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From the ACP Diabetes Care Guide
This tool lists what to consider before providing patients with these medications.
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.
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.
Use insulin in patients with gestational diabetes to achieve optimal glycemic control.
Switch all women with pregestational diabetes on oral diabetic treatments to insulin before conception.
Stop ACE inhibitor therapy and review the patient's other medications before conception.
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).
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.
ACP Summer Session was a two-day CME event that covered key topics and management strategies in the areas of cardiology, diabetes, pulmonary diseases, and neurological diseases. ACP Summer Session was held in Orlando, Florida on August 7-8, 2009 and in San Francisco, California on August 14-15, 2009. The following audio recordings with synchronized slides and course handouts are from the Orlando meeting and are available free to ACP members.
Login required (use ACP Online username/password)
ACP Summer Session was a two-day CME event that covered key topics and management strategies in the areas of cardiology, diabetes, pulmonary diseases, and neurological diseases. ACP Summer Session was held in Orlando, Florida on August 7-8, 2009 and in San Francisco, California on August 14-15, 2009. The following audio recordings with synchronized slides and course handouts are from the Orlando meeting and are available free to ACP members.
Login required (use ACP Online username/password)
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?
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?
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?
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?
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?
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?
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.
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.
A new one-page algorithm to guide treatment of patients with type 2 diabetes was released last week by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE).
The algorithm, part of a larger consensus statement, stratifies patients by A1c level into three groups and suggests medication choices to achieve target glycemic control. The algorithm recommends beginning with monotherapy for patients with A1c levels between 6.5%-7.5%, dual therapy for those in the 7.6%-9.0% range, and, depending on symptoms and prior exposure to medication, insulin and possibly additional agents for patients with a level over 9.0%.
Medication choices are prioritized according to risk of hypoglycemia, safety, efficacy, simplicity, and anticipated degree of patient adherence, as well as the overall cost of care. The consensus statement also includes a chart summarizing the key benefits and risks of diabetes medications. Biguanides, DPP-4 inhibitors, incretin mimetics, thiazolidinediones, alpha-glucosidase inhibitors, sulfonylureas, meglitinides, bile acid sequestrants, amylin analogs and insulin therapy are included.
The resource is intended to assist primary care physicians, endocrinologists and others in the management of type 2 diabetes, according to an AACE press release. The consensus statement, which was published in the September/October Endocrine Practice, was developed by a group of 14 clinicians, clinical researchers, practitioners and academicians and is based on AACE/ACE guidelines.
Changes have been made to the prescribing information for sitagliptin (Januvia) and sitagliptin/metformin (Janumet) because of reports of acute pancreatitis, the FDA said last week.
Eighty-eight post-marketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis in patients using sitagliptin, were reported to the agency between October 2006 and February 2009. It is recommended that health care professionals monitor patients carefully for the development of pancreatitis after initiation or dose increases of sitagliptin or sitagliptin/metformin, the FDA said.
Two lots of Accusure insulin syringes are being recalled by the manufacturer, according to an FDA alert. The syringes have been found to have needles that can detach from the syringe and become stuck in the insulin vial, push back into the syringe, or remain in the skin after an injection.
The syringes were distributed by Qualitest Pharmaceuticals between January 2007 and June 2008 and are labeled as Accusure Insulin Syringes 31 G-Short Needle, either 1/2 cc or 1 cc, lot number 6JCB1 or lot number 7CPT1. The lot number can be found on the white paper backing of each individual syringe. Anyone who has affected syringes should not use them and should contact Qualitest at 1-800-444-4011 for product replacement instructions.
A new large study found that rosiglitazone was associated with a significantly higher risk of heart failure and death than pioglitazone in type 2 diabetics, leading researchers to question its ongoing use.
In the retrospective cohort study, researchers studied records of almost 40,000 outpatients age 66 years or older taking pioglitazone or rosiglitazone and followed them for six years. At follow-up, 5.3% of patients taking pioglitazone suffered death or hospital admission for either acute myocardial infarction (MI) or heart failure, compared with 6.9% of patients taking rosiglitazone. Secondary analyses, after adjustment for demographic and clinical factors and drug doses, revealed a lower risk of death and heart failure with pioglitazone but no significant difference in risk of acute MI. The results appear in the Aug. 18 BMJ.
Rosiglitazone and pioglitazone have been associated with cardiovascular risks in previous studies but it was unclear whether it was a class effect of thiazolidinediones, the authors noted. This study provides evidence that pioglitazone is associated with a lower risk of adverse cardiovascular events and death than rosiglitazone in comparable patients.
