Comparing Medications for Adults With Type 2 Diabetes

1
Comparing Medications for Adults With Type 2
Diabetes

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
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.

3
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 billion116 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
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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

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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 20072009 National Health Interview
Survey.
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Background Treatment

• 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.

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Breakdown of Treatments for Diabetes in the
United States
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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.

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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.

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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.
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Priority Medication Comparisons
Monotherapy as main intervention Main Intervention Comparisons
Monotherapy as main intervention 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
Monotherapy as main intervention Thiazolidinedione Different thiazolidinedione, Sulfonylurea, DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist
Monotherapy as main intervention Sulfonylurea DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist
Monotherapy as main intervention DPP-4 inhibitor DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist
Monotherapy as main intervention 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 therapy as main intervention 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)
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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)

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Conceptual Model
KQ key question
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Comparative Effectiveness of Treatment Options
Intermediate Outcomes

• Glycemic control (HbA1c)
• Weight
• Lipids
• Low-density lipoprotein (LDL)
• High-density lipoprotein (HDL)
• Triglyceride (TG)

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Intermediate OutcomesOverview 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.

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Intermediate OutcomesOverview 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.

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Intermediate OutcomesOverview 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.

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Details of HbA1c and Weight Intermediate
Outcomes Comparisons of Monotherapies
Outcomes Drug Comparisons Strength of Evidence
HbA1c 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. High Moderate Moderate
Weight 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. 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. 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.
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Details of the Lipid Intermediate Outcomes
Comparisons of Monotherapies
Outcomes Drug Comparisons Strength of Evidence
LDL 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 High Moderate
HDL 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 High Moderate High Moderate
TG Pio is associated with lower levels of TG by -27.2 mg/dL when compared to MET. MET is associated with lower TG levels than were RSG, by -27 mg/dL SU, by -8.6 mg/dL TG levels for SU and MEG were similar. High Moderate Moderate Moderate
DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors HbA1c hemoglobin A1c HDL high-density lipoprotein LDL low-density lipoprotein MEG meglitinides MET metformin Pio pioglitazone RSG rosiglitazone SU second-generation sulfonylureas TG triglycerides. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors HbA1c hemoglobin A1c HDL high-density lipoprotein LDL low-density lipoprotein MEG meglitinides MET metformin Pio pioglitazone RSG rosiglitazone SU second-generation sulfonylureas TG triglycerides. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors HbA1c hemoglobin A1c HDL high-density lipoprotein LDL low-density lipoprotein MEG meglitinides MET metformin Pio pioglitazone RSG rosiglitazone SU second-generation sulfonylureas TG triglycerides.
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Details of the HbA1c and Weight Intermediate
Outcomes Monotherapy versus Two-Drug Combination
Therapy
Outcome Drug Comparisons Strength of Evidence
HbA1c 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
Weight 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 metforminSU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors HbA1c hemoglobin A1c MET metforminSU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors HbA1c hemoglobin A1c MET metforminSU second-generation sulfonylureas TZD thiazolidinediones.
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Details of the Lipid Intermediate Outcomes
Monotherapy versus Two-Drug Combination Therapy
Outcome Drug Comparisons Strength of Evidence
LDL MET/RSG is associated with higher levels of LDL, by 14.5 mg/dL, when compared to MET. High
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. High Moderate Low
TG MET is associated with lower TG levels, by 14.5 mg/dL, when compared to MET/RSG. 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. 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. 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.
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Details of HbA1c and Weight Intermediate
Outcomes Comparisons of Two-Drug Combination
Therapies
Outcome Drug Comparisons Strength of Evidence
HbA1c MET/SU and MET/TZD are associated with similar HbA1c levels. Moderate
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. 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. 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. 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.
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Details of Lipid Intermediate Outcomes
Comparisons of Two-Drug Combination Therapies
Outcome Drug Comparisons Strength of Evidence
LDL MET/SU is associated with lower levels of LDL, by -13.5 mg/dL, when compared with MET/RSG. Moderate
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. Moderate Moderate Low
TG 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. Moderate Moderate
HDL high-density lipoprotein LDL low-density lipoprotein MET metformin Pio pioglitazone RSG rosiglitazone SU second-generation sulfonylureas TG triglycerides. HDL high-density lipoprotein LDL low-density lipoprotein MET metformin Pio pioglitazone RSG rosiglitazone SU second-generation sulfonylureas TG triglycerides. HDL high-density lipoprotein LDL low-density lipoprotein MET metformin Pio pioglitazone RSG rosiglitazone SU second-generation sulfonylureas TG triglycerides.
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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

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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.

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Hypoglycemic Adverse Events Comparisons of
Monotherapies
Outcome Drug Comparisons Strength of Evidence
Mild to moderatehypoglycemia 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 High High Moderate Moderate Moderate
DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors MEG meglitinides MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors MEG meglitinides MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors MEG meglitinides MET metformin SU second-generation sulfonylureas TZD thiazolidinediones.
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Gastrointestinal Adverse Events Comparisons of
Monotherapies
Outcome Drug Comparisons Strength of Evidence
GI adverse events 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. High Moderate High
DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones.
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Other Adverse Events and Side Effects
Comparisons of Monotherapies
Outcome Drug Comparisons Strength of Evidence
Liver injury 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) High Moderate
Hip/nonhip fractures TZDs were associated with higher rates of bone fractures compared with MET. High
CHF Rates of CHF are higher for TZDs than for SUs MET Moderate Low
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. Moderate
CHF congestive heart failure GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. CHF congestive heart failure GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. CHF congestive heart failure GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones.
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Adverse Events and Side Effects Monotherapy
Versus Two-Drug Combination Therapy
Outcome Drug Comparisons Strength of Evidence
Mild to moderatehypoglycemia 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. Moderate Moderate Moderate
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 Moderate Moderate
Hip/nonhip fractures MET/TZD is associated with higher rates of bone fractures than MET. High
DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. DPP-4 inhibitors dipeptidyl peptidase-4 inhibitors GI gastrointestinal MET metformin SU second-generation sulfonylureas TZD thiazolidinediones.
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Adverse Events and Side Effects Comparisons of
Two-Drug Combination Therapies
Outcome Drug Comparisons Strength of Evidence
Mild to moderatehypoglycemia 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. 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. GI gastrointestinal GLP-1 receptor agonists glucagon-like peptide-1 receptor agonists MET metformin SU second-generation sulfonylureas TZD thiazolidinediones. GI gastrointestinal GLP-1 receptor agonists glucagon-like peptide-1 receptor agonists MET metformin SU second-generation sulfonylureas TZD thiazolidinediones.
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Macrovascular and Microvascular Long-Term
Clinical Outcomes of Diabetes

• All-cause mortality
• Cardiovascular mortality
• Cardiovascular and cerebrovascular disease
  morbidity
• Retinopathy
• Nephropathy
• Neuropathy

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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.

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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.

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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.

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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