From the ACP Diabetes Care Guide

This tool lists what to consider before providing patients with these medications.

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Set a target for glycemic control based on the patient's risk of hypoglycemia and underlying medical conditions.

Recognize the importance of insulin therapy in achieving glycemic targets to prevent complications.

Use insulin-adjustment algorithms and delivery systems individualized for each patient.

Take measures to avoid severe hypoglycemia.

Consider aspirin therapy for primary and secondary prevention of cardiovascular diseases.

Aggressively manage blood pressure.

Aggressively manage serum lipid levels.

Treat diabetic nephropathy with ACE inhibitors and dietary protein restriction.

Treat painful peripheral neuropathy and foot ulcerations.

Aggressively maintain blood glucose control in patients with acute cardiac and CNS ischemia.

Consider treatment of autonomic neuropathy in the overall management of type 1 diabetes.

Take measures to avoid severe hypoglycemia.

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Use patient characteristics and preferences to set treatment goals in the initial choice of pharmacologic agent.

Adjust diabetes medications as needed to achieve target level of glycemic control.

Consider using a combination of insulin and oral agents if oral agents do not achieve the desired level of glycemic control.

Consider using other insulin regimens if oral agents and bedtime insulin combined do not achieve the desired level of glycemic control.

Aim for optimal glucose control to reduce risk of microvascular and neuropathic outcomes in patients with type 2 diabetes.

Treat hypertension aggressively to reduce the risk of adverse microvascular (e.g., retinopathy, nephropathy) and macrovascular (e.g., MI, stroke) outcomes.

Treat hyperlipidemia with diet and pharmacologic agents to reduce the risk of adverse macrovascular outcomes.

Consider use of aspirin therapy for primary and secondary prevention of cardiovascular disease in all patients with diabetes, unless there are specific contraindications.

Take steps to prevent and treat diabetic nephropathy to reduce the risk of progression to end-stage renal failure in patients with type 2 diabetes.

Consider treating painful neuropathy with tricyclic antidepressants, carbamazepine, gabapentin, capsaicin, or duloxetine.

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From the ACP Diabetes Care Guide

The combination of progressive beta-cell dysfunction and increasing insulin resistance leads to the need for pharmacologic therapy to control hyperglycemia in most patients with type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) showed that fewer than 25% of persons treated with diet and exercise were able to maintain hemoglobin A1C levels of <7% after 3 years, and fewer than 10% achieved this goal after 9 years.

The goal of pharmacotherapy is to achieve target hemoglobin A1C and fasting and postprandial glucose values within a few months. This is achievable if medications are prescribed early and at adequate dosages. The two major categories of oral diabetes drugs are insulin secretagogues and insulin sensitizers that enhance insulin action.

Oral hypoglycemic drugs covered in this chapter include:

• Secretagogues: Sulfonylureas-1st generation (Tolbutamide, Tolazamide, Chloropropamide)
• Secretagogues: Sulfonylureas-2nd generation (Glyburide, Glipizide, Glimepiride)
• Nonsulfonylurea secretagogues (Repaglinide, Nateglinide)
• Biguanides (Metformin, Metformin extended release)
• Alpha-glucosidase inhibitors (Acarbose, Miglitol)
• Thiazolidinediones (Rosiglitazone, Pioglitazone)
• Dipeptidyl peptidase IV inhibitors (Sitagliptin)

NOTE: You may order free copies of the complete ACP Diabetes Care Guide (book and CD-ROM).

open document (pdf)

From the ACP Diabetes Care Guide

This, the most extensive chapter in the guide, includes information on the following:

• When does a patient with type 2 diabetes need to be started on insulin?
• What do I need to teach my patients about insulin?
• Types of Insulin
• Insulin Regimens for Type 2 Diabetes (Basal Insulin Only, Premixed Insulin at Supper, Combination Insulin Two or Three Times Daily, Basal-Bolus Regimens)
• What do I need to teach patients taking multiple daily insulin injections?
• Pattern Management - Fine-tuning Insulin Regimens (Insulin Correction Dose Adjustments - Basic Carbohydrate Counting, Advanced Carbohydrate Counting)
• Insulin Pump Therapy
• Helping Patients Make the Transition to Insulin (making the decision, overcoming fears)
• Insulin Regimens for Type 1 Diabetes
• Insulin for Gestational Diabetes
• Helping Patients Succeed with Insulin Therapy
• New Injectables (Exenatide, Pramlintide - Symlin)
• Injectable Drug Supplies (Syringes, Pen Injectors, Glucagon, Ketone Test Strips)
• Beta Cell Replacement Therapies

You may order free copies of the complete ACP Diabetes Care Guide (book and CD-ROM).

