Download Type 2 Diabetes

Comparing Medications for Adults With
Type 2 Diabetes
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
www.ahrq.gov
Background: Type 2 Diabetes
A chronic illness characterized by insulin resistance that
is worsened by obesity and inactivity.
Over time, pancreatic beta cells lose their ability to
maintain the high insulin levels needed to counter liver
and muscle insulin resistance and beta cell failure
occurs.
Background: Public Health Impact
In the United States, a total of 25.8 million children and
adults (8.3% of the population) have diabetes.
Like many chronic illnesses, diabetes disproportionately
affects older people and its prevalence is higher among
racial and ethnic minority populations.
The annual economic burden of diabetes is estimated to
be $174 billion—$116 billion for direct medical costs and
$58 billion for indirect costs (disability, work loss,
premature mortality)
 After adjusting for population age and sex differences,
average medical expenditures among people with
diagnosed diabetes is 2.3 times higher than what
expenditures would be in the absence of diabetes.
CDC. National Diabetes Fact Sheet, 2011. www.cdc.gov. accessed 6/2011
Background: Complications
Complications associated with long-standing diabetes
include:
 Retinopathy and blindness
 Neuropathy
 Nephropathy
 End-stage kidney disease
 Increased risk of death from cardiovascular disease
Background: Management
Management of hyperglycemia is a very important part of
treatment for type 2 diabetes to achieve improved
macrovascular and microvascular outcomes.
Controlling blood glucose levels for people with type 2
diabetes often requires several strategies.
The clinical approach includes weight loss if needed,
dietary control, increased physical activity, and
antidiabetic medications (ADA-EASD).
Source: 2007–2009 National Health Interview Survey.
Background: Treatment
 Treatment regimens include monotherapy and combinations of two
or three drugs from different classes.
 Eleven classes of diabetes medications are available:

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Biguanides
Thiazolidinediones
Sulfonylureas
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Insulins
Meglitinides
Glucagon-like peptide-1 (GLP-1) receptor agonists
An amylin analogue
Alpha-glucosidase inhibitors
Colesevalam (a bile-acid sequestrant)
Bromocriptine
 Choosing among the available medications requires consideration of
their benefits, mode of action/class, adverse effects, and cost.
Breakdown of Treatments for Diabetes in the
United States
Rationale for Update
In 2007, AHRQ published its first systematic review on
the comparative effectiveness of oral medications for
type 2 diabetes.
In 2011, this review was updated to include newer
medications and two-drug combination therapies:
 Noninsulin injectables: GLP-1 receptor agonists, exenatide, and
liraglutide (FDA-approved in 2005 and 2010, respectively).
 DPP-4 inhibitors: sitagliptin and saxagliptin (FDA-approved in 2006
and 2009, respectively).
 Evidence about combinations of medications, including combinations
of medications with insulin therapy.
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development
 Topics are nominated through a public process, which includes
submissions from health care professionals, professional
organizations, the private sector, policymakers, the public, and
others.
 A systematic review of all relevant clinical studies is conducted by
independent researchers, funded by AHRQ, to synthesize the
evidence in a report summarizing what is known and not known
about the select clinical issue. The research questions and the
results of the report are subject to expert input, peer review, and
public comment.
 The results of these reviews are summarized into Clinician Research
Summaries and Consumer Research Reviews for use in
decisionmaking and in discussions with patients. The research
reviews and the full report, with references for included and
excluded studies, are available at:
www.effectivehealthcare.ahrq.gov.
Rating the Strength of Evidence From the CER
 The strength of evidence was classified into four broad
categories:
High
Further research is very unlikely to change the confidence
in the estimate of effect.
Moderate
Further research may change the confidence in the estimate
of effect and may change the estimate.
Low
Further research is likely to change the confidence in the
estimate of effect and is likely to change the estimate.
Insufficient
Evidence either is unavailable or does not permit estimation
of an effect.
