#diabetesmatters - cadth update: type 2 diabetes - mitchelmore

CADTH Update: Type 2 Diabetes BRADLEY MITCHELMORE, BSC. (PHARM), ACPR,

PHARMD

MANAGER, CLINICAL RESEARCH

Disclosure

• Personal Disclosures:

• None

• CADTH Disclosures:

• Funded by federal, provincial, and territorial ministries of health.

• Application fees for three programs:

• CADTH Common Drug Review (CDR)

• CADTH pan-Canadian Oncology Drug Review (pCODR)

• CADTH Scientific Advice

1

Objectives

• Review the latest projects by CADTH on Type 2 Diabetes

and outline their corresponding recommendations and

supporting evidence and economic analyses:

• CADTH Common Drug Review Recommendations:

• Jardiance

• CADTH Therapeutic Review Update:

• New Drugs for Type 2 Diabetes: Second-Line Therapy

2

History of Optimal Use Projects at CADTH

3

Optimal Use: 2010 Initial Review

Objectives:

• Identify and appraise the clinical evidence pertaining to use of second-

line antidiabetes drugs for patients with type 2 diabetes inadequately

controlled on metformin monotherapy

• Identify and appraise information related to cost-effectiveness of

second-line antidiabetes drugs for patients with type 2 diabetes

inadequately controlled on metformin monotherapy, and if necessary

due to lack of evidence, conduct a cost-effectiveness analysis.

• Identify recommendations for optimal prescribing and use of second-line

antidiabetes drugs for patients with type 2 diabetes inadequately

controlled on metformin monotherapy, taking into consideration the

clinical- and cost-effectiveness evidence.

4

Optimal Use: 2010 Initial Review

Recommendation:

• CERC recommends that a sulfonylurea be added to metformin for most adults

with type 2 diabetes inadequately controlled on metformin alone. (Voting: agree

12, disagree 0; strong recommendation; low-quality evidence)

Underlying values and preferences:

• CERC placed a high value on:

• efficient use of limited resources (i.e., cost-effectiveness of the various

agents)

• evidence demonstrating a lack of clinically meaningful differences in

glycemic control, hypoglycemia, and weight gain among the various classes

of agents

• greater availability of long-term safety data for older drug classes (e.g.,

sulfonylureas) compared with newer classes.

5

Optimal Use: 2013 Update

Policy Question:

• What is the optimal second-line therapy for patients with type 2 diabetes

experiencing inadequate glycemic control with metformin monotherapy?

Research Question:

• What is the comparative efficacy and safety of second-line

antihyperglycemic drugs in adults with type 2 diabetes experiencing

inadequate glycemic control on metformin monotherapy?

• What is the cost-effectiveness of second-line antihyperglycemic drugs in

adults with type 2 diabetes experiencing inadequate glycemic control on

metformin monotherapy?

6

Optimal Use: 2013 Update Recommendation:

• The Canadian Drug Expert Committee (CDEC) recommends that a sulfonylurea be added

to metformin for most adults with type 2 diabetes inadequately controlled on metformin

alone

Reason for Recommendation:

• All of the drug classes demonstrated similar improvements in hemoglobin A1C.

Sulfonylureas were the most cost-effective treatment option, with an incremental cost-

utility ratio (ICUR) of $8,445 per quality-adjusted life-year (QALY) gained compared with

metformin alone.

• There are considerably more long-term safety data for sulfonylureas compared to drugs

from the newer classes of antihyperglycemic agents.

Of Note

• Although there were 69 randomized controlled trials (RCTs) included in the systematic

review, the evidence was limited by the lack of adequate data for clinically important

outcomes such as diabetes-related complications and severe hypoglycemia.

• The Committee identified the values of safety, efficacy, and cost-effectiveness as being of

particular importance in making this recommendation.

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Rationale for 2017 Therapeutic

Review Update

• Several new drugs now available that were not included in

previous 2013 update:

• New DPP-4 inhibitors

• New GLP-1 analogues

• New class: SGLT-2 inhibitors

• Several new cardiovascular safety trials

• New second-line recommendations from CDEC that were

not in alignment with previous OU recommendations

8

Individual Drug Reviews

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Individual Drug Reviews

• Prior to 2015, most new drugs have reflected previous

optimal use recommendations and recommended newer

drugs as third-line treatments for those unable to take

insulin.

