 mg in the evening

*p<0.050

Incid

en

ce (

%)

du

rin

gd

osin

g a

t 1000 m

g o

.d. 1500mg qd

1500mg bid

2000mg qd

IR 1500mg bid

Metformin XR – Improved Tolerability in Patients Switched from Standard

Metformin

Adapted from Levy J et al. Diabetol Metab Syndr 2010, 2:16

Open-label, prospective 24-week study conducted in hospital based outpatients (n=61) with type 2 diabetes Incidence of Gastrointestinal side effects before and after switchover to extended release metformin XR in patients completing the 6 month study. The metformin daily dose at baseline and following titration of metformin XR was 1861 +/- 711 mg and 1500 +/- 402 mg per day (p = 0.004) respectively

Total of 77% of patients were free of gastrointestinal side effects and 83% of patients stated a preference for metformin XR

Incid

en

ce (

%)

Metformin-IR Metformin-XR

0

20

30

10

40

50

60

Diarrhea

Nausea Abdominal pain

Epigastric pain

Diarrhea Nausea Vomiting

**

*

*vs metformin IR p = 0.013

Metformin XR – Improved Patient Adherence When Switched from

Standard Metformin

Adapted from Donnelly LA et al. Diabetes Obes Metab. 2009 Apr;11(4):338-42.

Metformin IR (n=10 019)

Metformin XL (n=80)

68

70

72

74

76

78

80

82

72%

80%

Adherence (%), Overall Population

Metformin IR (n=40)

Metformin XL (n=40)

50

55

60

65

70

75

80

85

90

62%

81%

Adherence (%) Before & After Switch from Standard

Metformin* p = 0.0026

Retrospective observational study, T2DM patients from a single diabetes clinic in Scotland

* p = 0.0001

Effect of Medication Dosing Frequency on Adherence in T2DM

– Systematic Review

Adapted from Saini SD et al. Am J Manag Care. 2009 Jun 1;15(6):e22-33.

QD dosing BID or TID0%

2500%

5000%

7500%

10000%

79% to 94%.

38% to 67%.

Adherence Range

(%)

Differences in adherence

ranged from 13% to 41%*

Study selection criteria included the use of MEMS to measure adherence

*with all studies reporting the differences across regimens to be statistically significant.

Adjusted Adherence to Oral Antidiabetic Therapy: A Comparison of Monotherapy, Combination

Therapy, and Fixed-Dose Combination Therapy

0

20

40

60

80

100

54

P<0.001

P<0.001

7771

87

Melikian C et al. Clin Ther 2002;24:460

Metformin and Glyburide

Metformin/Glyburide

Previously on Monotherapy

Metformin and Glyburide

Metformin/Glyburide

Previously on both, then switch to FDC

Adhe

renc

e Ra

te (%

)

Retrospective database analysis of pharmacy claims

A1c >7.5%, drug naïve, mono- vs combination therapy

At Week 18, the mean HbA1c change from baseline was -2.4% (95% CI: -2.5,-2.2) for sitagliptin/metformin FDC and -1.8% (95% CI: -1.9,-1.6) for metformin monotherapy,

10

9

8

70 6 12 18

% H

bA

1c (

LS

Mea

n±

SE

)

Week

Sitagliptin/Metformin FDCMetformin monotherapy

Difference in change from baseline = −0.6%; p<0.001

Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644

Change from baseline in HbA1c at Week 18 presented by baseline HbA1c subgroup

Sitagliptin/Metformin FDCMetformin monotherapy

**

**

**p<0.001

0.0

-0.5

-1.0

-1.5

-2.0

-3.0

-4.0

-2.5

-3.5

HbA1c (%) at baseline ≤ median (9.70%)

HbA1c (%) at baseline > median (9.70%)

N=288 N=291 N=271 N=273

Ch

ang

e fr

om

bas

elin

e in

Hb

A1c

(%

) at

Wee

k 18

(L

S M

ean

± S

E)


Initial Combination Therapy with Sitagliptin and Metformin

Summary of Adverse Events

*Drug-related, considered by the study investigator to be possibly, probably or definitely drug-related.