Priority Medication Comparisons
Monotherapy
as main
intervention
Combination
therapy as
main
intervention
Main Intervention
Comparisons
Metformin
• Thiazolidinedione, Sulfonylurea, DPP-4
inhibitor, Meglitinide, or a GLP-1 agonist
• Combination of metformin plus
thiazolidinedione
• Combination of metformin plus sulfonylurea
• Combination of metformin plus DPP-4 inhibitor
• Combination of metformin plus meglitinide
Thiazolidinedione
• Different thiazolidinedione, Sulfonylurea, DPP-4
inhibitor, Meglitinide, or a GLP-1 agonist
Sulfonylurea
• DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist
DPP-4 inhibitor
• DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist
Meglitinides
• GLP-1 agonist
Combination of metformin plus (a
thiazolidinedione or a sulfonylurea or one
of the meglitinides or a DPP-4 inhibitor or
a GLP-1 agonist or a basal insulin or a
premixed insulin)
Combination of metformin plus (a
thiazolidinedione or a sulfonylurea or a
meglitinides or DPP-4 inhibitor or GLP-1 agonist
or a basal insulin or a premixed insulin)
Combination of metformin plus (a
thiazolidinedione or a sulfonylurea or a
meglitinides or DPP-4 inhibitor or GLP-1
agonist or a basal insulin or a premixed
insulin)
Combination of a thiazolidinedione plus (a
sulfonylurea or a meglitinides or DPP-4 inhibitor
or GLP-1 agonist)
Results by Outcome
 Intermediate Outcomes





Glycemic control or Hemoglobin A1c (HbA1c)
Body weight
LDL cholesterol
HDL cholesterol
Triglycerides
 Adverse events and side effects





Mild to moderate hypoglycemia
Gastrointestinal (GI) side effects
Congestive heart failure
Liver injury
Hip and nonhip fractures
 Long-term clinical outcomes




All-cause mortality
Cardiovascular (CV) mortality
Nonfatal myocardial infarction and stroke
Microvascular outcomes (retinopathy, nephropathy, and neuropathy)
Comparative Effectiveness of Treatment
Options: Intermediate Outcomes
Glycemic control (HbA1c)
Weight
Lipids
 Low-density lipoprotein (LDL)
 High-density lipoprotein (HDL)
 Triglyceride (TG)
Intermediate Outcomes:
Overview of HbA1c Results
 MET, SUs, TZDs, and Rep reduce HbA1c levels by about 1
percentage point (moderate to high strength of evidence).
 MET lowers HbA1c 0.4% better than do DPP-4 inhibitors
(moderate strength of evidence).
 On average, two-drug combinations reduce HbA1c about 1
percentage point more than monotherapies (moderate to high
strength of evidence).
 MET + SUs and MET + TZDs are equally effective at lowering
HbA1c (moderate strength of evidence).
 Several other combinations therapies had similar efficacy at
reducing HbA1c (low strength of evidence).
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; HbA1c = hemoglobin A1c; MET = metformin; Rep =
repaglinide; SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Intermediate Outcomes:
Overview of Weight Results
MET is associated with less weight gain when compared
to other monotherapies or combinations (moderate to
high strength of evidence).
When compared to SUs, GLP-1 receptor agonists are
associated with less weight gain (moderate strength of
evidence).
MET + SUs are associated with less weight gain than are
combinations with TZDs (moderate strength of
evidence).
Some newer agents in combination show promise for
lower levels of weight gain (low strength of evidence).
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide-1
receptor agonists; MET = metformin; SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Intermediate Outcomes:
Overview of Lipid Results
In studies that lasted from 3 to 12 months, the effects of
antidiabetic medications on lipid levels were generally
small to moderate.
MET had more favorable effects on HDL, LDL, and TG
when compared to several monotherapy and combination
therapy medications (moderate to high strength of
evidence).
Some treatments had mixed effects on lipid outcomes.
HDL = high-density lipoprotein; LDL = low-density lipoprotein; MET = metformin; TG = triglycerides.
Details of HbA1c and Weight Intermediate
Outcomes: Comparisons of Monotherapies
Outcomes
HbA1c
Weight
Drug Comparisons
MET, SU, TZD, and Rep reduce HbA1c by about 1%.
Specific comparisons include:
• MET versus SU
• SU versus TZD; Pio versus RSG; MET versus TZD; SU versus Rep
• MET lowers HbA1c 0.4% better than do DPP-4 inhibitors.