• Three recommendations since 2015 have recommended

reimbursement for treatment of type 2 diabetes as a

second-line treatment after metformin.

10

Forxiga (dapagliflozin): Oct 2015 Recommendation:

• The CADTH Canadian Drug Expert Committee (CDEC) recommends that dapagliflozin be listed for use in patients with

type 2 diabetes mellitus to improve glycemic control, if the clinical criteria and condition are met for any one of the following

four scenarios:

Clinical criteria

• Added on to metformin for patients:

• Who have inadequate glycemic control on metformin

• Who have a contraindication or intolerance to a sulfonylurea

• For whom insulin is not an option.

• Added on to a sulfonylurea for patients:

• Who have inadequate glycemic control on a sulfonylurea

• Who have a contraindication or intolerance to metformin

• For whom insulin is not an option.

• Added on to insulin in combination with metformin for patients with inadequate glycemic control on insulin with

metformin.

• Added on to insulin without metformin for patients with the following:

• Inadequate glycemic control on insulin

• Contraindication or intolerance to metformin.

Condition

• Drug plan cost of treatment with dapagliflozin should not exceed the drug plan cost of treatment with the least costly

option from within the sodium-glucose cotransporter-2 (SGLT-2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor

classes.

11

Forxiga (dapagliflozin): Oct 2015

Of Note:

• CDEC noted that the most appropriate comparator for dapagliflozin may vary across the

CADTH Common Drug Review (CDR)-participating drug plans, due to differences in the

reimbursement status of SGLT-2 inhibitors and DPP-4 inhibitors.

• A large number of new agents have become available since the CADTH Therapeutic

Review was last updated. At the time of this review, no other SGLT-2 inhibitors have been

reviewed through the CDR process for dual therapy (i.e., in combination with metformin or

a sulfonylurea) or for use in combination with insulin. CDEC noted that there is uncertainty

regarding the role of dapagliflozin and other SGLT-2 inhibitors for these indications.

• CDEC noted that an updated CADTH therapeutic review is required to accurately evaluate

the comparative clinical benefit and cost-effectiveness of SGLT-2 inhibitors, including

dapagliflozin, relative to other available antihyperglycemic agents, particularly DPP-4

inhibitors.

12

Trulicity (dulaglutide): May 2016

Recommendation:

• The CADTH Canadian Drug Expert Committee (CDEC) recommends that

dulaglutide be reimbursed for the treatment of adults with type 2 diabetes

mellitus in combination with metformin to improve glycemic control, if the

following condition is met:

Condition:

• Drug plan cost not to exceed that of the least costly pharmacotherapy

reimbursed in combination with metformin.

13

Jardiance (empagliflozin): Sept 2016

Recommendation:

• The CADTH Canadian Drug Expert Committee (CDEC) recommends that

empagliflozin be reimbursed as an adjunct to diet, exercise, and standard care

therapy to reduce the incidence of cardiovascular (CV) death in patients with

type 2 diabetes mellitus (T2DM) and established cardiovascular disease who

have inadequate glycemic control, if the following criteria are met:

Criteria:

• Patients have inadequate glycemic control despite an adequate trial of

metformin.

• Patients have established cardiovascular disease as defined in the EMPA-REG

OUTCOME trial.

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Empagliflozin:

Reasons for Recommendation

• In the EMPA-REG OUTCOME trial, empagliflozin 10 mg and 25 mg

appeared to be safe and reduced CV mortality when used adjunctively

with standard antidiabetic medications in patients with T2DM who are at

high risk for CV disease when compared with placebo. The impact of

empagliflozin on myocardial infarction (MI), stroke, hospitalization for

heart failure, renal or other microvascular outcomes is unclear given the

limitations of the EMPA-REG OUTCOME trial.

• The manufacturer-submitted economic model indicated a high

probability of empagliflozin being cost-effective, and limitations to the

model were unlikely to significantly change the estimated incremental

cost-utility ratio.

