Comparing Medications for Adults With

Type 2 DiabetesPrepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

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: Type 2 Diabetes

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.

Background: Public Health Impact

CDC. National Diabetes Fact Sheet, 2011. www.cdc.gov. accessed 6/2011

Complications associated with long-standing diabetes include: Retinopathy and blindness Neuropathy Nephropathy End-stage kidney disease Increased risk of death from cardiovascular disease

Background: Complications

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).

Background: Management

Source: 2007–2009 National Health Interview Survey.

Treatment regimens include monotherapy and combinations of two or three drugs from different classes. Eleven classes of diabetes medications are available:

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.

Background: Treatment

Breakdown of Treatments for Diabetes in the United States

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.

Rationale for Update

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.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development

Rating the Strength of Evidence From the CER

The strength of evidence was classified into four broad categories:

Priority Medication Comparisons

Monotherapy as main intervention

Main Intervention ComparisonsMetformin • 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 therapy as main intervention

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)

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)

Results by Outcome

Conceptual Model

KQ = key question

Glycemic control (HbA1c) Weight Lipids

Low-density lipoprotein (LDL) High-density lipoprotein (HDL) Triglyceride (TG)

Comparative Effectiveness of Treatment Options: Intermediate Outcomes

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 HbA1c 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 Weight 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.

Intermediate Outcomes:Overview of Lipid Results

Details of HbA1c and Weight Intermediate Outcomes: Comparisons of Monotherapies

Details of the Lipid Intermediate Outcomes: Comparisons of Monotherapies

Details of the HbA1c and Weight Intermediate Outcomes: Monotherapy versus Two-Drug Combination Therapy

Details of the Lipid Intermediate Outcomes: Monotherapy versus Two-Drug Combination Therapy

Details of HbA1c and Weight Intermediate Outcomes: Comparisons of Two-Drug Combination Therapies

Details of Lipid Intermediate Outcomes: Comparisons of Two-Drug Combination Therapies

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

Comparative 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.

Overview of Adverse Events and Side Effects

Hypoglycemic Adverse Events: Comparisons of Monotherapies

Gastrointestinal Adverse Events: Comparisons of Monotherapies

Other Adverse Events and Side Effects: Comparisons of Monotherapies

Adverse Events and Side Effects: Monotherapy Versus Two-Drug Combination Therapy

Adverse Events and Side Effects: Comparisons of Two-Drug Combination Therapies

All-cause mortality Cardiovascular mortality Cardiovascular and cerebrovascular disease

morbidity Retinopathy Nephropathy Neuropathy

Macrovascular and Microvascular Long-Term Clinical Outcomes of Diabetes

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.

Long-Term Clinical Outcomes: Overview

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.

Comparative Effectiveness and Safety in Subpopulations

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.

Gaps in Knowledge

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

What to Discuss With Your Patients