Strength
of
Evidence
High
Moderate
Moderate
From the 2007 report, TZD, SU, and Rep increase weight by 1-5 kg, but
MET did not increase weight in placebo-controlled trials.
MET maintained or decreased weight when compared to other
monotherapies as shown below:
• MET versus TZD, -2.6 kg; MET versus SU, -2.7 kg
• MET versus DPP-4 inhibitors, -1.4 kg
GLP-1 receptor agonists were associated with less weight gain, by -2.5 kg,
when compared to SUs.
SU and MEG had similar effects on body weight.
High
Moderate
Moderate
High
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide-1 receptor
agonists; HbA1c = hemoglobin A1c; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG
= rosiglitazone; SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Details of the Lipid Intermediate Outcomes:
Comparisons of Monotherapies
Outcomes
LDL
HDL
TG
Drug Comparisons
MET is associated with lower LDL levels than are:
• SU, by -10.1 mg/dL
• RSG, by -12.8 mg/dL; Pio, by -14.2 mg/dL; DPP-4 inhibitors, by -5.9 mg/dL
Pio is associated with higher HDL levels when compared to:
• MET, by 3.2 mg/dL
• RSG, by 2.3 mg/dL; SU, by 4.3 mg/dL
MET is associated with HDL levels similar to those of:
• SU
• RSG
Strength
of Evidence
High
Moderate
High
Moderate
High
Moderate
Pio is associated with lower levels of TG by -27.2 mg/dL when compared to High
MET.
MET is associated with lower TG levels than were:
• RSG, by -27 mg/dL
Moderate
• SU, by -8.6 mg/dL
Moderate
TG levels for SU and MEG were similar.
Moderate
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = lowdensity lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; RSG = rosiglitazone; SU = second-generation
sulfonylureas; TG = triglycerides.
Details of the HbA1c and Weight Intermediate Outcomes:
Monotherapy versus Two-Drug Combination Therapy
Outcome
HbA1c
Weight
Drug Comparisons
Strength
of
Evidence
Two-Drug combination therapies are more effective than
monotherapies, reducing HbA1c by an additional 1%.
Specific comparisons include:
• MET versus MET/SU
• MET versus MET/TZD
• MET versus MET/DPP-4 inhibitors
High
High
Moderate
MET has a more favorable effect on weight when compared to
these combination therapies:
• MET/TZD, by -2.2 kg
• MET/SU, by -2.3 kg
High
High
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; HbA1c = hemoglobin A1c; MET = metformin;
SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Details of the Lipid Intermediate Outcomes:
Monotherapy versus Two-Drug Combination Therapy
Outcome
Drug Comparisons
LDL
MET/RSG is associated with higher levels of LDL, by 14.5
mg/dL, when compared to MET.
HDL
When compared to MET monotherapy:
• MET/RSG is associated with higher HDL levels by 2.8 mg/dL.
• MET/DPP-4 inhibitors are associated with similar levels of
HDL.
• MET/Pio is associated with higher levels of HDL.
TG
MET is associated with lower TG levels, by 14.5 mg/dL,
when compared to MET/RSG.
Strength
of
Evidence
High
High
Moderate
Low
High
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density
lipoprotein; MET = metformin; Pio = pioglitazone; RSG = rosiglitazone; TG = triglycerides.
Details of HbA1c and Weight Intermediate Outcomes:
Comparisons of Two-Drug Combination Therapies
Outcome
Drug Comparisons
HbA1c
MET/SU and MET/TZD are associated with similar HbA1c
levels.
Weight
MET/SU had a more favorable effect on weight
when compared to these combination therapies:
• TZD/SU, by -3.2 kg; MET/TZD, by -0.9 kg.
MET/GLP-1 receptor agonists has a more favorable effect on
weight, by about 1.9 to 12.3 kg, when compared to:
• MET/SU, MET/TZD, MET/basal insulin, and MET/DPP-4
inhibitor.
MET/DPP-4 inhibitors more favorably affect weight, by
about 1.5 to 2.5 kg, when compared to
• MET/TZD and MET/SU.
