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Even more about
diabetes…
Dollars and sensible
therapeutics
Sara Stafford MDCM, FRCPC
26 February 2014
Abbotsford Regional...
Outline
 Case
 Guidelines
 Hypoglycemia
 Driving and Diabetes
 Metformin & Combination Tablets: Side Effects &
Compli...
Case
 John is 47yo man with type 2 diabetes, diagnosed 5 years
ago. He is a truck driver, and has private insurance throu...
2013

Individualizing A1C Targets

Consider 7.1-8.5% if:

which must be
balanced against
the risk of
hypoglycemia
AT DIAGNOSIS OF TYPE 2 DIABETES
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

L
I
...
From prior page…

L
I
F
E
S
T
Y
L
E

If not at glycemic target
• Add another agent from a different class
• Add/Intensify ...
Hypoglycemia
RISK FACTORS FOR
HYPOGLYCEMIA
 Risk factors for hypoglycemia1,2,3,4











Older age
Renal Impairment
Long ...
Hypoglycemia in the
Community
 Based upon US public health surveillance data,
adverse drug events account for 1 in 67 eme...
Adverse Drug Events
 Four medications classes accounted for 67.0% of
hospitalizations:
 Warfarin 33.3%
 Insulin 13.9%
...
RELATIONSHIP BETWEEN SEVERE
HYPOGLYCEMIA AND HbA1c
Severe hypoglycemia correlated to poor control in intensively
treated p...
HYPOGLYCEMIA UNAWARENESS IS ASSOCIATED
WITH A HIGHER RATE OF SEVERE
HYPOGLYCEMIA
9-fold higher rate of severe
hypoglycemia...
SEVERE HYPOGLYCEMIA INCREASES THE
RISK FOR ADVERSE OUTCOMES
Hazard ratios represent the risk of an adverse cardiovascular ...
Hypoglycemia &
Sulphonylureas
Hypoglycemia in Patients with
Antihyperglycemic Therapy

Add-on to
metformin

Monotherapy

OR (95% CI)
Metformin
Sulfonylu...
Meta-analysis of Hypoglycemia:
Glyburide vs. Other
Secretagogues
RR, 95% CI

Baba 1983
Dills 1996
Draeger 1996
Haider 1976...
Proportion of patients experiencing
minor hypoglycemia at study end
Saxagliptin 5 mg QD + MET
Sitagliptin 100 mg QD + MET
...
Proportion of patients achieving HbA1c
goal of <7% after 52 weeks
Sitagliptin 100 mg QD
Glipizide

% of patients to HbA1c ...
Add on to metformin: Sitagliptin Was
Noninferior to Sulphonylureas in Reducing
HbA1c
Per-Protocol Population
LS mean chang...
Despite Similar Glycemic Efficacy to
Sulphonylureas, Sitagliptin are Associated with
a Lower Risk of Hypoglycaemia
50

Hyp...
A1C reductions with
antihyperglycemic agents
Network meta-analysis comparing antihyperglycemic drugs as
add-on to metformi...
Overall risk of hypoglycemia
Network meta-analysis comparing antihyperglycemic
drugs as add-on to metformin
Odds ratio vs....
Hypoglycemia & Driving in
BC: OSMV Regulations
 Drivers who have a medical condition that has the
potential to affect the...
Class 5-8 Licences
Type 2 Not Treated with
Insulin or Secretagogues
 DMER required
 Report to OSMV if beginning insulin
 Remain under medi...
Type 2 Treated with
Secretagogues
 DMER Required
 Fit to drive if:
 Good understanding of diabetes
 Follow medical car...
Diabetes treated with insulin
(Type 1 or 2)
 DMER Required

 Fit to drive if:
 Understand diabetes, follow medical care...
Drivers with an episode of
severe hypoglycemia
 DMER required
 Report to OSMV if episode of severe hypoglycemia
 For ne...
Class 1-4 Licences
Type 2 Diabetes – Not Treated
with insulin or secretagogues
 DMER required
 Report if beginning insulin

 Remain under ...
Type 2 treated with
secretagogues
 DMER required
 Fit to drive if good understanding of diabetes, and following
instruct...
Diabetes treated with insulin
(type 1 or 2)
 Diabetic Package: DMER (MD), Diabetic Driver Report

(MD), Driver’s Diabetes...
Drivers who have had severe
hypoglycemia
 DMER Required
 Fit to drive if:
 Log of BG at least 4/d, less than 5% below 4...
Side Effects & Compliance
Metformin
 Metformin remains first-line therapy for type 2 diabetes

 Standard dosing is 1g po bid
 Higher doses (e.g. ...
Metformin Dose-Response
Decrease in FPG from
Placebo [mg/dl]

100

3

2.5

80

2
60
1.5
40
1
20

0.5

0

0
500

1000

1500...
Metformin Dose-Response Curve

Reduction in A1C (%)

2,0

1,5

1,0

30
20

0,5
10
0
0

500

1000

1500

2000

2500

Dose
R...
Starting metformin
 Start with metformin 250mg once daily with largest
meal

 Ask patient to slowly increase dosing in 2...
Metformin XR
 Standard, immediate release metformin is limited by:

 Bid or tid dosing leading to poor compliance
 Part...
Metformin XR – Equivalent Efficacy to
Standard Metformin
10

Metformin XR 1500 mg QD

Metformin XR 2000 mg QD
Metformin IR...
Metformin XR – Improved Tolerability
25

Incidence (%) during
dosing at 1000 mg o.d.