While the reasons for the difference are unclear, the authors continued, pioglitazone has more favorable effects on serum lipids than rosiglitazone and may have anti-inflammatory and anti-atherogenic effects. Rosiglitazone can promote excessive salt and water retention, which may underlie the increased risk of death in patients taking it, they added.
The authors acknowledged that their study was limited by the possibility that patients taking rosiglitazone had a higher baseline risk of heart failure and death than those prescribed pioglitazone. However, the two groups were highly similar and baseline risk would not likely explain why rosiglitazone was associated with a higher risk of death and heart failure but not of acute MI. Given the evidence against rosiglitazone and the lack of clinical advantage over pioglitazone, the authors suggested that physicians reevaluate the appropriateness of any patients starting or continuing treatment with rosiglitazone.
The FDA approved the following drugs last week:
Saxagliptin (Onglyza), a dipeptidyl peptidase-4 (DPP-4) inhibitor taken once-daily to treat type 2 diabetes in adults. The most commonly observed side effects are upper respiratory tract infection, urinary tract infection, and headache; others include allergic-like reactions such as rash and hives. The FDA is requiring a postmarket study of the cardiovascular safety of the drug in a higher-risk population, though past clinical trials didn?t show an association between the drug and a higher risk of cardiovascular events in low-risk patients.
Pitavastatin (Livalo), to help lower blood cholesterol levels when diet and exercise don?t work. The most widely reported adverse reactions were muscle pain, back pain, joint pain and constipation. The statin, which comes in a 4-mg maximum dose, was approved on the basis of five clinical trials comparing its efficacy and safety to that of three currently marketed statins. It is expected to be available in the U.S. in early 2010.
Older patients with diabetes who were prescribed an antipsychotic drug had a significantly increased risk of hospitalization for hyperglycemia, particularly during the initial course of treatment, a recent study reported.
In the nested case-control, population-based study, researchers looked at records of patients age 66 years or older with diabetes who started taking an antipsychotic drug between April 1, 2002 and March 31, 2006 and were followed for up to five years from treatment start until March 31, 2007. Subjects were divided into three groups: insulin-treated, oral hypoglycemic agent only-treated, and no diabetes treatment. Antipsychotic treatment was associated with a higher risk of hyperglycemia compared with remote antipsychotic use in all diabetes treatment groups, with the risk highest among patients treated with atypical and typical agents, especially those just starting treatment. The results appear in the July 27 Archives of Internal Medicine.
The findings stress the importance of enhanced glycemic monitoring after initiation of antipsychotic therapy in older patients with diabetes, the authors said. Noting the prevalence of diabetes, the widespread use of antipsychotic drugs, and recent warnings regarding higher risk of stroke and death with antipsychotic agents, the authors recommended more careful consideration of the risks and benefits before prescribing them to vulnerable patients.
Further study is needed to determine whether the findings represent a causal effect of antipsychotics, said the authors. For now, physicians should consider other options to manage behavioral symptoms of dementia in older persons with diabetes, and families should be alerted to watch for signs of glycemic decompensation after antipsychotics are initiated, they said.
A long-term study further quantified the well-known benefits of intensive glucose control for patients with type 1 diabetes.
The analysis included patients from the Diabetes Control and Complications Trial (DCCT), which from 1983-1993 randomized diabetics to either intensive insulin therapy or what was at the time conventional therapy. The intensive group aimed for near-normal glycemic control with three or more daily injections or a pump. The conventional group received one or two injections and had no specific A1C target. For the new analysis, researchers also included 161 patients from an observational study who matched the DCCT criteria.
Overall, the analysis found that, after 30 years of diabetes, the cumulative incidence rates of proliferative retinopathy, nephropathy and cardiovascular disease were 50%, 25% and 14% in the conventional arm. Patients in the other observational trial had similar rates, 47%, 17% and 14% respectively. DCCT patients who received intensive control had substantially lower rates, 21% developed retinopathy, 9% nephropathy and 9% cardiovascular disease. In that group, fewer than 1% went blind, received a kidney transplant or had an amputation. The study was published in the July 27 Archives of Internal Medicine.
Stolen vials of long-acting Levemir insulin (generic: insulin detemir) have reappeared and are being sold in the U.S. market, the FDA said in a news release.
About 129,000 vials were stolen and may not have been stored or handled properly, and thus may not be safe to use. At least one patient has suffered an adverse event due to poor glucose control after using a stolen vial. Patients should not use Levemir with the affected lot numbers of XZF0036, XZF0037 and XZF0038.