Strength
of
Evidence
Moderate
Moderate
Low
Low
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide-1 receptor agonists; HbA1c
= hemoglobin A1c; MET = metformin; RSG = rosiglitazone; SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Details of Lipid Intermediate Outcomes:
Comparisons of Two-Drug Combination Therapies
Outcome
Drug Comparisons
LDL
MET/SU is associated with lower levels of LDL, by -13.5
mg/dL, when compared with MET/RSG.
HDL
When compared with MET/SU:
• MET/Pio is associated with higher HDL levels by 5 mg/dL.
• MET/RSG is associated with higher levels of HDL by 2.7
mg/dL.
• SU/Pio is associated with higher levels of HDL.
TG
Strength
of
Evidence
Moderate
Moderate
Moderate
Low
When compared with MET/SU:
• MET/Pio is associated with lower levels of TG, by -15 mg/dL.
• MET/RSG is associated with similar levels of TG.
HDL = high-density lipoprotein; LDL = low-density lipoprotein; MET = metformin; Pio = pioglitazone;
RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides.
Moderate
Moderate
Comparative Adverse Events and Side Effects
 Hypoglycemia
 Gastrointestinal side effects
 Liver injury
 Hip and nonhip fractures
 Congestive heart failure
 Severe lactic acidosis
 Cancer
 Severe allergic reactions
 Pancreatitis
 Cholecystitis
 Macular edema or decreased vision
Overview of Adverse Events and Side Effects
 SUs and MEGs may cause more hypoglycemia than MET, TZDs, or DPP-4 inhibitors
(moderate to high strength of evidence).
 Most MET combinations increased the risk of hypoglycemia
(moderate strength of evidence).
 MET is associated with more GI adverse events (mainly diarrhea) when compared to
other agents (moderate to high strength of evidence).
 TZDs are associated with a higher risk of CHF compared to SUs
(moderate strength of evidence).*
 TZDs alone or in combination are associated with a higher risk of fractures compared
to other agents (high strength of evidence).
In 2007, the FDA issued an alert and changed labeling to state that TZDs cause or exacerbate CHF in some
patients. In 2010, the FDA placed additional prescribing restrictions on rosiglitazone use for type 2
diabetes in response to data that suggest an elevated risk of cardiovascular events including myocardial
infarction and stroke.
CHF = congestive heart failure; DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GI = gastrointestinal;
MEG = meglitinides; MET = metformin; SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Hypoglycemic Adverse Events:
Comparisons of Monotherapies
Outcome
Mild to
moderate
hypoglycemia
Drug Comparisons
The risk of hypoglycemia for SUs was:
• 4.6-fold higher than with MET
• 3.9-fold higher than with TZDs
• Higher than with DPP-4 inhibitors
When compared with MET monotherapy:
• MEGs were associated with a 3-fold increase in
hypoglycemia
• TZDs were associated with a similar risk of
hypoglycemia
Strength
of
Evidence
High
High
Moderate
Moderate
Moderate
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; MEG = meglitinides; MET = metformin; SU = second-generation
sulfonylureas; TZD = thiazolidinediones.
Gastrointestinal Adverse Events:
Comparisons of Monotherapies
Outcome
GI
adverse
events
Drug Comparisons
MET was associated with more GI adverse
events than were:
•TZDs
•SU; DPP-4 inhibitors
TZDs and SUs were associated with similar
rates of GI adverse events.
Strength
of
Evidence
High
Moderate
High
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GI = gastrointestinal;
MET = metformin; SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Other Adverse Events and Side Effects:
Comparisons of Monotherapies
Outcome
Liver injury
Drug Comparisons
Rates of liver injury for TZDs were low (range, 0% to 0.9%) and were
similar to:
• SUs (range 0% to 1%)
• MET (range 0.8% to 2.2%)
Hip/nonhip
fractures
TZDs were associated with higher rates of bone fractures compared
with MET.
CHF
Rates of CHF are higher for TZDs than for:
• SUs
• MET
Severe lactic
acidosis
While the risk of severe lactic acidosis was low for MET, SU, and
MET/SU, studies excluded individuals with significant renal, liver, or
cardiovascular disease.