1500mg qd
20

15

1500mg bid

20.7
1...
Metformin XR – Improved Tolerability in
Patients Switched from Standard Metformin
60
*

Metformin-IR

Metformin-XR

Incide...
Metformin XR – Improved Patient
Adherence When Switched from
Standard Metformin
Adherence (%) Before & After
Switch from S...
Effect of Medication Dosing Frequency
on Adherence in T2DM – Systematic
Review
100%
79% to 94%.
Differences in
adherence r...
Adjusted Adherence to Oral Antidiabetic Therapy: A
Comparison of Monotherapy, Combination Therapy, and
Fixed-Dose Combinat...
% HbA1c (LS Mean± SE)

A1c >7.5%, drug naïve, mono- vs
combination therapy
10
Sitagliptin/Metformin FDC
Metformin monother...
Change from baseline in HbA1c at Week 18
presented by baseline HbA1c subgroup

Change from baseline in HbA1c (%) at Week 1...
Initial Combination Therapy with Sitagliptin and Metformin
Summary of Adverse Events
Sita/Met FDC
(N = 625)
n (%)

Metform...
Initial Combination Therapy with Sitagliptin and
Metformin
Incidence Rates for Gastrointestinal AEs of Interest
Sita/Met F...
Cumulative Percentage of Patients

Kaplan-Meier curves for the Addition of
AHAs over Time by Treatment Group
24

Metformin...
CV Risk with Oral Agents?
Mortality and Cardiovascular Risk With
Different Secretagogues1
 Cardiovascular outcomes were assessed in Danish patients...
CV events: Met vs. SU
Composite CV events (ITT analysis)
**Glipizide:
14 deaths [11 CV, 3 sudden],
6 nonfatal MI,
15 nonfa...
DPP-4 inhibitors and MACE
Meta-analysis of available RCTs
MACE

Events MH-OR

All

595 0.71 [0.59–0.86]

Sitagliptin

144 ...
Ongoing Cardiovascular Outcome
Trials With DPP-4 Inhibitors
Sitagliptin
TECOS1

Start: Dec 2008
Estimated Proj.
Completion...
Cost
BC Statistics
2013

2020 (estimated)

Prevalence

8.3%

10.3%

Number of people with
diabetes

400 253

548 000

Number of...
Out-of Pocket Cost
 Type 1 Diabetes
 Income < $15K: $475 (3.3%)
 Income $43K:
$1925 (4.5%)
 Income $75K:
$2481 (3.3%)
...
90 d supply
 Metformin 1g bid

 Glyburide 10mg bid

$42

$37

 Diamicron MR 60mg tabs, 120mg qAM

$67

 Gliclazide MR ...
Fair Pharmacare Assistance
Levels - Regular
Family Net
Income

Family
Deductible

Portion
Pharmacare
Pays after
Deductible...
Fair Pharmacare Assistance
Levels – Enhanced (born
before 1939)
Family Net
Income

Family
Deductible

Portion
Pharmacare
P...
Pharmacare coverage
 Fully or partially covered:
 aspart, glulisine, lispro, regular
insulin, glyburide, tolbutamide, me...
Pharmacare eligbility
 Gliclazide: Treatment failure or intolerance with
glyburide
 Hypoglycemia)

 Sitagliptin, Sitagl...
Pharmacare Eligibility
 Glargine or Detemir:
 Type 1 (any age), Type 2 (age > 17y)
 Currently taking NPH and/or pre-mix...
Private Insurance?
 Don’t forget that many private insurance programs for
public employees (teachers, nurses, etc.) are n...
CDA Toolkit
67
What is important to your patient?
Comparing antihyperglycemic agents

kg

hypo

Relative A1C
lowering

Change in
body wei...
What is important to your patient?
Comparing antihyperglycemic agents



kg

hypo

Relative A1C
lowering

Change in
body ...
What is important to your patient?
Comparing antihyperglycemic agents

A1C

kg



hypo

Relative A1C
lowering

Change in
...
What is important to your patient?
Comparing antihyperglycemic agents

kg

hypo

Relative A1C
lowering

Change in
body wei...
What is important to your patient?
Comparing antihyperglycemic agents

kg

hypo

Relative A1C
lowering

Change in
body wei...
What is important to your patient?
Comparing antihyperglycemic agents

Alpha glucosidase inhibitor
(acarbose)

• Improved ...
Case
 John is 47yo man with type 2 diabetes, diagnosed 5 years
ago. He is a truck driver, and has private insurance throu...
What agent would you add?
 Sulphonylurea

 DPP4 inhibitor
 GLP-1
 TZD
 Acarbose
 Insulin
Questions
 Thank you to Rudy Sedlak for drug price list
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Abbotsford feb 26 2014