There is no difference in death or major cardiovascular event rates for diabetic patients who undergo medical therapy compared with prompt revascularization, or between those who undergo insulin sensitization vs. insulin provision, a new study found.
The study results indicate that, for many patients with heart disease and diabetes--especially those with less severe disease--optimal medical therapy is a good first-line strategy, an editorial accompanying the study said. When revascularization is indicated, however, the study supports previous research suggesting that CABG may be preferred over PCI, the editorial said.
A new study found that rosiglitazone doubled the risk of heart failure among type 2 diabetes patients but did not raise overall cardiovascular hospitalizations or deaths compared with standard therapy.
The manufacturer-sponsored Rosiglitozone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes, or RECORD, trial's results conflict with the findings of a 2007 study showing that rosiglitazone significantly increased the risk of myocardial infarction. The RECORD trial confirmed, however, earlier findings that rosaglitazone doubles the risk of distal fracture in older women. The study results were presented at the American Diabetes Association's annual scientific sessions and published online by the Lancet.
The authors concluded that the data are inconclusive about rosiglitazone's effects on myocardial infarction and that the drug does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose lowering drugs. In an interview with Modern Medicine, a study author noted that rosiglitazone should not be used by patients who have heart failure or who are at increased risk of fracture but could be considered in other type 2 diabetics, particularly obese patients.
Disetronic Medical Systems Inc. is recalling ACCU-CHEK Spirit insulin pumps with up and/or down buttons that don't work, the FDA said in a release.
The buttons are used for changing the program in the menu or administering additional insulin. If they don't work, users may not be able to change any programmed setting on the pump. The recall applies to pumps with serial numbers from SN02119552 through SN10006093. Pumps with serial numbers including and above SN10006094 aren't affected and aren't being recalled.
Insulin pump users who experience button failure should call the ACCU-CHEK Spirit hotline at 1-800-778-5095.
The Agency for Healthcare Research and Quality (AHRQ) recently released new summary guides for the treatment of diabetes. The summary guides are a condensed synopsis of the available research on a specific condition. The guides are meant to aid both physicians and their patients, and each guide comes in two different versions tailored to each audience. The diabetes guides, Premixed Insulin Analogues: a Comparison with Other Treatments for Type 2 Diabetes for clinicians and Premixed Insulin for Type 2 Diabetes: a Guide for Adults for patients are available on the AHRQ Web site.
Patients taking glitazones were 2.6 times more likely to develop diabetic macular edema and, even after adjusting for confounding factors, people taking them were 60% more likely to develop the condition, according to a prospective cohort study.
About 170,000 diabetics taking glitazones were identified using diabetes and pharmacy databases of Kaiser Permanente Southern California. Most of the glitazone users in the study were taking pioglitazone (Actos), although both drugs in the class (rosiglitazone [Avandia] is the other) have been linked to fluid retention and edema, said a press release.
There were 996 new cases of macular edema in the study. Glitazone users were more likely to develop macular edema (odds ratio [OR], 2.6; 95% confidence interval [CI], 2.4 to 3.0). Glitazones were modestly associated with diabetic macular edema after adjusting for age, glycemic control and insulin use.
This study, published in the April American Journal of Ophthalmology, is not the first to show a link, authors said, but rather, confirms that glitazones are modestly associated with diabetic macular edema.
Atrial fibrillation (AF) dramatically increases diabetic patients' risk of death, but that increase can be mitigated with blood-pressure medication, new data from the ADVANCE trial revealed.
The ADVANCE study included 11,140 patients with type 2 diabetes who were randomized to receive either a fixed combination of perindopril and indapamide or placebo. Measured outcomes included total mortality and cardiovascular disease outcomes over a four-year follow-up. Overall, patients with AF had a 61% increased risk of dying from any cause, 77% higher risk of death from cardiovascular causes, and a 68% higher risk of heart failure or other cerebrovascular problems.
Treatment with the blood-pressure medications reduced the risk of cardiovascular death by 18% and the all-cause risk of death by 14%. The reductions were similar in patients both with and without AF, but because the patients with AF had a higher baseline risk, a greater number were helped by the drugs, a press release explained. The researchers estimated that five years of active treatment would prevent one death for every 42 diabetic patients with AF and one for every 120 diabetics without.
The study authors noted that while rate and rhythm control is the usual therapeutic focus in patients with AF, this study indicates the importance of treating overall cardiovascular risk factors, such as blood pressure. Diabetic patients should be actively evaluated for the presence of AF, an author said. The study was published by the European Heart Journal on March 11.