SPECIAL NOTE: Table 8-1 has been revised.

open document (pdf) | open revised Table 8-1 (pdf)

This session answers the following questions:

• Newer and better agents are becoming available each year. How does this influence when a patient should be switched to insulin?
• Newer insulins vs. standard, time-tested therapies: advantages and disadvantages.
• Oral and inhaled insulins - will they have a place in therapy?
• Complications: macrovascular and microvascular. How much of the risk is glycemic control vs. genetic susceptibility?

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This session answers the following questions:

• What are the benefits of combination drug therapy?
• Should all high-risk CHD patients receive statins regardless of their LDL cholesterol level?
• What is the low HDL cholesterol synderome, and how should it be treated?
• Should high-risk patients with diabetes be treated with statins, fibrates, or both?

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This session answers the following questions:

• What should be the goals of therapy?
• How should one choose among available oral agents?
• What is the role of insulin, and when should it be used?

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This session answers the following questions:

• What are the indications for initiating exenatide treatment in type 2 diabetes?
• What should be done with oral therapy for patients now requiring insulin for control of their diabetes?
• How should the new basal insulin analogues (glargine, determir) and rapidly active insulin analogues (lispro, aspart, glulisine) be used? Are there important differences between agents?
• Can diabetes be prevented? If so, how and in whom? Is there a role for thiazolidinediones?

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This session answers the following questions:

• Is it better to start with multiple drug therapy?
• Are there cardiovascular benefits with any diabetic oral agent?
• Are there adverse cardiac outcomes with any diabetic oral agent?

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This session answers the following questions:

• For patients with type 2 diabetes, failing combination therapy with sulfonylureas and metformin, what options would be considered to reach glycemic targets?
• How does one decide the best treatment for a 40-year old non-obese man with newly diagnosed diabetes?
• A 55-year-old woman is started on insulin glargine that is added to glipizide and metformin. Her initial A1c is 9.9% and after 6 months, it dropped to 8.5% with fasting glucose ranging from 105 to 125 mg/dL. Her glargine dose is 46 units at bedtime. What should be considered now?

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Type 2 diabetes is conventionally treated initially with diet (calorie restriction), weight loss, and exercise. Such lifestyle modifications are usually insufficient to attain glucose targets, and most patients require at least oral agents.

Type 2 diabetes is a progressive disease frequently requiring combination oral therapy within several years of diagnosis, with many patients at some point actually needing insulin injections. Most physicians initiate an oral agent as first-line therapy in the patient whose diabetes is not controlled by diet and exercise alone.

Subsequently, oral agents with different mechanisms of action are used together. Then, insulin is either added to oral agents or substituted entirely for the oral agent regimen.

Note: Subscription to MKSAP 14 is required to view this material. For more information, visit www.acponline.org.

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Background:
Patients with type 2 diabetes who do not achieve glycemic control with oral agent therapy eventually require insulin.

Objective:
To determine the effect on glycemic control of inhaled insulin alone or added to dual oral therapy (insulin secretagogue and sensitizer) after failure of dual oral therapy.

Design:
Open-label, randomized, controlled trial.

Setting:
48 outpatient centers in the United States and Canada.

Participants:
309 patients with type 2 diabetes, no clinically significant respiratory disease, and hemoglobin A1c level of 8% to 11% who were receiving dual oral therapy.

Intervention:
Inhaled insulin (Exubera; Pfizer Inc. [New York, New York], sanofi-aventis Group [Paris, France], and Nektar Therapeutics [San Carlos, California]), titrated to blood glucose, administered alone (n = 104) or added to dual oral agents (n = 103) versus oral therapy alone (n = 99).

