Increased mortality associated with aggressive glucose reduction raises safety concerns.
The National Heart, Lung, and Blood Institute has announced the early termination of one treatment arm of the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial because of an increased risk for death among patients assigned to intensive glucose-lowering therapy (press release, February 6, 2008). The 5128 participants (at 77 North American sites) randomized to treatment aimed at reducing HbA1c levels to <6.0% will now be treated to a target HbA1c level of 7.0% to 7.9%, the same as participants in the control group. Two concurrent trials of management strategies for cholesterol and hypertension will continue as planned.
The Data and Safety Monitoring Board of ACCORD recommended stopping intensive glucose-lowering therapy after it found that 257 patients in that group had died, compared with 203 in the standard therapy group: a difference of 3 per 1000 participants per year during a mean of about 4 years of treatment. Preliminary analyses have found no association of the mortality increase with any specific drug or drug combination. All participants in the ACCORD study have type 2 diabetes and either coronary heart disease or at least two risk factors for adverse cardiovascular events.
Comment: The ACCORD trial was inspired by previous research that found a link between tightly controlled blood sugar and reduced risk for many complications of type 2 diabetes. Why an increased risk for death was associated with tight glucose control in this trial remains unclear. These results raise questions about intensity of and appropriate targets for glucose-lowering treatment in patients with type 2 diabetes, but they do not alter current guidelines or treatment strategies for most diabetic patients.
— Joel M. Gore, MD
Published in Journal Watch Cardiology February 13, 2008
Showing posts with label diabetes. Show all posts
Showing posts with label diabetes. Show all posts
Friday, February 15, 2008
Friday, December 21, 2007
Thiazolidinediones and Heart Disease Risk
Pioglitazone had a mixed risk profile, and rosiglitazone increased risk for ischemic heart disease, but neither increased mortality.
Results from small clinical trials and early pooled analyses have raised concerns about cardiovascular risks associated with rosiglitazone, one of two thiazolidinediones used to treat patients with type 2 diabetes mellitus. Two new meta-analyses further clarify the risks associated with pioglitazone and rosiglitazone.
Independent researchers analyzed data provided by the manufacturer from 19 randomized trials (16,390 patients) that compared pioglitazone with placebo or an active comparator. Most treatment protocols were 12 to 24 months. The hazard ratios for myocardial infarction, stroke, or death each were reduced after about 1 year of treatment with pioglitazone, although only the 18% reduction in the combined endpoint was significant. Risk for serious heart failure was significantly increased by 41%.
In a review of 140 randomized trials, researchers found 4 trials (14,291 patients) that compared rosiglitazone with placebo or an active comparator and had at least 12 months of follow-up. The risk for myocardial infarction in patients who received rosiglitazone was increased by about 40%, and the risk for heart failure was more than doubled; however, the risk for death from cardiovascular disease was not increased.
Comment: Both thiazolidinediones are associated with increased risk for heart failure in patients with type 2 diabetes mellitus, but only rosiglitazone appears to increase risk for ischemic heart disease. Prescribing information for both drugs now includes a "black box" warning about heart failure; in addition, an FDA advisory committee has suggested that warnings about ischemic heart disease be included for rosiglitazone. Editorialists note how unlikely it would have been for either drug to have been approved initially had these risks been known. They call for tighter postmarketing surveillance, especially for new classes of drugs and in higher-risk patients.
— Thomas L. Schwenk, MD
Results from small clinical trials and early pooled analyses have raised concerns about cardiovascular risks associated with rosiglitazone, one of two thiazolidinediones used to treat patients with type 2 diabetes mellitus. Two new meta-analyses further clarify the risks associated with pioglitazone and rosiglitazone.
Independent researchers analyzed data provided by the manufacturer from 19 randomized trials (16,390 patients) that compared pioglitazone with placebo or an active comparator. Most treatment protocols were 12 to 24 months. The hazard ratios for myocardial infarction, stroke, or death each were reduced after about 1 year of treatment with pioglitazone, although only the 18% reduction in the combined endpoint was significant. Risk for serious heart failure was significantly increased by 41%.