15

Empagliflozin:

EMPA-REG OUTCOME

• Established CV disease defined as one of the following:

• history of MI

• multi-vessel coronary artery disease in two or more major coronary

arteries (irrespective of revascularization status)

• single-vessel coronary artery disease with significant stenosis and

either a positive non-invasive stress test or discharged from hospital

with a documented diagnosis of unstable angina within 12 months

prior to selection

• last episode of unstable angina > 2 months prior with confirmed

evidence of coronary multi-vessel or single-vessel disease

• history of ischemic or hemorrhagic stroke

• occlusive peripheral artery disease.

16

Committee Discussion Points on

EMPA-REG OUTCOME

• CDEC acknowledged the EMPA-REG OUTCOME trial had

significant methodological limitations. These limitations

included deviation from standard outcome definitions,

multiple protocol amendments before and after the interim

analysis, questions regarding the reliability of outcome

ascertainment, and lack of control for type 1 error. This trial

was designed predominately as a safety trial, not as an

efficacy trial, and in light of this CDEC recognizes that there

is a further need for evidence development to confirm the

results of this trial.

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EMPA-REG OUTCOME

• While the trial achieved a statistically significant reduction in the primary

composite outcome, several secondary outcomes did not achieve

statistical significance in exploratory analysis, including MI, non-fatal MI,

silent MI, stroke, non-fatal stroke, transient ischemic attack, coronary

revascularization procedures, and hospitalization for unstable angina.

There was a statistically significant reduction in hospitalization for heart

failure; however, these results are uncertain given the exploratory

nature of the analysis, a trial-specific definition of heart failure

hospitalization, and multiple protocol amendments to the definition of

heart failure hospitalization during the course of the trial.

18


EMPA-REG OUTCOME

• CDEC noted the patient population had a significant history

of CV disease, with 76% of patients reporting a history of

coronary artery disease and 23% reporting a history of

stroke. CDEC also noted that the majority of patients had

T2DM for more than 10 years, and most patients were on

two or more antidiabetic drugs at baseline.

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New Drugs for Type 2 Diabetes: Second-Line Recommendations

20

Policy Questions

• What is/are the preferred second-line agent(s) to consider

for the treatment of adults with T2DM with inadequate

glycemic control on metformin monotherapy?

Research Questions • For adults with T2DM on metformin monotherapy with inadequate glycemic control, what is the

comparative efficacy and safety of using a drug from one of the following classes as second-line agent:

• Sulfonylurea;

• Insulin;

• DPP-4 inhibitor;

• GLP-1 analogue;

• SGLT-2 inhibitor?

• For adults with T2DM on metformin monotherapy with inadequate glycemic control, what is the

comparative cost-effectiveness of using a drug from one of the following classes as second-line agent:

• Sulfonylurea;

• Insulin;


• GLP-1 analogue;


• For adults with T2DM, what are the comparative cardiovascular effects of drugs belonging to one of the

following classes:

• Insulin


• GLP-1 analogue;


22

Recommendation 1

• For patients with type 2 diabetes and without established

cardiovascular disease, CDEC recommends that a

sulfonylurea be added to metformin for adults inadequately

controlled on metformin alone.

23

Reasons for Recommendation 1

• The results of the clinical review and a network meta-

analysis (NMA) demonstrated that all classes of

antidiabetes drugs were associated with similar efficacy for

improving glycated hemoglobin (A1C) in adults with

diabetes inadequately controlled with metformin alone

(mean differences from baseline ranged from −0.58% for

dipeptidyl peptidase-4 [DPP-4] inhibitors to −0.94% for

biphasic insulin). No class demonstrated any clear clinical

superiority over sulfonylureas for any safety or efficacy

outcome.