Measurements:
Primary end point was change in hemoglobin A1c level from baseline to 12 weeks. Secondary outcomes included hemoglobin A1c level less than 8% and less than 7%, hypoglycemia, weight, lipid levels, pulmonary function, insulin antibody binding, and adverse events.

Results:
Reductions in hemoglobin A1c level were greater with inhaled insulin. Adjusted treatment group differences for inhaled insulin plus oral agents and inhaled insulin alone compared with continued oral agent therapy were -1.67 percentage points (95% CI, -1.90 to -1.44 percentage points; P < 0.001) and -1.18 percentage points (CI, -1.41 to -0.95 percentage point; P < 0.001), respectively. Hemoglobin A1c level less than 7% was achieved by 32% (inhaled insulin plus oral agents) and by 1% (oral agent therapy) of patients (adjusted odds ratio, 44.7 [CI, 6.0 to 335.2]). Hypoglycemia, mild weight gain, mild cough, and insulin antibodies were more frequent with inhaled insulin than with oral agent therapy alone. Pulmonary function was similar in all groups.

Limitations:
This study evaluated only patients with hemoglobin A1c levels of 8% to 11%, did not compare inhaled insulin with other insulins or oral therapy except a dual regimen of secretagogue and sensitizer, and lasted only 12 weeks.

Conclusions:
Inhaled insulin improved overall glycemic control and hemoglobin A1c level when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer. Consistent with other insulin therapies, hypoglycemia and mild weight gain occurred. Pulmonary function showed no between-group differences.

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A literature review on the benefits and harms of oral drugs for type 2 diabetes mellitus found that older agents, such as second-generation sulfonylureas and metformin, have similar or superior effects on glycemic control, lipids and other intermediate end points compared to newer, more expensive drugs, such as thiazolidinediones, alpha-glucosidase inhibitors and meglitinides.

This is the first systematic review to compare all drugs on a full range of intermediate end points-evidence that is urgently needed to guide therapy since new oral diabetes drugs continue to emerge on the market, authors say.

Note: This review, published early online, will appear in the Sept. 18, 2007, print edition of Annals of Internal Medicine.

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Diabetes drugs rosiglitazone and pioglitazone will carry black-box warnings about the risk of heart failure, the FDA announced last week. In addition to Avandia and Actos, the warning will apply to combination drugs Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin) and Duetact (pioglitazone and glimepiride).

An FDA review of adverse events associated with the drugs found cases of significant weight gain and edema as well as reports of continued therapy resulting in death, which led the agency to ask manufacturers GlaxoSmithKline and Takeda to add the stronger warnings.

The new warning advises health care professionals to observe patients carefully for signs of heart failure--including shortness of breath, edema and excessive and rapid weight gain--after starting drug therapy. Patients with these symptoms who then develop heart failure should receive appropriate management and reconsider use of the drug, the FDA said. The black box also warns that the drugs should not be used by people with serious or severe heart failure.

The new warning is separate from the FDA's ongoing review of evidence that rosiglitazone increases heart attack risk. Last month, an FDA advisory panel recommended that the drug stay on the market but have information added to the label about ischemic risks.

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Two meta-analyses released last week add to the growing array of data on the cardiovascular effects of diabetes drugs rosiglitazone and pioglitazone.

The meta-analysis of rosiglitazone included four studies of 14,000 people and concluded that use of the drug for at least 12 months was associated with a significantly increased risk of myocardial infarction (MI) and heart failure, but the study did not find a significantly increased risk of cardiovascular mortality compared with controls.

The second meta-analysis used a database of 19 trials involving 16,000 patients provided by the manufacturer for independent analysis. Researchers found that pioglitazone was associated with a significantly lower risk of death, MI or stroke than controls. The drug did increase serious heart failure, although without an associated increase in mortality.

Authors of both analyses noted that it is unclear why the drugs--both thiazolidinediones--have such different effects on cardiovascular outcomes. The authors of the pioglitazone research concluded that the net clinical benefit of therapy with the drug is favorable. In their view, the reduction in irreversible ischemic events is not attenuated by the risk of more frequent heart failure complications.