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.
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.
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.
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.
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.
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.
The newly approved OneTouch Ping Glucose Management System allows patients to calculate and deliver insulin doses without touching their pumps.
In patients with type 2 diabetes, tight blood-pressure control reduces complications in the short-term but the benefits disappear after the intensive treatment stops, according to a new study.
In the United Kingdom Prospective Diabetes Study, 1,148 newly diagnosed patients (who also had hypertension) were randomly assigned to four years of tight or less-tight control of blood pressure. After the study, 884 of the patients were followed, through questionnaires and/or clinic visits, for 10 more years. The results were published in the Sept. 10 online New England Journal of Medicine.
During the trial, the two groups had significant differences in blood pressure, several diabetes-related endpoints (including diabetes-related death), and stroke. However, the differences in blood pressure disappeared within two years of the trial's termination. There was a continuing risk reduction in peripheral vascular disease in the tight-control group, but otherwise, the researchers found no sustained benefit for patients who had tight control of blood pressure. The two groups had no significant differences in myocardial infarction, death, or any of the additional endpoints.
The authors concluded that optimal blood-pressure control is important to reducing diabetic patients' risk of micro- and macrovascular disease, but that the treatment must be maintained in order for patients to sustain the benefits over the long term.
According to a National Health Interview Survey, 28% of patients with type 2 diabetes use insulin alone or in combination with oral antidiabetic agents to control their glucose levels. Because of the increasing prevalence of type 2 diabetes, the number of patients who use insulin for glycemic control, and the importance of glycemic control in decreasing mortality and morbidity, researchers wanted to establish the weight of evidence for the safety and effectiveness of premixed insulin compared with other antidiabetic agents. Researchers at the Agency for Healthcare Research and Quality found that premixed insulin provides tighter glycemic control than long-acting insulin and non-insulin antidiabetic agents. However, researchers cautioned that studies with longer follow-up are needed to determine long-term outcomes. The article will be published in the October 21 print issue of Annals of Internal Medicine.
In an updated consensus statement on the management of type 2 diabetes, experts offered new guidance about thiazolidinediones, including advising against the use of rosiglitizone due to cardiovascular risks.
The update of the 2006 statement by the American Diabetes Association and the European Association for the Study of Diabetes notes that several analyses have suggested a 30%-40% increased risk for myocardial infarction with rosiglitazone, whereas pioglitazone has been shown to have no significant effects on cardiovascular disease. Given that there are other options, the committee recommended against using rosiglitazone but recommended use of pioglitazone or glucagons-like peptide-1 agonists (exenatide) in cases where hypoglycemia is particularly undesirable, such as in patients with hazardous jobs.
The groups continued to recommend a tiered approach to diabetes management:
- lifestyle interventions and metformin at diagnosis with a glycemic goal of less than 7% A1C;
- basal insulin or sulfonylurea if the target is not reached;
- Initiation of insulin if none of the above therapies work.
Use of newer, more expensive medications is increasing the average cost of treating diabetes, but metformin appears to be the most effective means of reducing cardiovascular complications, according to two new studies.
In the first study, researchers analyzed medications prescribed during all U.S. office visits for type 2 diabetes patients age 35 or older. In 1994, there were 25 million visits and the mean number of diabetes medications per treated patient was 1.14. In 2007, the number of visits had increased to 36 million and the meds to 1.63 per patient.
Over the same time period, insulin use declined from 38% of visits to 28%, and sulfonylurea use declined from 67% to 34%. In 2007, biguanides and glitazones were the leading therapeutic classes. Newer drugs were largely responsible for the increase in mean cost per prescription ($56 in 2001 to $76 in 2007) and aggregate drug expenditures ($6.7 billion in 2001 to $12.5 billion in 2007), researchers concluded. The study was published in the Oct. 27 Archives of Internal Medicine.
In a meta-analysis published in the same issue, data from 40 controlled trials tracked cardiovascular events in adults with type 2 diabetes. Metformin decreased the risk of cardiovascular mortality more than any other oral diabetes agent or placebo (odds ratio=0.74), and similar but not statistically significant trends were seen for cardiovascular morbidity and overall mortality. No other drug had a significant positive effect.
Manufacturer Covidien is recalling one lot of ReliOn hypodermic insulin syringes because of possible mislabeling that may cause patients to get up to 2.5 times the intended dose, the FDA said in a news release.