Sita/Met FDC(N = 625)

n (%)

Metformin (N = 621)

n (%)

One or more AEs 271 (43.4) 303 (48.5)

Drug-related* AEs 109 (17.4) 118 (18.7)

Serious AEs (SAEs) 13 (2.1) 20 (3.2)

Drug related* Serious AEs 1 (0.2) 1 (0.2)

Deaths 1 (0.2) 1 (0.2)

Discontinued due to AEs 25 (4.0) 25 (4.0)

Discontinued due to drug-related* AEs 18 (2.9) 16 (2.6)

Discontinued due to SAEs 6 (1.0) 5 (0.8)

Discontinued due to serious drug-related* AEs 1 (0.2) 1 (0.2)


Initial Combination Therapy with Sitagliptin and Metformin

Incidence Rates for Gastrointestinal AEs of Interest

Inci

den

ce R

ates

(%

)

Diarrhea Nausea VomitingAbdominal Pain*

P<0.05

P<0.05

*Includes abdominal pain lower, abdominal pain upper, abdominal pain, abdominal discomfort and epigastric pain.

P=0.622

P=0.735

12.0

5.6

2.9

16.6

6.3

2.61.1

3.9

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

Sita/Met FDC (n=625)Metformin (n=621)

P=0.002

P=0.612

P=0.742

P=0.021


Kaplan-Meier curves for the Addition of AHAs over Time by Treatment Group

Metformin

Sita/Met FDCC

um

ula

tive

Per

cen

tag

e o

f P

atie

nts

0

12

8

4

24

20

16

Time to First Additional AHA (Weeks)Patients at Risk

Sita/Met FDC 625 563 514 472 414 264

Metformin 621 562 509 458 374 238

0 6 12 18 31 44

Olansky L et al Diabetes, Obesity and Metabolism 2011;13: 841–9

CV Risk with Oral Agents?

Mortality and Cardiovascular Risk With Different Secretagogues1

MI=myocardial infarction; SU=sulfonylurea.1. Schramm TK et al. Eur Heart J. 2011; 32:1900–1908.

No Prior MI Prior MI

Metformin

Gliclazide

Glimepiride

Glibenclamide

Glipizide

Tolbutamide

Repaglinide

0 1 2

MI, Stroke, and Cardiovascular Death

Hazard Ratios (95% confidence intervals)

11.29 (1.20, 1.39)1.18 (1.02, 1.36)1.16 (1.04, 1.29)1.24 (1.09, 1.40)1.17 (1.03, 1.33)0.87 (0.49, 1.54)

Metformin

Gliclazide

Glimepiride

Glibenclamide

Glipizide

Tolbutamide

Repaglinide

0 1 2

Hazard Ratios (95% confidence intervals)

1

1.22 (1.30, 1.46)

0.71 (0.52, 1.99)

1.10 (0.85, 1.41) 1.54 (1.12, 2.10)1.44 (1.01, 2.05)1.10 (0.67, 1.82)

MI, Stroke, and Cardiovascular Death

Cardiovascular outcomes were assessed in Danish patients who initiated an insulin secretagogue or metformin as monotherapy between 1997 and 2006

– 75,354 patients were eligible for propensity score matching, including 6,448 with prior MI

010203040506070

Metformin Glipizide

Events

60**

metformin composite CV event HR 0.54 (95%CI 0.30–0.90; P = 0.026 adjusted for baseline diabetes duration, CAD duration, age, sex,

smoking hx

43*

p = 0.026

Co

mp

osi

te C

V e

ven

ts a

fte

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ars

Hong J. et al. Diabetes Care 2013 36(5)

Composite CV events (ITT analysis)**Glipizide: 14 deaths [11 CV, 3 sudden], 6 nonfatal MI, 15 nonfatal strokes, 25 revascularizations,

* Metformin:7 deaths [all CV], 5 nonfatal MI,10 nonfatal strokes, 21 revascularizations

CV events: Met vs. SU

DPP-4 inhibitors and MACEMeta-analysis of available RCTs

MACE

All

Sitagliptin

Vildagliptin

Saxagliptin

Linagliptin

Alogliptin

Events MH-OR

595 0.71 [0.59–0.86]

144 0.86 [0.60–1.24]

149 0.61 [0.43–0.86]

108 0.67 [0.45–0.99]

78 0.72 [0.45–1.16]

16 0.86 [0.25–2.93]

MH-OR, Mantel–Henzel odds ratio.Monami M, et al. Diabetes Obes Metab 2013;15:112–20.

