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Comparing Medications for Adults With Type 2 Diabetes

Clinician Summary – Jun. 30, 2011

Comparing Medications for Adults With Type 2 Diabetes

Formats

Table of Contents

Focus of Research for Clinicians

A systematic review of 166 clinical studies published between January 1966 and April 2010 examined the comparative effectiveness, benefits, and adverse effects of available monotherapy and two-drug combinations of medications for adults with type 2 diabetes. The review did not cover treatment of type 1 diabetes or gestational diabetes nor does it review evidence regarding the effectiveness of diet, exercise, and weight loss. The full report, listing all studies, is available at http://www.effectivehealthcare.ahrq.gov/diabetesmeds.cfm. This summary, based on the full report of research evidence, is provided to inform discussions with patients of options and to assist in decisionmaking along with consideration of a patient’s values and preferences. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.

Background Information

The management of hyperglycemia is an important focus of treatment to achieve improved macrovascular and microvascular outcomes in patients with type 2 diabetes. Controlling blood-glucose levels often requires several strategies, including weight loss if needed, dietary control, increased physical activity, and antidiabetic medications.1

Treatment regimens include single drugs and combinations of drugs from different classes. Choosing among the available medications requires consideration of benefits, adverse effects, mechanism of action, and cost. In 2007, the Agency for Healthcare Research and Quality published its first systematic review on the comparative effectiveness of oral medications for type 2 diabetes. The 2011 update includes newer medications and two-drug combinations.

1 American Diabetes Association; European Association for the Study of Diabetes

Conclusion

Evidence on the comparative effectiveness of antidiabetic medications for long-term macrovascular and microvascular outcomes is limited. However, evidence is available on intermediate outcomes. Many antidiabetic medications given as monotherapy work equally well to lower blood glucose. Two-drug combinations decrease hemoglobin A1c (HbA1c) further. Most agents (except metformin [MET] and glucagon-like peptide-1 [GLP-1] receptor agonists) are associated with increases in weight. The risk of mild to moderate hypoglycemia varies—it is highest for second-generation sulfonylureas (SU) and is increased for some two-drug combinations over monotherapy. MET may cause gastrointestinal (GI) upset. A United States Food and Drug Administration (FDA) warning indicates that thiazolidinediones (TZD) are associated with increased risks for cardiac failure, cardiovascular events, hip and nonhip fractures, and other risks in some patients. Tables 1, 2, and 3 summarize evidence about benefits, adverse events, and long-term benefits.

Clinical Bottom Line

(Detailed comparisons: Tables 1–3)

Glycemic Control (HbA1c)

  • On average, many of the single agents reduce HbA1c levels by 1 percentage point (evidence medium to evidence high).
  • On average, two-drug combination therapies reduce HbA1c about 1 percentage point more than monotherapies (evidence medium to evidence high).
  • Some two-drug combinations are equally effective (evidence medium) and others, though less studied, show promise (evidence low).


Weight

  • MET monotherapy was associated with less weight gain when compared with other monotherapies or two-drug combinations (evidence medium to evidence high).
  • When compared to second-generation sulfonylureas (SUs), GLP-1 receptor agonists were associated with less weight gain (evidence medium).
  • The combination MET/SU was associated with less weight gain than were two-drug combinations with TZDs (evidence medium).
  • Some newer agents in two-drug combinations show promise for lower levels of weight gain (evidence low).

Risk of Adverse Effects

  • SUs and meglitinides (MEG) are more likely to cause mild to moderate hypoglycemia than monotherapy with MET, TZD, or a dipeptidyl peptidase-4 (DPP-4) inhibitor (evidence medium to evidence high).
  • When compared to MET monotherapy, two-drug combinations with MET increase the risk of mild to moderate hypoglycemia, except for MET/DPP-4 inhibitor combinations (evidence medium).
  • MET is associated with more GI adverse events when compared with other single agents (evidence medium to evidence high).
  • TZDs are associated with a higher risk of congestive heart failure when compared with SUs (evidence medium). (See FDA Alerts for TZDs on page 5.)
  • TZDs alone or in combination are associated with a higher risk of hip and nonhip fractures when compared with other agents (evidence high).
  • FDA warnings indicate that TZDs are associated with increased risks for cardiac failure, cardiovascular events, fractures, and other risks. (See section titled "FDA Alerts for TZDs.")