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DR Stafford DM Grand Rounds

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  • May start Metformin at the time of diagnosisChange to 8.5% as threshold Start metformin immediately as an optionConcept of individualizing therapy based on patient and agent characteristicsWith that in mind, the next figure shows the characteristics of the agents ….
  • Concept of RELATIVE A1c lowering – not absoluteConcept of RELATIVE cost considerationsChange to achieve target within 3-6 months.
  • Notes to facilitator:No difference in hypoglycemia rates has been observed between DPP-4 inhibitors and GLP-1 receptor agonists.Reducing the dose of concomitant sulphonylurea may be considered to reduce the risk of hypoglycemia.Slide background:SaxagliptinAt week 24, the overall incidence of hypoglycemia for saxagliptin 5 mg versus placebo when added to metformin was 8.9% vs. 10.1%.SitagliptinThe incidence of hypoglycemia with sitagliptin 100 mg, was 1.3% vs. 2.1% placebo all in combination with metformin. When compared to add-on therapy with a SU, the incidence was 3.3% sitagliptin vs. 29.0% glipizide, all in combination with metformin. ExenatideWhen combined with metformin, the incidence of hypoglycemia was 4.5% and 5.3% for exenatide 5 g and 10 g vs. 5.3% placebo. LinagliptinWhen combined with metformin, the incidence of hypoglycemia was 2.8% and 0.6% for placebo and linagliptin.LiraglutideThe proportion of patients with hypoglycemia was 3.3%, 0.8%, 2.5%, 2.5% and 16.9% for liraglutide 0.6 mg, liraglutide 1.2 mg, liraglutide 1.8 mg, placebo and glimepiride all in combination with metformin. In a separate trial, the proportion of patients with hypoglycemia was 5.4%, 5.0% and 4.6% for liraglutide 1.2mg, liraglutide 1.8 mg and sitagliptin 100 mg all in combination with metformin.References:Pratley R et al. Lancet 2010;375:1447-56.Pratley R et al. Int J Clin Pract 2011;published online ahead of print.Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2013 Sitagliptin Canadian Product Monograph, Merck Frosst, 2013Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2013Exenatide Canadian Product Monograph, Bristol Myers Squibb, 2013Taskinen M-R et al. Diabetes, Obes, Metab 2011;13:65-74.
  • Notes to facilitatorThis meta-analysis compared antihyperglycemic agents as add-on to metformin.This graph depicts typical A1C reductions observed in clinical trials. GLP-1 receptor agonists and insulin have the greatest effect on A1C compared to other agents. REFERENCE:1. Liu, Sung-Chen et al. Diab Obes &amp; Metab 2012; 14:810-820. BACKGROUND INFORMATION:Aim: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight.Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.Results: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon-like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors [−0.20% (95% CI −0.34 to −0.04%), −0.31% (95% CI −0.61 to −0.02%), −0.20% (95% CI −0.38 to −0.00), −0.36% (95% CI −0.64 to −0.07%), −0.32% (95% CI −0.47 to −0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [−0.12% (−0.23 to −0.03%)], and for biphasic insulin compared with glinides (−0.36%; 95% CI −0.82 to −0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α-glucosidase inhibitors and GLP-1 analogues.Conclusions: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.
  • Notes to facilitatorThis meta-analysis compared antihyperglycemic agents as add-on to metformin.This graph depicts the risk of hypoglycemia observed in clinical trials. Insulins, meglitinides, and sulphonylureas had statistically significantly greater risk of hypoglycemia compared to placebo.Alpha-glucosidase inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists and TZDs were not statistically significantly different from placebo.REFERENCE:1. Liu, Sung-Chen et al. Diab Obes &amp; Metab 2012; 14:810-820. BACKGROUND INFORMATION:Aim: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight.Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.Results: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon-like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors [−0.20% (95% CI −0.34 to −0.04%), −0.31% (95% CI −0.61 to −0.02%), −0.20% (95% CI −0.38 to −0.00), −0.36% (95% CI −0.64 to −0.07%), −0.32% (95% CI −0.47 to −0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [−0.12% (−0.23 to −0.03%)], and for biphasic insulin compared with glinides (−0.36%; 95% CI −0.82 to −0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α-glucosidase inhibitors and GLP-1 analogues.Conclusions: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.
  • OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a extended-release metforminRESEARCH DESIGN AND METHODS: Adults with type 2 diabetes (newly diagnosed,treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial.RESULTS: Significant decreases (P&lt;0.001) in mean HbA1c (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (-0.73 and -0.74%) were not significantly different from the change in the immediate-release metformin group (-0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (-1.06%; mean difference [2,000 mg extended-release metformin - immediate-release metformin]: -0.36 [98.4% CI -0.65 to -0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group.CONCLUSIONS: Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.
  • OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a extended-release metforminRESEARCH DESIGN AND METHODS: Adults with type 2 diabetes (newly diagnosed,treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial.RESULTS: The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group.
  • Open-label, prospective 24-week study conducted in patients with type 2 diabetes who were outpatients of the diabetes clinic at the State University of Rio de Janeiro.Aims: To determine prospectively the efficacy, tolerability and patient satisfaction of an extended release formulation of metformin (metformin XR) in hospital based outpatients with type 2 diabetes mellitus currently treated with standard metformin.Methods: Patients on immediate release standard metformin either alone or combined with other oral agents were switched to extended release metformin XR 500 mg tablets and titrated to a maximum dose of 2000 mg/day Measurements to include glucose and lipid control, blood pressure, body weight, waist circumference, C-reactive protein, adverse events and patient satisfaction were recorded at baseline, three and six months.Results: Complete data were obtained for 35 of the 61 patients enrolled to the study. At three and six months no changes were reported for any of the cardiovascular risk factors except for lipids where there was a modest rise in plasma triglycerides. These effects were achieved with a reduced dose of metformin XR compared to pre-studydosing with standard metformin (1500 mg +/- 402 vs 1861 +/- 711 p = 0.004). A total of 77% of patients were free of gastrointestinal side effects and 83% of patients stated a preference for metformin XR at the end of the study. Ghost tablets were reported in the faeces by the majority of the patients (54.1%).Conclusions: Patients switched to extended release metformin XR derived the same clinical and metabolicbenefits as for standard metformin but with reduced dosage, fewer gastrointestinal side effects and a greater senseof well being and satisfaction on medication.