Strength
of
Evidence
High
Moderate
High
Moderate
Low
Moderate
CHF = congestive heart failure; GI = gastrointestinal; MET = metformin; SU = second-generation sulfonylureas;
TZD = thiazolidinediones.
Adverse Events and Side Effects:
Monotherapy Versus Two-Drug Combination Therapy
Outcome
Drug Comparisons
Mild to
moderate
hypoglycemia
When compared with MET monotherapy:
• MET/SU is associated with an increased risk.
• MET/TZD is associated with an increased risk.
• MET/DPP-4 inhibitors are associated with a similar risk.
GI adverse
events
MET is associated with more GI adverse events than
these combinations if the dose of MET is higher in the
monotherapy arm:
• MET/SUs
• MET/TZDs
Hip/nonhip
fractures
MET/TZD is associated with higher rates of bone
fractures than MET.
Strength
of
Evidence
Moderate
Moderate
Moderate
Moderate
Moderate
High
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GI = gastrointestinal; MET = metformin; SU = second-generation
sulfonylureas; TZD = thiazolidinediones.
Adverse Events and Side Effects:
Comparisons of Two-Drug Combination Therapies
Outcome
Mild to
moderate
hypoglycemia
Drug Comparisons
MET/SU is associated with higher levels of
hypoglycemia than these combinations:
• MET/TZDs
• MET/GLP-1 receptor agonists
• Modestly lower risk of hypoglycemia when MET
is combined with a basal insulin rather than a
premixed insulin.
Strength
of
Evidence
High
Moderate
Moderate
GI adverse
events
MET/SU is associated with more GI adverse events than
SU/TZD.
Moderate
Hip/nonhip
fractures
TZD combinations are associated with higher rates of
bone fractures than MET/SU.
High
GI = gastrointestinal; GLP-1 receptor agonists = glucagon-like peptide-1 receptor agonists; MET = metformin;
SU = second-generation sulfonylureas; TZD = thiazolidinediones.
Macrovascular and Microvascular Long-Term
Clinical Outcomes of Diabetes
All-cause mortality
Cardiovascular mortality
Cardiovascular and cerebrovascular disease morbidity
Retinopathy
Nephropathy
Neuropathy
Long-Term Clinical Outcomes: Overview
Metformin was associated with slightly lower all-cause
mortality and cardiovascular disease mortality than were
sulfonylureas (low strength of evidence).
Pioglitazone was better than metformin at reducing the
albumin-to-creatinine ratio, likely indicating less
nephropathy (moderate strength of evidence).
There was insufficient evidence to draw conclusions
about other comparisons of antidiabetic medications.
Comparative Effectiveness and Safety in
Subpopulations
 Twenty-eight studies addressed medication effectiveness and
safety in subpopulations.
 When compared to men, women taking RSG either as
monotherapy or in combination were at higher risk for bone
fractures than were those taking MET alone or in combination
with SUs.
 However, for the majority of comparisons, the available
studies did not have sufficient power to allow for subgroup
analyses, and few studies occurred exclusively in a
subpopulation.
 There was no conclusive information to predict which
subgroups of patients might differentially respond to
alternative treatments.
MET = metformin; RSG = rosiglitazone; SU = second-generation sulfonylureas.
Gaps in Knowledge
 Studies are needed to address the efficacy of treatments for:
 Patients with type 2 diabetes who have varying levels of
underlying cardiovascular and renal disease.
 Persons of different ethnic groups or variant forms of type 2
diabetes.
 Additional comparative studies are needed including:
 Comparisons of newer medications.
 Combinations with basal or premixed insulin and MET or other
antidiabetic agents.
 Additional two-drug combinations.
 Sufficient data on event rates are needed to analyze major
clinically important outcomes, adverse events, and long-term
complications of type 2 diabetes.
What to Discuss With Your Patients
Establishing a goal for HbA1c and strategies to help
accomplish that goal, including weight loss and exercise
along with consistent use of medication
Strategies to increase adherence include creating a
medication schedule, addressing the costs of
medications, and reporting adverse events in a timely
manner
The need for regular glucose testing and routine blood
tests for HbA1c