Ongoing Cardiovascular Outcome Trials With DPP-4 Inhibitors

55

SitagliptinTECOS1

Start: Dec 2008Estimated Proj. Completion: Dec 2014N = 14,000

Sitagliptin vs Placebo added to stable doses of either monotherapy or dual combination therapy with metformin, pioglitazone, or a sulphonylurea

AlogliptinEXAMINE2,5

Start: Sept 2009Estimated Proj. Completion: Dec 2014N = 5,400

5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) randomized to alogliptin vs placebo

SaxagliptinSAVOR3,6

Start: May 2010Estimated Proj. Completion: April 2014N = 16,500

16,500 patients with T2DM either treatment naive or on any background antidiabetic treatment (except incretin therapy) with history of established cardiovascular (CV) disease or multiple risk factors randomized 1:1 to saxagliptin vs. placebo

LinagliptinCAROLINA4

Start: Oct 2010Estimated Proj. Completion: Sept 2018N = 6,000

head-to-head cardiovascular outcome study comparing linagliptin with glimepiride

CV=cardiovascular; DPP-4=dipeptidyl peptidase-4; MI=myocardial infarction.ClinicalTrials.gov NCT identifiers: 1. 00790205; 2. 00968708; 3. 01107886; 4. 01243424.5. White W et al. Am Heart J. 2011;162:620-626; 6. Scirica B et al. Am Heart J. 2011;162:818-825.

Cost

BC Statistics2013 2020 (estimated)

Prevalence 8.3% 10.3%

Number of people with diabetes

400 253 548 000

Number of people with type 1

31 356 35 522

Cost $1.5B $1.9B

Prevalence Increase 37%

Cost Increase 25%

Out-of Pocket CostType 1 Diabetes

Income < $15K: $475 (3.3%) Income $43K: $1925 (4.5%) Income $75K: $2481 (3.3%)

Type 2 Diabetes Income < $15K: $2033 (6.8%) Income $43K: $2313 (5.4%) Income $75K: $2880 (3.8%)

90 d supply Metformin 1g bid $42

Glyburide 10mg bid $37

Diamicron MR 60mg tabs, 120mg qAM $67

Gliclazide MR 30mg tabs, 120mg qAM $75

Sitagliptin (Januvia) 100mg $324

Linagliptin (Trajenta) 5mg $251

Liraglutide (Victoza) 1.2mg $546

Janumet 50/1000mg bid or Janumet XR $350

Jentadueto 2.5/1000mg bid $263

Lantus 20 U qHS $123 plus Needles $35

Fair Pharmacare Assistance Levels -

Regular

Family Net Income

Family Deductible

Portion Pharmacare Pays after Deductible

Family Maximum (Pharmacare pays 100% once maximum met)

< $15 000 0 70% $300

$30 000 $900 70% $1200

$60 000 $1800 70% $2400

$90 000 $2750 70% $3675

$120 000 $3500 70% $4675

Fair Pharmacare Assistance Levels –

Enhanced (born before 1939)

Family Net Income

Family Deductible

Portion Pharmacare Pays after Deductible

Family Maximum (Pharmacare pays 100% once maximum met)

$15 000 0 70% $200

$30 000 0 70% $400

$60 000 $1200 70% $1800

$90 000 $1800 70% $2700

$120 000 $2500 70% $3750

Pharmacare coverageFully or partially covered:

aspart, glulisine, lispro, regular insulin, glyburide, tolbutamide, metformin (glucophage & glumetza)

Only if meeting eligibility criteria and preapproved by BC drug formulary: sitagliptin, sitagliptin & metformin (Janumet), linagliptin,