  • Methods: Retrospective observational study, examined adherence and glycaemic control in patients prescribed metformin IR and XL preparations in Tayside, UK.Results: Metformin XL was used by 137 patients during the study period. Overall adherence was greater in the XL group (80%) compared with the 10 772 patients in the IR group (72%, p =0.0026). In the 40 patients who changed from metformin IR to metformin XL who had sufficient data to determine adherence, the adherence increased from 62% in the IR group to 81% in the XL group (p &lt; 0.0001). This was associated with an HbA1c reduction from 9.1 to 8.4% (p = 0.0739, n =29).Conclusions: Metformin XL use is associated with increased adherence compared with the IR preparation, although the mechanism for this cannot be determined from this study. In patients intolerant of metformin IR the XL preparation should be considered.
  • Objective: To systematically review available data on the effect of daily medication dosing frequency on medication adherence in chronic disease states, as assessed by precise medication event monitoring systems (MEMS).Study Design: Systematic review of relevant literature published between January 1986 and August 2007.Methods: Four electronic databases were searched to identify appropriate studies. Study selection criteria included prospective study design, patient population with quiescent chronic disease, medication intervention prescribed to each treatment arm for at least 6 weeks, and the use of MEMS to measure adherence. Data were extracted on the chronic disease being treated, the frequency of medication dosing, and the proportion of days with correct number of doses.Results: Twenty studies met the selection criteria (NOTE: 4 for T2DM). All studies reported higher adherence rates in patients using less frequently dosed medications, and these differences were statistically significant (P &lt;.05) in 75% (15 of 20) of studies. For 5 of 6 studies comparing once-daily versus thrice-daily dosing, patients receiving once-daily dosing had 22% to 41% more adherent days compared withpatients receiving thrice-daily dosing. For studies comparing once-daily versus twice-daily dosing, patients receiving once-daily dosing had 2% to 44% more adherent days compared with patients receiving twice-daily dosing, with most studies clustering around 13% to 26%. T2DM studies: For once-daily dosing, adherence ranged from 79% to 94%. For twice-daily or thrice-daily dosing, the adherence rate ranged from 38% to 67%. The within-study differences in adherence for once-daily versus twice-daily or thrice-daily dosing regimens ranged from 13% to 41%, with all studies reporting the differences across regimens to be statistically significantConclusion: Patients are more compliant with once-daily compared with twice-daily or thrice daily treatment regimens.
  • Mortality and Cardiovascular Risk With Different Secretagogues In a study of Danish patients with type 2 diabetes, CV outcomes were assessed. The study population included patients who had initiated monotherapy with an insulin secretagogue or metformin between 1997 and 2006. Patients receiving insulin monotherapy and combination therapy were excluded. Patients were also stratified by CV risk, with patients with a prior MI considered “high risk” and patients without a prior MI considered “low risk.”1The total study population comprised 107,806 patients, including 9607 patients with a prior MI. Of these, 75,354 patients were eligible for propensity score matching, including 6448 with a prior MI. Patients were followed for up to 9 years (median follow-up duration was 3.3 years).1The major end points of the study were all-cause death, CV death, and the combined end point of MI, stroke, and CV death. In patients without a prior MI, hazard ratios were similar among all SUs. In patients with a prior MI, hazard ratios were statistically significant for glimepiride, glipizide, and tolbutamide.
  • Multicenter RCT, 304 Type 2 diabetic patients with CAD, mean age 63.3y. Randomly assigned to either glipizide 30mg qd or metformin 1.5g qd for 3y. Primary end point composite CV events. Both groups achieved a significant decrease in A1c (7.1% in glipizide, 7.0% in metformin),at 5.0y, 91 patients had 103 primary end points. ITT shows HR 0.54 (p=0.025) for patients receiving metformin compared to glipizide
  • Notes to facilitator:Although with the 2013 guidelines, the CDA has released multiple online interactive tools and guides to help physicians in the management of their patients with diabetes. Similarly to the following slide, there is an online tool to help individualize treatment selection according to agent and patient characteristics. guidelines.diabetes.ca is an active link to the website; only accessible when connected to internet.
  • Notes to facilitatorThis table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. While using this interactive portion of the presentation keep in mind what factors are important to Jason when choosing an antihyperglycemic agent.Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol.REFERENCE:1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
  • Notes to facilitatorThis table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol.REFERENCE:1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
  • Notes to facilitatorThis table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol.REFERENCE:1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
  • Notes to facilitatorThis table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol.REFERENCE:1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
  • Notes to facilitatorThis table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol.REFERENCE:1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
  • Notes to facilitatorThis slide depicts the final column of the CDA guidelines table regarding key considerations for second-line therapies in the treatment of type 2 diabetes.
  • Transcript of "Abbotsford feb 26 2014"