The extra dose of the single-use, disposable syringes could lead to hypoglycemia and/or death. The recall applies to lot number 813900 of the product labeled ReliOn 1cc, 31-gauge, 100 units for use with U-100 insulin. Some syringes labeled for use with U-40 insulin were mixed with these, packaged together, and sold at Wal-Mart and Sam's Club stores from Aug. 1 to Oct. 8.
Thus far, one adverse event has been reported to Covidien, which distributed 471,000 individual syringes of the recalled lot. Providers and patients can call (866) 780-5436 or go online for more information.
Psychological issues may interfere with type 1 diabetes management tasks such as insulin injections, diet and exercise. To find out whether psychological therapy could improve diabetes management, researchers assigned 344 patients to either regular care, cognitive behavioral therapy or a combination of nurse-delivered cognitive behavioral therapy and motivational enhancement therapy (brief counseling that focuses on self-motivation). Researchers collected information on change in blood sugar levels, low blood sugar episodes, depression, quality of life, diabetes self-care activities and weight for one year. Patients who received both psychological therapies fared the best, having a greater decrease in blood sugar levels than patients who received usual care. However, the changes were small and this study cannot determine whether they would persist beyond 12 months.
AHRQ released plain-language guides for consumers and clinicians comparing the efficacy, effectiveness, and side effects of newer premixed insulin analogues to conventional insulin (human insulin) and other preparations used to control Type 2 diabetes.
The consumer guide, called Premixed Insulin for Type 2 Diabetes: A Guide for Adults , is a primer on diabetes, diabetes testing, and treatments.
The clinician guide, called Premixed Insulin Analogues: A Comparison with Other Treatments for Type 2 Diabetes, includes additional information, including a confidence scale that rates available evidence.
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.
The 2007 ADA Clinical Practice Recommendations provide an in depth review of diabetes care and their current recommendations for practice.
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.
The ADA has issued their 2008 Comprehensive Guidelines for Diabetes Care
Question
In patients with type 2 diabetes, is rosiglitazone (RGZ) as add-on therapy to metformin (MFN) or sulfonylurea (SFU) noninferior to MFN plus SFU for cardiovascular (CV) outcomes?
Conclusion
In patients with type 2 diabetes, rosiglitazone added to metformin (MFN) or sulfonylurea (SFU) was noninferior to MFN plus SFU for overall cardiovascular safety but increased risk for heart failure and fractures.
Question
Does intensive glucose control reduce cardiovascular (CV) events and mortality in patients with type 2 diabetes mellitus?
Conclusion
In patients with type 2 diabetes mellitus, intensive glucose control reduced some cardiovascular events but did not change overall mortality.
Question
In patients with type 2 diabetes, how do various oral diabetes medications compare for long-term cardiovascular (CV) risk?
Conclusion
Metformin reduced risk for cardiovascular mortality compared with other oral diabetes drugs or placebo in type 2 diabetes.
Question
In patients with newly diagnosed type 2 diabetes mellitus, does intensive insulin therapy improve glycemic control and remission rates more than oral hypoglycemic agents (OHAs)?
Conclusion
In patients with newly diagnosed type 2 diabetes mellitus, intensive insulin therapy reduced time to glycemic control and had a higher remission rate than oral hypoglycemic agents.
Question
In type 2 diabetes, does intensive glucose control prevent adverse outcomes more than standard glucose control?
Conclusion
Compared with standard glucose control in type 2 diabetes, intensive glucose control with gliclazide and other drugs had no effect on macrovascular events, prevented new or worsening albuminuria, but led to greater hypoglycemia.
Question
In patients with type 2 diabetes and cardiovascular disease or risk factors, does intensive glucose control prevent cardiovascular events more than standard glucose control?
Conclusion
In patients with type 2 diabetes and cardiovascular disease or risk factors, intensive glucose control increased mortality and did not prevent cardiovascular events more than standard glucose control.
Question
What are the benefits and harms for mother and baby of screening for and treating gestational diabetes mellitus (GDM)?
Conclusions
Little evidence exists on the benefits and harms of screening for gestational diabetes. Limited evidence suggests that treatment of gestational diabetes after 24 weeks of gestation may improve maternal and neonatal outcomes.
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.
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.
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.
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.
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.
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.
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.
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 .
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.
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.
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.
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.
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.
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.
ACP Journal Club > 2006 - Simvastatin was cost-effective across a broad range of risk and age groups
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 A1c 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.
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 A1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients.
Statement 2: The goal for hemoglobin A1c 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.