The authors of the rosiglitazone analysis said that their research suggests a reversal of the benefit-to-harm balance that led the FDA to approve the drug. They propose that regulatory agencies reevaluate whether the drug belongs on the market. Physicians should not wait for a government decision, the authors advised, and should avoid prescribing the drug for patients who are at risk of cardiovascular events. Both meta-analyses were published in the Sept. 12 Journal of the American Medical Association.

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A documentary on diabetes, for which physicians can earn CME credit, debuted on the Discovery Channel this month. The documentary, "Diabetes: A Global Epidemic" can also be viewed online or downloaded as a podcast.

The documentary is divided into four hour-long segments:

• Insulin initiation: glycemic control with postprandial glucose monitoring
• Effectively managing anticoagulation
• Insulin initiation: targeting type 2 diabetes
• Diabetes: A global epidemic

The series is supported by an unrestricted educational grant to Discovery Health from Novo Nordisk.

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Thiazolidinediones, primarily rosiglitazone (Avandia), increase the risk of congestive heart failure, acute myocardial infarction and death for older patients with diabetes, a new study found.

The retrospective cohort study used health care databases in Ontario to examine 159,026 diabetes patients age 66 years and older who had been treated with at least one hypoglycemic agent between 2002 and 2005. Follow up was for a median of 3.8 years. The study was published in the Dec. 12 Journal of the American Medical Association.

Patients treated with thiazolidinedione monotherapy had a 60% higher risk of congestive heart failure, a 40% higher risk of acute myocardial infarction and a 29% higher risk of death compared with people taking other hypoglycemic agent combination therapies. Patients treated with thiazolidinedione combination therapy had a 31% higher risk of congestive heart failure, and a 24% higher risk of death, but no higher risk of heart attack, compared with those taking other therapies. The association between thiazolidinedione treatment and cardiac events appears limited to rosiglitazone, the authors said.

Past research has indicated that rosiglitazone and pioglitazone may increase the risk of congestive heart failure, while two meta-analyses have suggested rosiglitazone may increase the risk of acute myocardial infarction. The FDA recently added boxed warnings to the drugs' labels to reflect these risks, but has stopped short of recommending that the drugs be pulled from the market.

"These findings provide evidence from a real-world setting and support data from clinical trials that the harms of thiazolidinediones may outweigh their benefits," though further studies are needed, the authors said. For now, clinicians need to weigh the potential benefits and harms of treatment on an individual basis, especially with high-risk elderly populations, they said.

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A large government trial of diabetes treatments was halted last week after it was found that intensive efforts to lower patients? blood sugar were associated with higher mortality rates.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial included more than 10,000 patients who had diabetes and at least two other risk factors for heart disease. The patients were randomized to either intensively low blood sugar goals (A1c of less than 6%) or standard goals and treatment (A1c between 7% and 7.9%). Over the almost four-year study period, 257 patients in the intensive group had died, compared with 203 patients in the standard group, NIH officials announced last week. Based on that survival difference (which works out to 3 deaths per 1,000 participants per year), officials decided to halt the intensive treatment arm of the trial.

The researchers have not uncovered an explanation for the difference in survival, although an investigation is ongoing. Overall, death rates in both groups were lower than in similar populations in other studies. Because of recent concerns, the researchers specifically looked at rosiglitazone for a link to the increased deaths, but they found no association. The standard treatment arm of the ACCORD study, as well as related trials of blood pressure and lipid treatment, will continue until the planned conclusion date of June 2009.

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The newly approved OneTouch Ping Glucose Management System allows patients to calculate and deliver insulin doses without touching their pumps.

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The ADA recently published this algorithm that provides guidance on how to start oral agents, which oral agents to use, which to add on and when, and when to initiate insulin therapy.

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The 2007 ADA Clinical Practice Recommendations provide an in depth review of diabetes care and their current recommendations for practice.

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The AHRQ evidence-based practice center's Comparitive Effectiveness Review provides a systematic review of the evidence for the effectiveness and safety of oral diabetes medications currenlty available. A summary article can be found in early release in the July 17 Annals of Internal Medicine and in the September 18th print issue.

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The ADA has issued their 2008 Comprehensive Guidelines for Diabetes Care

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Question
In older patients with type 2 diabetes, do thiazolidinediones (TZDs) increase risk for heart failure (HF), myocardial infarction (MI), and mortality more than other oral hypoglycemic agents?