    1. 1. Even more about diabetes… Dollars and sensible therapeutics Sara Stafford MDCM, FRCPC 26 February 2014 Abbotsford Regional Hospital
    2. 2. Outline  Case  Guidelines  Hypoglycemia  Driving and Diabetes  Metformin & Combination Tablets: Side Effects & Compliance  CV Risk with Oral Agents  Cost analysis & Pharmacare coverage  CDA Toolkit
    3. 3. 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
    4. 4. 2013 Individualizing A1C Targets Consider 7.1-8.5% if: which must be balanced against the risk of hypoglycemia
    5. 5. AT DIAGNOSIS OF TYPE 2 DIABETES Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin L I F E S T Y L E A1C <8.5% If not at glycemic target (2-3 mos) Start / Increase metformin A1C 8.5% Symptomatic hyperglycemia with metabolic decompensation Start metformin immediately Consider initial combination with another antihyperglycemic agent Initiate insulin +/metformin If not at glycemic targets Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other 2013 See next page…
    6. 6. From prior page… L I F E S T Y L E If not at glycemic target • Add another agent from a different class • Add/Intensify insulin regimen 2013 Make timely adjustments to attain target A1C within 3-6 months
    7. 7. Hypoglycemia
    8. 8. 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.
    9. 9. 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
    10. 10. Adverse Drug Events  Four 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
    11. 11. RELATIONSHIP BETWEEN SEVERE HYPOGLYCEMIA AND HbA1c Severe hypoglycemia correlated to poor control in intensively treated patients 6 Incidence per 100 person-years 5 4 3 2 1 0 6.0 7.0 Updated average HbA1c 8.0 9.0
    12. 12. HYPOGLYCEMIA UNAWARENESS IS ASSOCIATED WITH A HIGHER RATE OF SEVERE HYPOGLYCEMIA 9-fold higher rate of severe hypoglycemia 2.5 Severe hypoglycemia* (episodes/patient/year) 2.15 2.0 1.5 1.0 0.5 0.22 0 Normal awareness Impaired awareness (n=144) (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. 12
    13. 13. SEVERE HYPOGLYCEMIA INCREASES THE RISK FOR ADVERSE OUTCOMES 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 Clinical Outcome and Interval After Hypoglycemia Hazard Ratio (95% CI)† Microvascular events 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 *Severe 2.07 (1.32-3.26)‡ 3.78 (2.34-6.11)‡ 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.
    14. 14. Hypoglycemia & Sulphonylureas
    15. 15. Hypoglycemia in Patients with Antihyperglycemic Therapy Add-on to metformin Monotherapy OR (95% CI) Metformin Sulfonylureas Glucosidase inhibitors Glinides Thiazolidinediones DPP-4 inhibitors AHA monotherapy AHA dual combination therapy 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) Sulfonylureas Glucosidase inhibitors Glinides Thiazolidinediones DPP-4 inhibitors 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) 0.01 0.1 Less frequent 1.0 10.0 More frequent AHA = antihyperglycemic agent; CI = confidence interval; DPP-4 = dipeptidyl peptidase 4; OR = odds ratio Adapted from: Tschöpe D et al. Cardiovasc Diabetol 2011; 10:66. 15
    16. 16. Meta-analysis of Hypoglycemia: Glyburide vs. Other Secretagogues RR, 95% CI Baba 1983 Dills 1996 Draeger 1996 Haider 1976 Hamblin 1970 Harrower 1994 Landgraf 1999 Mafauzy 2002 Marbury 1999 Rosenstock 1993 UKPDS 13 1995 Wolffenbuttel 1999 Gliclazide Glimipiride Glimipiride Chlorpropamide Chlorpropamide Gliclazide Repaglinide Repaglinide Repaglinide Glipizide Chlorpropamide Repaglinide 2.23 1.42 1.24 5.26 3.29 3.58 0.93 1.23 1.25 2.96 2.39 1.03 0.1 0.2 0.5 1 2 Secretogogue more CI = confidence interval; RR = relative risk Adapted from: Gangji AS et al. Diabetes Care 2007; 30(2):389-94. 1.08–4.59 0.94–2.13 0.90–1.71 0.26–07.81 0.72–15.05 0.77–16.76 0.39–2.24 0.66–2.31 0.86–1.81 0.32–27.74 1.78–3.20 0.55–1.94 1.52 Total (95% CI) Test for heterogeneity I2 = 42.1% RR (95% CI) 1.21–1.92 5 10 Glyburide more 16
    17. 17. Proportion of patients experiencing minor hypoglycemia at study end Saxagliptin 5 mg QD + MET Sitagliptin 100 mg QD + MET 35% Proportion of Patients (%) Linagliptin 5 mg QD + MET 29.0% 30% 25% Exenatide 5 μg BID + MET Exenatide 10 μg BID + MET Liraglutide 1.2 mg QD + MET Liraglutide 1.8 mg QD + MET Sulphonylurea + MET Placebo + MET 16.9% R 20% 15% 10% 8.9% 10.1% 5% 3.3% 4.5% 5.3% 5.3% 2.8% 0.6% 0.8% 2.5% 2.5% 0% SAXA PBO n=191 n=179 SITA SU n=979 n=748 EXE 5 μg EXE 10 μg PBO n=110 n=113 n=113 LINA PBO n=523 n=177 LIRA 1.2 mg n=240 LIRA PBO SU 1.8 mg n=121 n=242 n=242 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.
    18. 18. Proportion of patients achieving HbA1c goal of <7% after 52 weeks Sitagliptin 100 mg QD Glipizide % of patients to HbA1c goal 70.0 60.0 62.8% 50.0 58.9% 40.0 30.0 20.0 HbA1c <7% at 52 weeks Nauck MA, et al. Diabetes Obes Metab. 2007;9:194–205.