24

Reasons for Recommendation 1

• The CADTH pharmacoeconomic evaluation demonstrated

that sulfonylureas are the most cost-effective second-line

treatment option for adults with diabetes inadequately

controlled on metformin alone. For a base case

representing a typical Canadian patient with diabetes,

sulfonylureas were associated with an incremental cost-

utility ratio (ICUR) of $38,643 per quality-adjusted life-year

(QALY) gained compared with metformin alone. Compared

with metformin monotherapy, the ICURs for the other drug

classes, when added to metformin, were SGLT-2 inhibitors

($100,459), glucagon-like peptide-1 (GLP-1) analogues

($119,997), DPP-4 inhibitors ($178,127), basal insulins

($324,968), and biphasic insulins ($268,496).

25

Of Note:

Weight Gain & Hypoglycemia

• CDEC noted that the clinical trial data suggest that, among all patients

with diabetes, clinically meaningful hypoglycemic events are rare across

all drug classes, with low absolute rates of severe hypoglycemia

reported. Weight gain associated with treatment involving sulfonylureas

is relatively small (i.e., approximately 2 kg). CDEC reviewed several

sensitivity analyses of the cost-utility analyses completed to evaluate

increased impacts of weight gain and hypoglycemia on the reported

ICURs and treatment rankings. These adjustments to utility scores were

based on values that well exceeded estimates found in the literature.

Sulfonylureas remained the most cost-effective treatment option for

most of these analyses.

26

Recommendation 2

• For adults with type 2 diabetes and established

cardiovascular disease, CDEC recommends that therapy be

considered in accordance with CDEC recommendations for

individual drugs that have been reviewed specifically for this

indication.

27


• Data regarding the comparative long-term efficacy and safety of

different classes of second-line antidiabetes drugs on clinically

important complications of diabetes, particularly cardiovascular

outcomes, are currently sparse and of limited quality. Similarly, there are

limited long-term safety data regarding the adverse events associated

with long-term use of antidiabetes drugs from different classes.

However, CDEC noted that data in patients at high risk for a

cardiovascular event are emerging. CDEC noted that, in most cases,

the gaps in evidence and limitations of the existing evidence are too

large to support a specific drug-class recommendation based on these

data. The committee recognized that this review is based on data

available up to June 2016, and that relevant data will continue to be

published over the next four to five years; these data may impact these

recommendations.

28


• CDEC has previously provided recommendations regarding the use of

empagliflozin for patients at high risk of cardiovascular events, if

evidence was sufficient to support this recommendation. Empagliflozin

is the only drug at the time of this recommendation to have a specific

indication from Health Canada for the prevention of cardiovascular

death. CDEC continues to endorse the reimbursement of empagliflozin

for this specific population until more evidence becomes available to

comprehensively evaluate all drug classes for patients with diabetes

and established cardiovascular disease.

29

What evidence was reviewed?

1. Patient group input

2. Systematic review and network meta-analysis of drugs

used as a second-line agent after metformin

3. Systematic review and network meta-analysis of trials that

use major adverse cardiovascular events as a primary

outcome

4. Pharmacoeconomic analysis using the UKPDS model

5. Stakeholder feedback

6. Clinical expert (endocrinologist) engagement

30

Research Question 1:

Second-Line Treatments

• 175 unique RCTs

• 166 reported outcomes that were of interest for this review

• Evidence was available for the following eight drug classes:

sulfonylureas, SGLT-2 inhibitors, DPP-4 inhibitors,

thiazolidinediones (TZDs), GLP-1 analogues, basal insulin,

alpha-glucosidase inhibitors, meglitinides, and biphasic

insulin.

• 37 outcomes were extracted

• 84 RCTs used in network meta-analysis for glycemic control

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Key Efficacy & Safety Endpoints

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Comparative Efficacy:

Statistically Significant Outcomes

Outcome Comparison

A1C DPP-4 inhibitors did not decrease A1C as much as sulfonylureas or GLP-1 agonists

Weight All noninsulin treatments reduced mean body weight relative to SU SGLT-2 inhibitors and GLP-1 agonists reduced mean body weight relative to DPP-4 inhibitors

Blood Pressure SGLT-2 inhibitors and GLP-1 reduced SBP vs metformin monotherapy, sulfonylureas, and DPP-4 inhibitors Basal insulin increased SBP vs SGLT-2 inhibitors All treatments other than SU lowered DBP SGLT-2 inhibitors reduced DBP vs sulfonylureas and DPP-4 inhibitors