Conclusion
In older patients with type 2 diabetes, thiazolidinediones (in particular, rosiglitazone) were associated with higher risks for heart failure, myocardial infarction, and mortality than other oral hypoglycemic agents.

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Question
In patients with diabetes mellitus, what is the efficacy of long-acting insulin analogues (LAIAs) compared with human insulin or oral antidiabetic agents?

Conclusion
Long-acting insulin analogues do not reduce HbA1c levels more than NPH insulin but do reduce nocturnal hypoglycemia.

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Question
In patients with prediabetes or type 2 diabetes, do thiazolidinediones (TZDs) increase the risk for congestive heart failure (CHF) and cardiovascular death?

Conclusion
In patients with prediabetes or type 2 diabetes, thiazolidinediones increase the risk for congestive heart failure but not cardiovascular death.

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Question
In adults with type 2 diabetes, is incretin therapy effective and safe for glycemic control?

Conclusions
In type 2 diabetes, incretin therapy is more effective than placebo for glycemic control; results of comparisons with other hypoglycemic agents are inconsistent. Glucagon-like peptide 1 analogues are associated with weight loss and dipeptidyl peptidase 4 inhibitors with weight gain.

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Question
In patients with type 2 diabetes, what is the risk for heart failure (HF) associated with thiazolidinediones (TZDs)?

Conclusion
Thiazolidinediones increase risk for heart failure in patients with type 2 diabetes.

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Question
In patients with type 2 diabetes mellitus (DM), are meglitinide analogues (MAs) effective and safe?

Conclusion
In patients with type 2 diabetes mellitus, meglitinide analogues (especially repaglinide) reduce glucose levels, but morbidity and mortality effects are undocumented.

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Question
In patients with type 2 diabetes, how does rosiglitazone (RGZ) compare with placebo or other drugs for cardiovascular (CV) outcomes?

Conclusion
Rosiglitazone increases risk for myocardial infarction and cardiovascular death in patients with type 2 diabetes.

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Question
In patients with type 2 diabetes, is rosiglitazone (RGZ) as add-on therapy noninferior to metformin (MFN) plus sulfonylurea (SFU) for cardiovascular (CV) outcomes?

Conclusion
At interim analysis (mean 3.75 y), rosiglitazone as add-on therapy increased risk for heart failure but did not differ from metformin plus sulfonylurea for other cardiovascular outcomes in patients with type 2 diabetes .

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Question
In patients with type 2 diabetes mellitus, how effective and safe are long-acting insulin analogues compared with human isophane (NPH) insulin?

Conclusion
In patients with type 2 diabetes, the long-acting insulin analogues glargine and detemir reduce risk for hypoglycemia compared with human isophane insulin, without sacrificing glycemic control.

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Question
In patients with type 2 diabetes inadequately controlled with metformin monotherapy, is vildagliptin (VDGP) effective as add-on therapy for 24 weeks?

Conclusion
Vildagliptin was effective as add-on therapy for 24 weeks in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

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Question
In patients having cardiac surgery, does intraoperative intensive insulin therapy (IIT) reduce morbidity and mortality?

Conclusion
Intensive insulin therapy during cardiac surgery did not reduce morbidity and mortality but increased risk for stroke more than conventional insulin therapy.

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Question
In patients with type 2 diabetes, what are the relative efficacy and tolerability of vildagliptin and rosiglitazone?

Conclusion
In patients with type 2 diabetes, vildagliptin was noninferior to rosiglitazone for glycemic control and resulted in less weight gain and a better lipid profile.

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Question
In patients with diabetes, what is the relative efficacy, safety, and acceptability of inhaled insulin compared with subcutaneous (SC) insulin and oral hypoglycemic agents?

Conclusions
In patients with diabetes, inhaled insulin provides better glycemic control than oral hypoglycemic agents but not subcutaneous insulin. Inhaled insulin increases the risk for hypoglycemia more than do oral agents and the risk for pulmonary side effects more than do the other treatments.

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Question
In patients with type 2 diabetes, is sitagliptin (a dipeptidyl peptidase-4 inhibitor) more effective than placebo for glycemic control?