    19. 19. Add on to metformin: Sitagliptin Was Noninferior to Sulphonylureas in Reducing HbA1c Per-Protocol Population LS mean change from baseline at 30 weeks (for both groups): –0.5% Difference in LS Mean HbA1c= -0.03 (95% CI: –0.13, 0.07) 7.8 Glipizide (up to 20 mg/d; mean 9.5 mg/d)+metformin (n=256) Sitagliptin (100 mg/day)+metformin (n=248) 8.0 7.4 7.6 HbA1c (%) 7.0 HbA1c (%) 7.2 6.6 6.8 6.2 5.8 6.4 0 12 24 38 52 60 Weeks 78 CI=confidence interval; LS=least-squares; SD=standard deviation. SE=standard error. 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. 91 104 6.0 Glimepiride (up to 6 mg/d; mean 2.1 mg/d)+metformin (n=436) Sitagliptin (100 mg/d)+metformin (n=443) 0 6 12 18 Weeks 24 30
    20. 20. Despite Similar Glycemic Efficacy to Sulphonylureas, Sitagliptin are Associated with a Lower Risk of Hypoglycaemia 50 Hypoglycemia over 104 weeks Between-groups difference = –28.8% 50 40 40 30 30 20 20 Hypoglycemia Over 30 Weeks Between groups difference = –15.0% P<0.001 P<0.001 10 10 0 0 Sitagliptin (100 mg/d)+metformin Glipizide (mean 9.5 mg/d)+metformin 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. Sitagliptin (100 mg/d)+metformin Glimepiride (mean 2.1mg/d)+metformin
    21. 21. A1C reductions with antihyperglycemic agents Network meta-analysis comparing antihyperglycemic drugs as add-on to metformin Mean difference from placebo AGIs DPP-4i Meglitinides SUs TZDs Basal insulin GLP-1 RA Premixed insulin 21 *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.
    22. 22. Overall risk of hypoglycemia Network meta-analysis comparing antihyperglycemic drugs as add-on to metformin Odds ratio vs. placebo Premixed Meglitinides SUs insulin Basal insulin DPP-4i Placebo GLP-1 RA (Ref) TZDs AGIs 22 *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.
    23. 23. 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
    24. 24. Class 5-8 Licences
    25. 25. 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
    26. 26. 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
    27. 27. 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
    28. 28. 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
    29. 29. Class 1-4 Licences
    30. 30. Type 2 Diabetes – Not Treated with insulin or secretagogues  DMER required  Report if beginning insulin  Remain under medical supervision to monitor for progression or complications  Reassess q5y, or if insulin or secretagogue therapy initiated
    31. 31. 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
    32. 32. 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
    33. 33. 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
    34. 34. Side Effects & Compliance
    35. 35. Metformin  Metformin 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)
    36. 36. Metformin Dose-Response Decrease in FPG from Placebo [mg/dl] 100 3 2.5 80 2 60 1.5 40 1 20 0.5 0 0 500 1000 1500 2000 2500 Dose [mg/d] Garber et al. Am J Med 1997; 102:491
    37. 37. Metformin Dose-Response Curve Reduction in A1C (%) 2,0 1,5 1,0 30 20 0,5 10 0 0 500 1000 1500 2000 2500 Dose Riddle M. Am J Med. 2000;108(6A):15S-22S
    38. 38. Starting metformin  Start with metformin 250mg once daily with largest meal  Ask patient to slowly increase dosing in 250mg increments  250mg bid  500mg AC-B, 250mg AC-S  500mg bid …  Target 1g bid
    39. 39. Metformin XR  Standard, immediate release metformin is limited by:  Bid or tid dosing leading to poor compliance  Particularly 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, 2:16 1- Garber AJ et al. Am J Med 1997; 103: 491.
    40. 40. Metformin XR – Equivalent Efficacy to Standard Metformin 10 Metformin XR 1500 mg QD Metformin XR 2000 mg QD Metformin IR 1500 mg (AM/PM) † HbA1c (%) 9 8 * * 7 * 11. 1 Fasting Plasma Glucose (mmol/L) Metformin XR 1500 mg (AM/PM) † 12. 2 * 10 * * 8.9 * * * * * 20 24 7.8 6 6.7 5 5.6 0 4 8 12 Treatment Week 16 20 24 0 4 8 12 16 Treatment Week 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 Adapted from Schwartz S et al. Diabetes Care. 2006 Apr;29(4):759-64.
    41. 41. Metformin XR – Improved Tolerability 25 Incidence (%) during dosing at 1000 mg o.d. 1500mg qd 20 15 1500mg bid 20.7 19.3 18.9 ExtendedRelease Metformin 2000mg qd IR 1500mg bid 15.5 10 * 10.5 8.3 8.9 8.2 6.9 5 2.9 3.9 2.4 0 Any gastrointestinal event Diarrhea Nausea *p<0.050 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 Adapted from Schwartz S et al. Diabetes Care. 2006 Apr;29(4):759-64.
    42. 42. Metformin XR – Improved Tolerability in Patients Switched from Standard Metformin 60 * Metformin-IR Metformin-XR Incidence (%) 50 Total of 77% of patients were free of gastrointestinal side effects and 83% of patients stated a preference for metformin XR 40 30 *vs metformin IR p = 0.013 20 * * 10 0 Diarrhea Nausea Epigastric pain Diarrhea Nausea Vomiting Abdominal pain 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 Adapted from Levy J et al. Diabetol Metab Syndr 2010, 2:16
    43. 43. Metformin XR – Improved Patient Adherence When Switched from Standard Metformin Adherence (%) Before & After Switch from Standard Metformin Adherence (%), Overall Population * 82 90 80 80% 78 76 p = 0.0001 80 81% 75 70 74 65 72 70 * p = 0.0026 85 72% 60 62% 55 68 Metformin IR (n=10 019) Metformin XL (n=80) 50 Metformin IR (n=40) Metformin XL (n=40) Retrospective observational study, T2DM patients from a single diabetes clinic in Scotland Adapted from Donnelly LA et al. Diabetes Obes Metab. 2009 Apr;11(4):338-42.