Strength of Evidence

High: evidence high
There are consistent results from good-quality studies. Further research is very unlikely to change the conclusions.

Moderate: evidence medium
Findings are supported, but further research could change the conclusions.

Low: evidence low
There are very few studies, or existing studies are flawed.

Insufficient: evidence insufficient
Evidence either is unavailable or does not permit estimation of an effect.

Type 2 Diabetes Medications Studied by Class With Abbreviations

Class Generic Name Brand Name
Biguanides Metformin (MET) Glucophage®, Glucophage XR®
Second-generation sulfonylureas (SU) Glimepiride Amaryl®
Glipizide Glucotrol®, Glucotrol XL®, GITS®
Glyburide Diabeta®, Micronase®, Glynase Prestab®
Meglitinides (MEG) Repaglinide (Rep) Prandin®
Nateglinide Starlix®
Thiazolidinediones (TZD) Pioglitazone (Pio) Actos®
Rosiglitazone (RSG) Avandia®
Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin Januvia®
Saxagliptin Onglyza®
Glucagon-like peptide-1 (GLP-1) receptor agonists Exenatide injection Byetta®
Liraglutide injection Victoza®
Insulin NPH insulin Humulin N®, Novolin N®
Insulin detemir Levemir®
Insulin glargine Lantus®
70% NPH: 30% Regular Humulin® 70/30, Novolin® 70/30
50% lispro protamine suspension: 50% lispro Humalog® Mix50/50™
75% lispro protamine suspension: 25% lispro Humalog® Mix75/25™
70% aspart protamine suspension: 30% aspart NovoLog® Mix 70/30

Clinical Outcomes Table 1: Benefits

(Findings followed by evidence on specific comparisons.)
Clinical Outcomes Benefits: Monotherapy Versus Monotherapy
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide–1 receptor agonists; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides; TZD = thiazolidinediones.
HbA1c Monotherapy with MET, SU, TZD, or Rep reduced HbA1c levels by about 1 percent:
  • MET versus SU evidence high
  • SU versus TZD evidence medium
  • Pio versus RSG evidence medium
  • MET versus TZD evidence medium
  • SU versus Rep evidence medium
MET lowers HbA1c 0.4% better than do DPP-4 inhibitors. evidence medium
Weight From the 2007 report, many oral diabetes medications (TZD, SU, and Rep) increased weight by 1–5 kg; however, MET did not increase weight in placebo-controlled trials. evidence medium to evidence high
MET maintained or decreased weight when compared with other monotherapies, as shown below:
  • MET versus TZD, -2.6 kg evidence high
  • MET versus SU, -2.7 kg evidence high
  • MET versus DPP-4 inhibitor, -1.4 kg evidence medium
GLP-1 receptor agonists were associated with less weight gain, by -2.5 kg, when compared with SUs. evidence medium
SU and MEG had similar effects on body weight. evidence high
LDL MET was associated with lower LDL levels when compared with:
  • SU, by -10.1 mg/dL evidence high
  • RSG, by -12.8 mg/dL evidence medium
  • Pio, by -14.2 mg/dL evidence medium
  • DPP-4 inhibitors, by -5.9 mg/dL evidence medium
HDL Pio was associated with higher HDL levels when compared with:
  • MET, by 3.2 mg/dL evidence high
  • RSG, by 2.3 mg/dL evidence medium
  • SU, by 4.3 mg/dL evidence medium
MET was associated with HDL levels similar to those of:
  • SUs evidence high
  • RSG evidence medium
TG MET was associated with lower TG levels when compared with:
  • RSG, by -27 mg/dL evidence medium
  • SU, by -8.6 mg/dL evidence medium
Pio was associated with lower levels of TG by -27.2 mg/dL when compared with MET. evidence high
TG levels for SU and MEG were similar. evidence medium
Clinical Outcomes Benefits: Monotherapy Versus Combination Therapy
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide–1 receptor agonists; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides; TZD = thiazolidinediones.
HbA1c Two-drug combination therapies were more effective than monotherapy, reducing HbA1c by an additional 1 percent.
  • MET versus MET/SU evidence high
  • MET versus MET/TZD evidence high
  • MET versus MET/DPP-4 inhibitors evidence medium
Weight MET had a more favorable effect on weight when compared with these combination therapies:
  • MET/TZD, by -2.2 kg evidence high
  • MET/SU, by -2.3 kg evidence high
LDL MET/RSG was associated with higher levels of LDL, by 14.5 mg/dL, when compared with MET. evidence high
HDL When compared with MET monotherapy:
  • MET/RSG was associated with higher HDL levels by 2.8 mg/dL. evidence high
  • MET/DPP-4 inhibitor was associated with similar levels of HDL. evidence medium
  • MET/Pio was associated with higher levels of HDL. evidence low
TG MET was associated with lower TG levels, by -14.5 mg/dL, when compared with MET/RSG. evidence high
Clinical Outcomes Benefits: Combination Therapy Versus Combination Therapy
DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide–1 receptor agonists; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides; TZD = thiazolidinediones.
HbA1c MET/SU and MET/TZD were associated with similar HbA1c levels. evidence medium
Several other combinations had similar efficacy at reducing HbA1c:
  • MET/TZD versus MET/Rep evidence low
  • MET/TZD versus MET/sitagliptin evidence low
  • MET/TZD versus MET/GLP-1 receptor agonist evidence low
  • MET/SU versus MET/DPP-4 inhibitor evidence low
  • MET/GLP-1 receptor agonist versus MET/basal insulin evidence low
Weight MET/SU had a more favorable effect on weight when compared with these combinations:
  • TZD/SU, by -3.2 kg evidence medium
  • MET/TZD, by -0.9 kg evidence medium
MET/GLP-1 receptor agonists had a more favorable effect on weight, by about -1.9 to -12.3 kg, when compared with the following combinations:
  • MET/SU evidence low
  • MET/TZD evidence low
  • MET/basal insulin evidence low
  • MET/DPP-4 inhibitor evidence low
MET/DPP-4 inhibitors had a more favorable effect on weight, by about -1.5 to -2.5 kg, when compared with:
  • MET/TZD evidence low
  • MET/SU evidence low
LDL MET/SU was associated with lower levels of LDL, by about -13.5 mg/dL, when compared with MET/RSG. evidence medium
HDL When compared with the combination of MET/SU:
  • MET/Pio was associated with 5-mg/dL higher levels of HDL. evidence medium
  • MET/RSG was associated with 2.7-mg/dL higher levels of HDL. evidence medium
  • SU/Pio was associated with higher levels of HDL. evidence low
TG When compared with the combination of MET/SU:
  • MET/Pio was associated with lower levels of TG. evidence medium
  • MET/RSG was associated with similar levels of TG. evidence medium