NPH, detemir, glargine, gliclazide, pioglitazone

Not available through BC drug formulary: saxagliptin, liraglutide, exenatide, glimepiride,

nateglindine, repaglinide, linagliptin & metformin (Jentadueto), rosiglitizone

Removed from formulary: acarbose

Pharmacare eligbilityGliclazide: Treatment failure or intolerance with

glyburideHypoglycemia)

Sitagliptin, Sitagliptin/Metformin, Linagliptin: When insulin NPH is not an optionANDAfter inadequate glycemic control on maximum

tolerated doses of dual therapy of metformin AND a sulphonylurea

Pharmacare EligibilityGlargine or Detemir:

Type 1 (any age), Type 2 (age > 17y)Currently taking NPH and/or pre-mix at optimal

dosing

ANDHas experienced unexplained nocturnal hypoglycemia

at least once a month despite optimal management

OrHas experienced or continues to experience severe

systemic or local allergic reaction to existing insulin treatment

Private Insurance?Don’t forget that many private insurance

programs for public employees (teachers, nurses, etc.) are now based upon the BC drug formulary

CDA Toolkit

Available at guidelines.diabetes.ca

The CDA website has new interactive tools to help tailor treatment to your patient

67

http://guidelines.diabetes.ca/

Relative A1C lowering

Change in body weight


Cost

Alpha glucosidase inhibitor (acarbose)

Neutral to Rare $$

DPP-4 inhibitors Neutral to Rare $$$

GLP-1 receptor agonists to Rare $$$$

Insulin Yes $-$$$$

Meglitinides Yes $$

Sulfonylureas Yes $

TZDs Rare $$

Weight loss agent (orlistat)

None $$$

A1C kg hypo $

What is important to your patient?

TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

Comparing antihyperglycemic agents

CDA 2013 Clinical Practice Guidelines

68




Cost

Insulin Yes $-$$$$



Meglitinides Yes $$

Sulfonylureas Yes $

TZDs Rare $$


Neutral to Rare $$


None $$$

A1C kg hypo $



A1C


69




Cost



None $$$


Neutral to Rare $$


Meglitinides Yes $$

Sulfonylureas Yes $

TZDs Yes $-$$$$

Insulin Rare $$

A1C kg hypo $



Weight


70




Cost


None $$$


Neutral to Rare $$



TZDs Rare $$

Insulin Yes $-$$$$

Meglitinides Yes $$

Sulfonylureas Yes $

A1C kg hypo $



Hypoglycemia


71




Cost

Sulfonylureas Yes $


Neutral to Rare $$

Meglitinides Yes $$

TZDs Rare $$



None $$$


Insulin Yes $-$$$$

A1C kg hypo $



Cost


72



Alpha glucosidase inhibitor (acarbose) • Improved postprandial control, GI side effects

DPP-4 inhibitors

• GI side effectsGLP-1 receptor agonists

Insulin • No dose ceiling, flexible regimens

Meglitinides • Less hypoglycemia in context of missed meals but usually requires TID to QID dosing

Sulfonylureas • Gliclazide and glimepiride associated with less hypoglycemia than glyburide

TZDs • CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

Weight loss agent (orlistat) • GI side effects

Other therapeutic considerations


73

Case John is 47yo man with type 2 diabetes, diagnosed 5 years

ago. He is a truck driver, and has private insurance through his work. He has hypertension and dyslipidemia, but no microvascular or macrovascular complications. His work schedule is irregular. He sometimes forgets to take his medication, and find that his metformin bothers his stomach a bit if he misses dinner on the road.

Medications: Metformin 1g bid, perindopril 4mg, atorvastatin 20mg

On examination: BMI 32.1 kg/m2, BP 127/76

Labs: A1c 7.9%, eGFR 72, urine ACR negative

What agent would you add?

Sulphonylurea

DPP4 inhibitor

GLP-1

TZD

Acarbose

Insulin

QuestionsThank you to Rudy Sedlak for drug price list

Date post:	07-May-2015
Category:	Health & Medicine
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Abbotsford feb 26 2014

Health & Medicine