    44. 44. Effect of Medication Dosing Frequency on Adherence in T2DM – Systematic Review 100% 79% to 94%. Differences in adherence ranged from 13% to 41%* 75% Adherence Range (%) 50% 38% to 67%. 25% 0% QD dosing BID or TID *with all studies reporting the differences across regimens to be statistically significant. Study selection criteria included the use of MEMS to measure adherence Adapted from Saini SD et al. Am J Manag Care. 2009 Jun 1;15(6):e22-33.
    45. 45. Adjusted Adherence to Oral Antidiabetic Therapy: A Comparison of Monotherapy, Combination Therapy, and Fixed-Dose Combination Therapy Adherence Rate (%) 100 80 87 P<0.001 P<0.001 77 71 60 54 40 20 0 Metformin and Glyburide Metformin/Glyburide Previously on Monotherapy Retrospective database analysis of pharmacy claims Metformin and Glyburide Metformin/Glyburide Previously on both, then switch to FDC Melikian C et al. Clin Ther 2002;24:460
    46. 46. % HbA1c (LS Mean± SE) A1c >7.5%, drug naïve, mono- vs combination therapy 10 Sitagliptin/Metformin FDC Metformin monotherapy 9 Difference in change from baseline = −0.6%; p<0.001 8 7 0 6 Week 12 18 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, Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644
    47. 47. Change from baseline in HbA1c at Week 18 presented by baseline HbA1c subgroup Change from baseline in HbA1c (%) at Week 18 (LS Mean ± SE) HbA1c (%) at baseline ≤ median (9.70%) 0.0 N=288 N=291 HbA1c (%) at baseline > median (9.70%) N=271 N=273 -0.5 -1.0 -1.5 -2.0 ** -2.5 -3.0 -3.5 Sitagliptin/Metformin FDC Metformin monotherapy ** -4.0 **p<0.001 Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644
    48. 48. Initial Combination Therapy with Sitagliptin and Metformin Summary of Adverse Events 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) *Drug-related, considered by the study investigator to be possibly, probably or definitely drug-related. Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644
    49. 49. Initial Combination Therapy with Sitagliptin and Metformin Incidence Rates for Gastrointestinal AEs of Interest Sita/Met FDC (n=625) Metformin (n=621) P<0.05 P=0.021 16.6 Incidence Rates (%) 18.0 16.0 14.0 12.0 P=0.622 P=0.612 12.0 10.0 8.0 6.0 P<0.05 P=0.002 3.9 4.0 2.0 5.6 6.3 P=0.735 P=0.742 2.9 2.6 1.1 0.0 Abdominal Pain* Diarrhea Nausea Vomiting *Includes abdominal pain lower, abdominal pain upper, abdominal pain, abdominal discomfort and epigastric pain. Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644
    50. 50. Cumulative Percentage of Patients Kaplan-Meier curves for the Addition of AHAs over Time by Treatment Group 24 Metformin Sita/Met FDC 20 16 12 8 4 0 0 Patients at Risk 6 12 18 31 Time to First Additional AHA (Weeks) 44 Sita/Met FDC 625 563 514 472 414 264 Metformin 621 562 509 458 374 238 Olansky L et al Diabetes, Obesity and Metabolism 2011;13: 841–9
    51. 51. CV Risk with Oral Agents?
    52. 52. Mortality and Cardiovascular Risk With Different Secretagogues1  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 No Prior MI Prior MI MI, Stroke, and Cardiovascular Death Metformin Glimepiride Gliclazide Glibenclamide Glipizide Tolbutamide Repaglinide MI, Stroke, and Cardiovascular Death Metformin 1 Glimepiride 1.29 (1.20, 1.39) Gliclazide 1.18 (1.02, 1.36) 1.16 (1.04, 1.29) Glibenclamide 1.24 (1.09, 1.40) Glipizide 1.17 (1.03, 1.33) Tolbutamide 0.87 (0.49, 1.54) 0 1 2 Hazard Ratios (95% confidence intervals) MI=myocardial infarction; SU=sulfonylurea. 1. Schramm TK et al. Eur Heart J. 2011; 32:1900–1908. Repaglinide 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) 0 1 2 Hazard Ratios (95% confidence intervals)
    53. 53. CV events: Met vs. SU Composite CV events (ITT analysis) **Glipizide: 14 deaths [11 CV, 3 sudden], 6 nonfatal MI, 15 nonfatal strokes, 25 revascularizations, Composite CV events after 5 years 70 60 p = 0.026 50 60** 40 30 Events 43* 20 10 0 Metformin Glipizide * Metformin: 7 deaths [all CV], 5 nonfatal MI, 10 nonfatal strokes, 21 revascularizations 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 Hong J. et al. Diabetes Care 2013 36(5)
    54. 54. DPP-4 inhibitors and MACE Meta-analysis of available RCTs MACE Events MH-OR All 595 0.71 [0.59–0.86] Sitagliptin 144 0.86 [0.60–1.24] Vildagliptin 149 0.61 [0.43–0.86] Saxagliptin 108 0.67 [0.45–0.99] Linagliptin 78 0.72 [0.45–1.16] Alogliptin 16 0.86 [0.25–2.93] MH-OR, Mantel–Henzel odds ratio. Monami M, et al. Diabetes Obes Metab 2013;15:112–20.
    55. 55. Ongoing Cardiovascular Outcome Trials With DPP-4 Inhibitors Sitagliptin TECOS1 Start: Dec 2008 Estimated Proj. Completion: Dec 2014 N = 14,000 Start: Sept 2009 Alogliptin EXAMINE2,5 Estimated Proj. Completion: Dec 2014 N = 5,400 Sitagliptin vs Placebo added to stable doses of either monotherapy or dual combination therapy with metformin, pioglitazone, or a sulphonylurea 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) randomized to alogliptin vs placebo Saxagliptin SAVOR3,6 Start: May 2010 Estimated Proj. Completion: April 2014 N = 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 Linagliptin CAROLINA Start: Oct 2010 Estimated Proj. Completion: Sept 2018 N = 6,000 head-to-head cardiovascular outcome study comparing linagliptin with glimepiride 4 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. 55