In a review of 140 randomized trials, researchers found 4 trials (14,291 patients) that compared rosiglitazone with placebo or an active comparator and had at least 12 months of follow-up. The risk for myocardial infarction in patients who received rosiglitazone was increased by about 40%, and the risk for heart failure was more than doubled; however, the risk for death from cardiovascular disease was not increased.
Comment: Both thiazolidinediones are associated with increased risk for heart failure in patients with type 2 diabetes mellitus, but only rosiglitazone appears to increase risk for ischemic heart disease. Prescribing information for both drugs now includes a "black box" warning about heart failure; in addition, an FDA advisory committee has suggested that warnings about ischemic heart disease be included for rosiglitazone. Editorialists note how unlikely it would have been for either drug to have been approved initially had these risks been known. They call for tighter postmarketing surveillance, especially for new classes of drugs and in higher-risk patients.
— Thomas L. Schwenk, MD
Monday, October 29, 2007
Initiating Insulin in Type 2 Diabetes – The "4-T" Trial
First-year comparisons among prandial, biphasic, and basal insulins reveal tradeoffs in efficacy and safety.
We now have a variety of options for initiating insulin in type 2 diabetic patients. In this trial — dubbed "Treating to Target in Type 2 Diabetes," or "4-T" — U.K. researchers compared three options.
The study included 708 adults with type 2 diabetes and hemoglobin A1c between 7% and 10% (mean, 8.5%) despite treatment with sulfonylurea plus metformin. Patients with recurrent major hypoglycemia were excluded. Patients continued oral agents initially and were randomized to receive twice-daily biphasic insulin aspart 30 (NovoMix 30), thrice-daily prandial insulin aspart (NovoRapid), or once-daily (twice if required) basal insulin detemir (Levemir). A protocol specified dose titration, glucose monitoring, and follow-up visits. Novo Nordisk supported the trial.
During 1 year of follow-up, the following outcomes occurred:
Mean fall in HbA1c was significantly greater in the biphasic and prandial groups (about 1.3%) than in the basal group (0.8%).
The proportion of patients with HbA1c 6.5% was significantly greater in the biphasic (17%) and prandial (24%) groups than in the basal group (8%). Better glycemic control with biphasic and prandial insulins occurred primarily among patients whose baseline HbA1c exceeded 8.5%.
Symptomatic hypoglycemia was more common with prandial than biphasic insulin, and with biphasic than basal insulin.
Patients in the basal group gained less weight than those in the other two groups.
Comment: Biphasic or prandial insulin, added to two-drug oral therapy, was more effective than basal insulin in achieving optimal glycemic control, but at the expense of more hypoglycemia and weight gain. Weighing these tradeoffs — along with the greater ease of once-daily insulin injections — the authors and editorialists offer the reasonable conclusion that once-daily basal insulin is probably the best initial approach for initiating insulin in type 2 diabetic patients. If good glycemic control is not achieved with a simple basal regimen, more complex regimens can be introduced later; indeed, more complex regimens will be examined in the next 2 years of this trial. Finally, the editorialists state a preference for glargine (Lantus) as a basal insulin (because it appears to have less of a peak and is slightly longer-acting than detemir), and they believe that sulfonylureas should be stopped when insulin is begun (because their mechanism of action is not synergistic with insulin).
— Allan S. Brett, MD
Published in Journal Watch General Medicine October 23, 2007
Citation(s):
Holman RR et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007 Oct 25; 357:1716. (http://dx.doi.org/10.1056/NEJMoa075392)
Original article (Subscription may be required)
Medline abstract (Free)
McMahon GT and Dluhy RG. Intention to treat – Initiating insulin and the 4-T study. N Engl J Med 2007 Oct 25; 357:1759. (http://dx.doi.org/10.1056/NEJMe078196)
Original article (Subscription may be required)
Medline abstract (Free)
We now have a variety of options for initiating insulin in type 2 diabetic patients. In this trial — dubbed "Treating to Target in Type 2 Diabetes," or "4-T" — U.K. researchers compared three options.