Background:
Evidence comparing premixed insulin analogues (a mixture of rapid-acting and intermediate-acting insulin analogues) with other antidiabetic agents is urgently required to guide appropriate therapy.
Purpose:
To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues compared with other antidiabetic agents in adults with type 2 diabetes.
Data Sources:
The authors searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008 and sought unpublished data from the U.S. Food and Drug Administration, European Medicines Agency, and industry.
Study Selection:
Studies with control groups that compared premixed insulin analogues with another antidiabetic medication in adults with type 2 diabetes.
Data Extraction:
2 reviewers using standardized protocols performed serial abstraction.
Data Synthesis:
Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels, hemoglobin A1c levels, and the incidence of hypoglycemia but were more effective in decreasing postprandial glucose levels (mean difference, −1.1 mmol/L; 95% CI, −1.4 to −0.7 mmol/L [−19.2 mg/dL; 95% CI, −25.9 to −12.5 mg/dL]). Compared with long-acting insulin analogues, premixed insulin analogues were superior in decreasing postprandial glucose levels (mean difference, −1.5 mmol/L; CI, −1.9 to −1.2 mmol/L [−27.9 mg/dL; CI, −34.3 to −21.5 mg/dL]) and hemoglobin A1c levels (mean difference, −0.39% [CI, −0.50% to −0.28%]) but were inferior in decreasing fasting glucose levels (mean difference, 0.7 mmol/L; CI, 0.3 to 1.0 mmol/L [12.0 mg/dL; CI, 6.0 to 18.1 mg/dL]) and were associated with a higher incidence of hypoglycemia. Compared with noninsulin antidiabetic agents, premixed insulin analogues were more effective in decreasing fasting glucose levels (mean difference, −1.1 mmol/L; CI, −1.7 to −0.6 mmol/L [−20.5 mg/dL; CI, −29.9 to −11.2 mg/dL]), postprandial glucose levels (mean difference, −2.1 mmol/L; CI, −3.4 to −0.8 mmol/L [−37.4 mg/dL; CI, −61.0 to −13.7 mg/dL]), and hemoglobin A1c levels (mean difference, −0.49% [CI, −0.86% to −0.12%]) but were associated with a higher incidence of hypoglycemia.
Limitations:
The literature search was restricted to studies published in English. Data on clinical outcomes were limited. The small number of studies for each comparison limited assessment of between-study heterogeneity.
Conclusion:
Premixed insulin analogues provide glycemic control similar to that of premixed human insulin and may provide tighter glycemic control than long-acting insulin analogues and noninsulin antidiabetic agents.
Background:
Results from clinical trials examining the effect of intensive glucose control on cardiovascular disease have been conflicting.
Purpose:
To summarize clinical benefits and harms of intensive versus conventional glucose control for adults with type 2 diabetes.
Data Sources:
Studies were retrieved by systematically searching the MEDLINE database (January 1950 to April 2009) with no language restrictions.
Study Selection:
Two independent reviewers screened abstracts or full-text articles to identify randomized trials that compared clinical outcomes in patients with type 2 diabetes receiving intensive glucose control and those receiving conventional glucose control.
Data Extraction:
Two investigators independently abstracted data on study variables and outcomes, including severe hypoglycemia, cardiovascular disease, and all-cause mortality.
Data Synthesis:
5 trials involving 27 802 adults were included. Intensive glucose targets were lower in the 3 most recent trials. Summary analyses showed that compared with conventional control, intensive glucose control reduced the risk for cardiovascular disease (relative risk [RR], 0.90 [95% CI, 0.83 to 0.98]; risk difference per 1000 patients per 5 years [RD], −15 [CI, −24 to −5]) but not cardiovascular death (RR, 0.97 [CI, 0.76 to 1.24]; RD, −3 [CI, −14 to 7]) or all-cause mortality (RR, 0.98 [CI, 0.84 to 1.15]; RD, −4 [CI, −17 to 10]). Intensive glucose control increased the risk for severe hypoglycemia (RR, 2.03 [CI, 1.46 to 2.81]; RD, 39 [CI, 7 to 71]). As was seen in the overall analyses, pooled findings from the early and more recent trials showed that intensive glucose control reduced the risk for cardiovascular disease and increased the risk for severe hypoglycemia.
Limitation:
Summary rather than individual data were pooled across trials.
Conclusion:
Intensive glucose control reduced the risk for some cardiovascular disease outcomes (such as nonfatal myocardial infarction), did not reduce the risk for cardiovascular death or all-cause mortality, and increased the risk for severe hypoglycemia.
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