Conclusion
In patients with type 2 diabetes, sitagliptin is more effective than placebo for improving glycemic control and β-cell function.

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Question
Is 40 mg/d of generic simvastatin continued for life cost-effective in patients of different ages with differing risks for vascular disease?

Conclusion
Lifetime generic simvastatin, 40 mg/d, was cost-effective in patients of different ages with a range of vascular risks.

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Question
In patients with type 2 diabetes, is atorvastatin more effective than placebo for preventing cardiovascular (CV) events?

Conclusions
In low-risk patients with type 2 diabetes, atorvastatin did not prevent cardiovascular events.

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Question
In patients with type 2 diabetes mellitus poorly controlled with sulfonylurea monotherapy, is adjunctive inhaled human insulin (INH) better than adjunctive metformin?

Conclusion
Patients with type 2 diabetes mellitus that was poorly controlled with sulfonylurea monotherapy had better glycemic control but more hypoglycemic events after the addition of premeal inhaled insulin than did those after the addition of metformin.

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Question
In women with gestational diabetes mellitus (GDM), does a screening and active management intervention reduce serious perinatal complications more than routine care?

Conclusion
In women with gestational diabetes mellitus, screening and active management reduced perinatal complications more than routine care.

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Question
In patients with type 2 diabetes mellitus, are α-glucosidase inhibitors effective for improving glycemic control?

Conclusions
In patients with type 2 diabetes, α-glucosidase inhibitors improve glycemic control in studies mainly 24 weeks in duration. Data are lacking on the effects of α-glucosidase inhibitors on mortality, diabetes-related morbidity, and quality of life.

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Question
In patients with type 2 diabetes mellitus and inadequate glycemic control, how do insulin monotherapy and insulin combined with oral hypoglycemic agents (OHAs) compare?

Conclusion
In patients with type 2 diabetes, insulin monotherapy and insulin combined with oral hypoglycemic agents provide similar improvements in glycemic control.

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Question
In patients with diabetes, is a short-acting insulin analogue more effective than regular human insulin?

Conclusions
In adults with type 1 diabetes, short-acting insulin analogue reduces glycosylated hemoglobin more than regular human insulin. No difference is seen for hypoglycemic episodes. In adults with type 2 diabetes, children, and women with gestational diabetes, insulin analogues and regular human insulin do not differ in effect.

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Question
In patients with type 2 diabetes mellitus, what is the efficacy of pharmacotherapy for weight loss?

Conclusion
In patients with type 2 diabetes mellitus, fluoxetine, orlistat, and sibutramine modestly reduce weight and fluoxetine and orlistat improve blood sugar control.

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Questions

Conclusion
In patients with type 2 diabetes mellitus, metformin is not associated with an increased risk for lactic acidosis or with an increase in lactate levels.

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Question
In patients with impaired glucose tolerance (IGT), does acarbose reduce the risk for cardiovascular disease and hypertension?

Conclusion
In patients with impaired glucose tolerance, acarbose reduced the risk for cardiovascular disease and hypertension.

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Question
In patients with type 2 diabetes mellitus, is rosiglitazone or pioglitazone more effective than other antidiabetic agents when used either as monotherapy or add-on therapy?

Conclusions
In patients with type 2 diabetes, little evidence exists to support rosiglitazone or pioglitazone being more effective monotherapy than existing antidiabetic agents. When added to a nonthiazolidinedione agent, both drugs reduce glycosylated hemoglobin and fasting plasma glucose levels more than monotherapy with a nonthiazolidinedione agent.

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Question
In postmenopausal women with coronary heart disease (CHD), does hormone replacement therapy (HRT) prevent an increase in fasting glucose level and reduce the incidence of diabetes in those at risk?

Conclusion
In postmenopausal women with coronary heart disease, hormone replacement therapy slowed increase in fasting glucose level and reduced the incidence of diabetes in those at risk.

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Question
Does training in flexible intensive insulin management (combining dietary freedom and insulin adjustment) improve glycemic control and quality of life in patients with type 1 diabetes?

Conclusion
In patients with type 1 diabetes, training in flexible intensive insulin management (combining dietary freedom and insulin adjustment) improved glycemic control and quality of life at 6 months.