Clinical Outcomes Table 2: Adverse Events

(Findings followed by evidence on specific comparisons.)
Clinical Outcomes Adverse Events: Monotherapy Versus Monotherapy
CHF = congestive heart failure; DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GI = gastrointestinal; GLP-1 receptor agonists = glucagon-like peptide–1 receptor agonists; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides; TZD = thiazolidinediones.
Mild to moderate hypoglycemia The risk of mild to moderate hypoglycemia for SU alone was:
  • 4.6-fold higher than MET evidence high
  • 3.9-fold higher than TZD evidence high
  • higher than with DPP-4 inhibitors evidence medium
When compared with MET monotherapy:
  • MEG was associated with a 3-fold increase in hypoglycemia evidence medium
  • TZD was associated with a similar risk of hypoglycemia evidence medium
GI adverse events MET was associated with more GI adverse events than were:
  • TZD evidence high
  • SU evidence medium
  • DPP-4 inhibitors evidence medium
TZDs and SUs were associated with similar rates of GI adverse events. evidence high
Liver injury Rates of liver injury for TZDs were low (range, 0% to 0.9%) and were similar to:
  • SUs (range, 0% to 1%) evidence high
  • MET (range, 0.8% to 2.2%) evidence medium
Hip/nonhip fractures TZDs were associated with higher rates of bone fractures when compared with MET. evidence high
CHF
(see FDA alert below)
Rates of CHF were higher for TZDs than for: SUs evidence medium
There were no long-term trials that provided a robust assessment of the comparative safety of the DPP-4 inhibitors and GLP-1 receptor agonists with respect to the risk of heart failure. evidence insufficient
Severe lactic acidosis While the risk of severe lactic acidosis was low for MET, SU, and MET/SU, individuals with significant renal, liver, or cardiovascular disease were excluded from the studies. evidence medium
Clinical Outcomes Adverse Events: Monotherapy Versus Combination Therapy
CHF = congestive heart failure; DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GI = gastrointestinal; GLP-1 receptor agonists = glucagon-like peptide–1 receptor agonists; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides; TZD = thiazolidinediones.
Mild to moderate hypoglycemia When compared with MET monotherapy:
  • MET/SU was associated with an increased risk. evidence medium
  • MET/TZD was associated with an increased risk. evidence medium
  • MET/DPP-4 inhibitor was associated with a similar risk. evidence medium
GI adverse events If the dose of MET was higher in the monotherapy arm than in the combination component, MET monotherapy was associated with more GI adverse events than these combinations:
  • MET/SU evidence medium
  • MET/TZD evidence medium
Hip/nonhip fractures MET/TZD was associated with higher rates of bone fractures than was MET. evidence high
Clinical Outcomes Adverse Events: Combination Therapy Versus Combination Therapy
Mild to moderate hypoglycemia MET/SU was associated with higher levels of hypoglycemia than were these combinations:
  • MET/TZD evidence high
  • MET/GLP-1 receptor agonist (liraglutide) evidence medium
MET/basal insulin combinations were associated with lower rates of hypoglycemia than were
MET/premixed insulin combinations. evidence medium
GI adverse events MET/SU was associated with more GI adverse events than was SU/TZD. evidence medium
Hip/nonhip fractures Combination therapy with a TZD was associated with higher rates of bone fractures than was MET/SU. evidence high