33



34

Outcome Comparison

Hypoglycemia Only sulfonylureas increased the risk of severe hypoglycemia when compared with metformin monotherapy GLP-1 agonists and SGLT-2 and DPP-4 inhibitors reduced the risk of severe hypoglycemia vs SU Compared with metformin monotherapy, the odds of nonsevere hypoglycemia were higher with SU and with basal and biphasic insulin All classes except biphasic insulin significantly reduced odds of nonsevere hypoglycemia relative to SU

Cholesterol SGLT-2 inhibitors increased LDL vs DPP-4 inhibitors SGLT-2 inhibitors increased HDL cholesterol vs metformin alone, and relative to sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists


Adverse Effects

• Overall all drugs have similar tolerability when looking at adverse

events and withdrawals due to adverse events:

• No class increased serious AEs vs metformin monotherapy

• Relative to metformin monotherapy, sulfonylureas, DPP-4

inhibitors, and basal insulin, GLP-1 agonists were the only

class to increase WDAE

• Biphasic insulin increased the odds of WDAE vs basal insulin

• GLP-1 agonists and basal or biphasic insulin increased AE

• Basal and biphasic insulin increased AE vs all classes

• GLP-1 agonists increased AEs vs DPP-4 and SGLT-2

inhibitors

35


Cardiovascular Events

• Systematic Review of 17 RCTs

• Includes LEADER (liraglutide) and EMPA-REG-

OUTCOME (empagliflozin)

• Patient populations:

• High risk of CV events or with pre-existing CVD

• Mixed background therapies

36

Key Endpoints

37



Outcome Result

MACE No SS differences

Mortality SGLT-2 inhibitors reduced the risk of all-cause mortality when compared with placebo (OR 0.67; 95% CI, 0.47 to 0.95) or DPP-4 inhibitors (OR 0.66; 95% credible interval [CrI], 0.45 to 0.99) Data were insufficient to conclude that any other treatments reduced the risk of all-cause mortality None of the selected classes significantly lowered the risk of CV mortality when compared with placebo or with each other

Heart Failure No SS differences

38


Pharmacoeconomic Analysis

• Update of the previous reviews included:

• Using updated costs

• Using an updated UKPDS model

• Addition of new class of drugs

• Additional sensitivity analyses

39

Drug Costs

40

Cost-Utility

41

Summary

• Recommendations for most patients remains consistent

• No clear clinical superiority of any treatment

• Significant gaps remain in evidence of impact on CV

outcomes

• Sulfonylureas remain the most cost-effective second-line

treatment

• Sensitivity analyses on weight gain and hypoglycemia do

not change this ranking

42

How does this align with clinical practice guidelines?

43

Diabetes Canada:

November 2016

• Pharmacologic Treatment:

• First-line:

• Metformin

• Second-line:

• Any agent as second-line treatment, individualized

based on patient characteristics, or

• Clinical cardiovascular disease, use a drug with

evidence of CV benefit, including empagliflozin or

liraglutide

American Diabetes Association:

January 2015

• Pharmacologic Treatment:

• First-line:

• Metformin

• Second-line:

• Add a second oral agent, a GLP-1 receptor agonist,

or basal insulin

• Considerations include efficacy, cost, potential side

effects, weight, comorbidities, hypoglycemia risk, and

patient preferences

International Diabetes Federation:

2012

• First-line:

• Metformin

• Second-line:

• Sulfonylurea

• Other options include adding metformin if not used

• first-line, an a-glucosidase inhibitor, a DPP-4 inhibitor or

TZD.

• A rapid-acting insulin secretagogue is an alternative

• option to sulfonylureas.

Summary

47

Summary

• Currently in a rapid phase of evidence development for new

drugs for type 2 diabetes

• Significant limitations and gaps remain to our current

evidence landscape

• At this time, for second-line treatments for type 2 diabetes,

CDEC recommends a sulfonylurea for patients without

cardiovascular disease, and for patients with cardiovascular

disease, CDEC has previously recommended empagliflozin

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#diabetesmatters - cadth update: type 2 diabetes - mitchelmore

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