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Question
In patients with diabetes, essential hypertension, and signs of left ventricular hypertrophy (LVH), is losartan-based therapy more effective than atenolol-based therapy?

Conclusion
In patients with diabetes, essential hypertension, and signs of left ventricular hypertrophy, losartan reduced cardiovascular morbidity and mortality and all-cause mortality more than atenolol.

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Question
In patients with type 2 diabetes mellitus, does metformin increase the risk for fatal and nonfatal lactic acidosis or increase blood lactate levels compared with placebo or other hypoglycemic therapies?

Conclusion
In patients with type 2 diabetes mellitus, metformin does not increase the risk for fatal or nonfatal lactic acidosis or increase blood lactate levels compared with placebo or other hypoglycemic therapies.

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Question
In patients with type 1 diabetes mellitus receiving intensive treatment with injections of regular insulin before meals, is the administration of regular insulin with the evening meal and neutral protamine Hagedorn (NPH) insulin at bedtime (split regimen) more effective than administering both with the evening meal (mixed regimen) for reducing nocturnal hypoglycemia?

Conclusion
In patients with type 1 diabetes mellitus receiving intensive treatment, administration of regular insulin before each meal and neutral protamine Hagedorn (NPH) insulin at bedtime reduced nocturnal hypoglycemia and improved control of blood glucose levels more than mixing the evening dose of regular insulin with NPH and administering this mix with the evening meal.

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Question
In overweight persons with elevated fasting and postload plasma glucose levels, does an intensive lifestyle intervention or treatment with metformin plus standard lifestyle recommendations prevent or delay the onset of type 2 diabetes mellitus?

Conclusion
In overweight persons with elevated fasting and postload plasma glucose concentrations, an intensive lifestyle intervention or treatment with metformin plus standard lifestyle recommendations was more effective than standard lifestyle recommendations alone for preventing or delaying the onset of type 2 diabetes mellitus.

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Question
In patients with type 1 diabetes mellitus, is continuous subcutaneous insulin infusion (pump therapy) as effective as multiple insulin injections for glycemic control?

Conclusion
In patients with type 1 diabetes, continuous subcutaneous insulin infusion resulted in slightly better glycemic control than did multiple insulin injections.

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Question
In patients with type 2 diabetes mellitus, do medications for intensive reduction of cholesterol and glucose levels and blood pressure prevent cardiovascular disease (CVD)?

Conclusions
In patients with type 2 diabetes mellitus, medications to lower cholesterol levels or blood pressure substantially reduce cardiovascular disease (CVD). Medications to lower glucose levels appear to have less, if any, effect on CVD.

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Question
In patients with type 1 diabetes mellitus, is patient satisfaction greater with inhaled insulin use than with subcutaneous insulin injection?

Conclusion
In patients with type 1 diabetes mellitus, increases in overall satisfaction and convenience or ease of use were greater with inhaled insulin than with subcutaneous insulin injection, but groups did not differ for increase in social comfort.

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Question
In patients with type 1 diabetes mellitus and microalbuminuria, what is the effect of angiotensin-converting enzyme (ACE) inhibitors independent of confounding variables?

Conclusions
In patients with type 1 diabetes mellitus and microalbuminuria, angiotensin-converting enzyme inhibitors reduce progression to macroalbuminuria and increase regression to normoalbuminuria. Beneficial treatment effects are greatest for those with the highest levels of baseline microalbuminuria, but no difference exists according to other baseline risk factors. Changes in systemic blood pressure from angiotensin-converting enzyme inhibitors explains some, but not most, of the benefits.

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Question
Is glyburide as effective and safe as insulin in women with gestational diabetes mellitus?

Conclusion
Glyburide was as safe and effective as insulin in the treatment of women with gestational diabetes mellitus.

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Question
What is the effectiveness and safety of combination therapy with metformin and rosiglitazone in patients with type 2 diabetes mellitus that is poorly controlled by metformin alone?

Conclusion
Once-daily metformin plus rosiglitazone improved glycemic control more effectively than did treatment with metformin alone in patients with poorly controlled type 2 diabetes mellitus.