FDA Alerts for TZDs

According to FDA boxed warnings, TZDs may cause or exacerbate CHF in some patients and are contraindicated in patients with serious or severe heart failure. In 2010, the FDA placed additional prescribing restrictions on rosiglitazone use for type 2 diabetes in response to data that suggested an elevated risk of cardiovascular events, including myocardial infarction and stroke. In 2011, the FDA released a Safety Announcement that the use of pioglitazone for more than 1 year may be associated with an increased risk of bladder cancer (for more information visit www.fda.gov).

Gaps in Knowledge

  • Studies are needed to address the efficacy of treatments for hyperglycemia in patients with type 2 diabetes who have varying levels of underlying cardiovascular and renal disease, who come from different ethnic groups, or who have 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 oral agents, and 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.

Clinical Outcomes Table 3: Long-Term Benefits

(Findings followed by evidence on specific comparisons.)

Studies examining long-term benefits were limited. Only low levels of evidence were available for long-term outcomes (except as noted below for Pio, which may provide benefit for renal function), making it difficult to draw conclusions.

Clinical Outcomes Long-Term Benefits: Monotherapy Versus Monotherapy
All-cause mortality MET was associated with a lower risk of all-cause mortality when compared with SU. evidence low
There was insufficient evidence for all other comparisons, including:
  • DPP-4 inhibitor comparisons evidence insufficient
  • RSG versus Pio combinations evidence insufficient
  • Oral agent/insulin combinations evidence insufficient
  • GLP-1 receptor agonist comparisons evidence insufficient
  • All other combination therapy comparisons evidence insufficient
Cardiovascular mortality MET was associated with a slightly lower risk of cardiovascular mortality when compared with SU. evidence low
MET was associated with rates of cardiovascular mortality similar to those of TZDs. evidence low
Cardiovascular and cerebrovascular morbidity MET versus TZD was inconclusive. evidence low
Nephropathy Pio lowered the albumin-to-creatinine ratio better than MET, likely indicating less nephropathy. evidence medium
Retinopathy Evidence was insufficient for all comparisons. evidence insufficient
Clinical Outcomes Long-Term Benefits: Monotherapy Versus Combination Therapy
Cardiovascular mortality MET alone was slightly favored over MET/RSG. evidence low
Evidence was insufficient for all other comparisons. evidence insufficient
Cardiovascular and cerebrovascular morbidity MET alone was favored over MET/RSG for risk of fatal and nonfatal ischemic heart disease. evidence low
Evidence was insufficient for all other comparisons. evidence insufficient
Clinical Outcomes Long-Term Benefits: Combination Therapy Versus Combination Therapy
Cardiovascular mortality Evidence was insufficient for all comparisons of combination therapies. evidence insufficient
Cardiovascular and cerebrovascular morbidity Evidence was insufficient for all comparisons of combination therapies. evidence insufficient

CHF = congestive heart failure; DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GI = gastrointestinal; GLP-1 receptor agonists = glucagon-like peptide–1 receptor agonists; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MEG = meglitinides; MET = metformin; Pio = pioglitazone; Rep = repaglinide; RSG = rosiglitazone; SU = second-generation sulfonylureas; TG = triglycerides; TZD = thiazolidinediones.