    56. 56. Cost
    57. 57. BC Statistics 2013 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%
    58. 58. Out-of Pocket Cost  Type 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%)
    59. 59. 90 d supply  Metformin 1g bid  Glyburide 10mg bid $42 $37  Diamicron MR 60mg tabs, 120mg qAM $67  Gliclazide MR 30mg tabs, 120mg qAM $75  Sitagliptin (Januvia) 100mg $324  Linagliptin (Trajenta) 5mg  Liraglutide (Victoza) 1.2mg $251 $546  Janumet 50/1000mg bid or Janumet XR  Jentadueto 2.5/1000mg bid  Lantus 20 U qHS  plus Needles $35 $350 $263 $123
    60. 60. 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
    61. 61. 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
    62. 62. Pharmacare coverage  Fully 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, pioglita zone  Not available through BC drug formulary:  saxagliptin, liraglutide, exenatide, glimepiride, nateglindine, rep aglinide, linagliptin & metformin (Jentadueto), rosiglitizone  Removed from formulary: acarbose
    63. 63. Pharmacare eligbility  Gliclazide: Treatment failure or intolerance with glyburide  Hypoglycemia)  Sitagliptin, Sitagliptin/Metformin, Linagliptin:  When insulin NPH is not an option  AND  After inadequate glycemic control on maximum tolerated doses of dual therapy of metformin AND a sulphonylurea
    64. 64. Pharmacare Eligibility  Glargine or Detemir:  Type 1 (any age), Type 2 (age > 17y)  Currently taking NPH and/or pre-mix at optimal dosing AND  Has experienced unexplained nocturnal hypoglycemia at least once a month despite optimal management Or  Has experienced or continues to experience severe systemic or local allergic reaction to existing insulin treatment
    65. 65. Private Insurance?  Don’t forget that many private insurance programs for public employees (teachers, nurses, etc.) are now based upon the BC drug formulary
    66. 66. CDA Toolkit
    67. 67. 67
    68. 68. What is important to your patient? Comparing antihyperglycemic agents kg hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost  Neutral to  Rare $$  Neutral to  Rare $$$  to   Rare $$$$   Yes $-$$$$ Meglitinides   Yes $$ Sulfonylureas   Yes $ TZDs   Rare $$   None $$$ A1C Alpha glucosidase inhibitor (acarbose) DPP-4 inhibitors GLP-1 receptor agonists Insulin Weight loss agent (orlistat) 68 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.
    69. 69. What is important to your patient? Comparing antihyperglycemic agents  kg hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost   Yes $-$$$$  to   Rare $$$$ DPP-4 inhibitors  Neutral to  Rare $$$ Meglitinides   Yes $$ Sulfonylureas   Yes $ TZDs   Rare $$ Alpha glucosidase inhibitor (acarbose)  Neutral to  Rare $$ Weight loss agent (orlistat)   None $$$ A1C Insulin GLP-1 receptor agonists 69 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.
    70. 70. What is important to your patient? Comparing antihyperglycemic agents A1C kg  hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost  to   Rare $$$$ Weight loss agent (orlistat)   None $$$ Alpha glucosidase inhibitor (acarbose)  Neutral to  Rare $$ DPP-4 inhibitors  Neutral to  Rare $$$ Meglitinides   Yes $$ Sulfonylureas   Yes $   Yes $-$$$$   Rare $$ GLP-1 receptor agonists TZDs Insulin 70 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.
    71. 71. What is important to your patient? Comparing antihyperglycemic agents kg hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost Weight loss agent (orlistat)   None $$$ Alpha glucosidase inhibitor (acarbose)  Neutral to  Rare $$  Neutral to  Rare $$$  to   Rare $$$$   Rare $$   Yes $-$$$$ Meglitinides   Yes $$ Sulfonylureas   Yes $ DPP-4 inhibitors GLP-1 receptor agonists TZDs Insulin  A1C 71 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.
    72. 72. What is important to your patient? Comparing antihyperglycemic agents kg hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost   Yes $  Neutral to  Rare $$ Meglitinides   Yes $$ TZDs   Rare $$ DPP-4 inhibitors  Neutral to  Rare $$$   None $$$  to   Rare $$$$   Yes $-$$$$ Sulfonylureas Alpha glucosidase inhibitor (acarbose) Weight loss agent (orlistat) GLP-1 receptor agonists Insulin  A1C 72 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.
    73. 73. What is important to your patient? Comparing antihyperglycemic agents Alpha glucosidase inhibitor (acarbose) • Improved postprandial control, GI side effects DPP-4 inhibitors GLP-1 receptor agonists • GI side effects 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 73 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.
    74. 74. 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
    75. 75. What agent would you add?  Sulphonylurea  DPP4 inhibitor  GLP-1  TZD  Acarbose  Insulin
    76. 76. Questions  Thank you to Rudy Sedlak for drug price list
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