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Question
How effective and safe is low-dose rosiglitazone combined with sulfonylurea for treating hyperglycemia in patients with type 2 diabetes mellitus?

Conclusion
Combination therapy with low-dose rosiglitazone and sulfonylurea was associated with lower hemoglobin A1c and fasting plasma glucose levels than was sulfonylurea monotherapy and was safe in patients with type 2 diabetes mellitus.

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Background:

The emergence of multiple insulin products has provided new opportunities to achieve diabetes control. However, the number of options has raised concerns about the optimal choices of products.

Purpose:

To briefly review the pharmacologic characteristics of currently available insulin products and to suggest an initial insulin regimen based on common blood glucose profiles among patients with diabetes.

Data Sources:

Relevant manuscripts were identified through a MEDLINE search (1996 to 25 February 2006) of the English-language literature. The key phrase used was therapeutic use of insulin. The literature search was limited to core clinical journals that have accessible full texts.

Study Selection:

Clinical trials and authoritative reviews published between 1996 and February 2006 were selected. A total of 420 manuscripts was reviewed.

Data Extraction:

The authors independently reviewed the relevant available literature. This literature, along with the authors' clinical experience, was used to construct practical suggestions.

Data Synthesis:

Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial insulin (for example, insulin lispro, insulin aspart, or insulin glulisine) and basal insulin (for example, insulin glargine or insulin detemir), the analogues simulate physiologic insulin profiles more closely than the older conventional insulins. There is currently no strong rationale favoring glargine, neutral protamine Hagedorn insulin, insulin detemir, or fixed-ratio insulin preparations as the preferred agent for initiating insulin therapy.

Limitations:

This was a retrospective review of previously published manuscripts chosen at the authors' discretion.

Conclusions:

The advent of recombinant DNA technology made it possible to overcome limitations in the time-action profiles of conventional insulins. Insulin therapy must be individualized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. On the basis of the blood glucose profile, the authors suggest an initial insulin regimen that can be used to evaluate individual responsiveness and plan a long-term regimen.

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Background:

As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.

Purpose:

To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and α-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.

Data Sources:

The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched.

Study Selection:

216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States.

Data Extraction:

Using standardized protocols, 2 reviewers serially abstracted data for each article.

Data Synthesis:

Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A_1c level of about 1 percentage point). Nateglinide and α-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents.

Limitations:

Data on major clinical end points were limited. Studies inconsistently reported adverse events other than hypoglycemia, and definitions of adverse events varied across studies. Some harms not assessed in trials or observational studies may have been overlooked.

Conclusions:

Compared with newer, more expensive agents (thiazolidinediones, α-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.

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This guidance statement is derived from other organizations' guidelines and is based on an evaluation of the strengths and weaknesses of the available guidelines. We used the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) appraisal instrument to evaluate the guidelines from various organizations. On the basis of the review of the available guidelines, we recommend:

Statement 1: To prevent microvascular complications of diabetes, the goal for glycemic control should be as low as is feasible without undue risk for adverse events or an unacceptable burden on patients. Treatment goals should be based on a discussion of the benefits and harms of specific levels of glycemic control with the patient. A hemoglobin A_1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients.

Statement 2: The goal for hemoglobin A_1c level should be based on individualized assessment of risk for complications from diabetes, comorbidity, life expectancy, and patient preferences.

Statement 3: We recommend further research to assess the optimal level of glycemic control, particularly in the presence of comorbid conditions.

*This paper, written by Amir Qaseem, MD, PhD, MHA; Sandeep Vijan, MD, MS; Vincenza Snow, MD; J. Thomas Cross, MD, MPH; Kevin B. Weiss, MD, MPH; and Douglas K. Owens, MD, MS, was developed for the American College of Physicians' Clinical Efficacy Assessment Subcommittee: Douglas K. Owens, MD, MS (Chair); Donald E. Casey Jr., MD, MPH, MBA; J. Thomas Cross Jr., MD, MPH; Paul Dallas, MD; Nancy C. Dolan, MD; Mary Ann Forciea, MD; Lakshmi Halasyamani, MD; Robert H. Hopkins Jr., MD; and Paul Shekelle, MD, PhD. Approved by the ACP Board of Regents on 28 October 2006.

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