Average Wholesale Prices for Diabetes Medicines

Drug Type Generic Brand Dose Price for 1-Month Supply: Generic Price for 1-Month Supply: Brand
These prices are the Federal median price for generic medicines and the average wholesale price for brand name medicines rounded to the next $5. These prices come from Red Book: Pharmacy’s Fundamental Reference, 2011 Edition.

XR/XL = extended release

NA = not available as a generic
Biguanides Metformin Glucophage® 500 mg once a day $25 $35
500 mg twice a day $50 $70
500 mg three times a day $75 $105
850 mg once a day $40 $60
850 mg twice a day $80 $115
850 mg three times a day $120 $175
1,000 mg once a day $45 $70
1,000 mg twice a day $90 $140
Glucophage XR® 500 mg once a day $25 $35
1,000 mg once a day $50 $70
1,500 mg once a day $75 $105
2,000 mg once a day $100 $140
Second-Generation Sulfonylureas Glimepiride Amaryl® 1 mg once a day $15 $20
2 mg once a day $25 $35
4 mg once a day $40 $60
8 mg once a day $80 $120
Glipizide Glucotrol® 5 mg once a day $15 $25
10 mg once a day $25 $40
10 mg twice a day $50 $80
20 mg twice a day $100 $160
Glucotrol XL® 5 mg once a day $15 $25
20 mg once a day $65 $90
Glyburide Diabeta® Micronase® 2.5 mg twice a day $40 $45
5 mg once a day $30 $40
5 mg twice a day $60 $80
Glynase PresTab® 1.5 mg once a day $9 $30
3 mg once a day $18 $45
6 mg twice a day $72 $145
Meglitinides Repaglinide Prandin® 0.5 mg three times a day NA $255
1 mg three times a day NA $255
4 mg three times a day NA $505
Nateglinide Starlix® 60 mg three times a day NA $195
120 mg three times a day NA $200
Thiazolidinediones Pioglitazone Actos® 15 mg once a day NA $180
30 mg once a day NA $275
45 mg once a day NA $300
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Sitagliptin Januvia® 100 mg once a day NA $230
Saxagliptin Onglyza® 2.5 mg–
5 mg once a day
NA $220
Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Exenatide Byetta® Injection of 5 mcg twice a day NA $300
Injection of 10 mcg twice a day NA $330
Liraglutide Victoza® Injection of 0.6 mg once a day NA $160
Injection of 1.2 mg once a day NA $315
Injection of 1.8 mg once a day NA $470

What To Discuss With Your Patients

  • Establishing a goal for HbA1c and strategies to help accomplish that goal, including weight loss, exercise, and consistent use of medication.
  • Strategies to increase adherence, including creating a medication schedule, addressing the costs of medications, and reporting adverse effects in a timely manner.
  • The need for regular glucose testing and routine blood tests for HbA1c.
  • What side effects to expect from the chosen medicines, and when to contact you if side effects occur.

Resource for Patients

Medicines for Type 2 Diabetes, A Review of the Research for Adults is a companion to this clinician research summary. It can help people talk to their health care professionals about medications for type 2 diabetes. It provides information about:

  • Types of diabetes medications.
  • The benefits and risks of medications.
  • Costs of medications.

Ordering Information

For electronic copies of Medicines for Type 2 Diabetes, A Review of the Research for Adults, this clinician research summary, and the full systematic review, visit www.effectivehealthcare.ahrq.gov/diabetesmeds.cfm. To order free print copies, call the AHRQ Publications Clearinghouse at 800-358-9295.

Source

The information in this summary is based on Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update, Comparative Effectiveness Review No. 27, prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018 for the Agency for Healthcare Research and Quality, March 2011. AHRQ Publication No.11-EHC038-EF. Available at: www.effectivehealthcare.ahrq.gov/diabetesmeds.cfm.

This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Andrea Humphries, Ph.D., Thomas Workman, Ph.D., Ashok Balasubramanyam, M.D., and Michael Fordis, M.D. 

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