The study included 708 adults with type 2 diabetes and hemoglobin A1c between 7% and 10% (mean, 8.5%) despite treatment with sulfonylurea plus metformin. Patients with recurrent major hypoglycemia were excluded. Patients continued oral agents initially and were randomized to receive twice-daily biphasic insulin aspart 30 (NovoMix 30), thrice-daily prandial insulin aspart (NovoRapid), or once-daily (twice if required) basal insulin detemir (Levemir). A protocol specified dose titration, glucose monitoring, and follow-up visits. Novo Nordisk supported the trial.
During 1 year of follow-up, the following outcomes occurred:
Mean fall in HbA1c was significantly greater in the biphasic and prandial groups (about 1.3%) than in the basal group (0.8%).
The proportion of patients with HbA1c 6.5% was significantly greater in the biphasic (17%) and prandial (24%) groups than in the basal group (8%). Better glycemic control with biphasic and prandial insulins occurred primarily among patients whose baseline HbA1c exceeded 8.5%.
Symptomatic hypoglycemia was more common with prandial than biphasic insulin, and with biphasic than basal insulin.
Patients in the basal group gained less weight than those in the other two groups.
Comment: Biphasic or prandial insulin, added to two-drug oral therapy, was more effective than basal insulin in achieving optimal glycemic control, but at the expense of more hypoglycemia and weight gain. Weighing these tradeoffs — along with the greater ease of once-daily insulin injections — the authors and editorialists offer the reasonable conclusion that once-daily basal insulin is probably the best initial approach for initiating insulin in type 2 diabetic patients. If good glycemic control is not achieved with a simple basal regimen, more complex regimens can be introduced later; indeed, more complex regimens will be examined in the next 2 years of this trial. Finally, the editorialists state a preference for glargine (Lantus) as a basal insulin (because it appears to have less of a peak and is slightly longer-acting than detemir), and they believe that sulfonylureas should be stopped when insulin is begun (because their mechanism of action is not synergistic with insulin).
— Allan S. Brett, MD
Published in Journal Watch General Medicine October 23, 2007
Citation(s):
Holman RR et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007 Oct 25; 357:1716. (http://dx.doi.org/10.1056/NEJMoa075392)
Original article (Subscription may be required)
Medline abstract (Free)
McMahon GT and Dluhy RG. Intention to treat – Initiating insulin and the 4-T study. N Engl J Med 2007 Oct 25; 357:1759. (http://dx.doi.org/10.1056/NEJMe078196)
Original article (Subscription may be required)
Medline abstract (Free)
Wednesday, July 11, 2007
ADA/EASD consensus guidelines and algorithm
**also see memo on palm under "endo"
The ADA/EASD consensus guidelines and algorithm emphasize:1
Achievement and maintenance of normal glycemic goals
Initial therapy with lifestyle intervention and (usually) metformin
Rapid addition of medications, and/or transition to new interventions/regimens as rapidly as possible — when target glycemic goals are not achieved or sustained
Early addition of insulin therapy in patients who do not meet target goals using other medications, or promptly in patients with greater hyperglycemia
Selecting antihyperglycemic interventions
As seen in algorithm below, the ADA/EASD consensus is that metformin therapy should be initiated concurrently with lifestyle intervention at diagnosis in all but the mildest patients with T2 DM (without contraindications). However, given the progressive nature of T2 DM, more than one medication will be necessary for the majority of patients over time.1 The goal is “to achieve and maintain glycemic levels as close to the nondiabetic range as possible and to change interventions at as rapid a pace as titration of medication allows.” 1
Note that the ADA/EASD algorithm above does not include the incretin mimetics, synthetic amylin, or DPP-4 inhibitors, as limited clinical data were available on these relatively new classes of medication at the time of the guideline publication. However, these drugs may be appropriate choices in selected patients.
Per the guidelines, a number of factors influence the selection of antihyperglycemic medications: their effectiveness in lowering glucose, their extraglycemic effects that may reduce long-term complications, safety profiles, tolerability, and cost.1
When adding a second and potentially third antihyperglycemic medication, the physician should consider potential synergy and other interactions of particular combinations. Generally, agents with different mechanisms of action have greater synergy. For example, insulin plus metformin or insulin plus a thiazolidinedione (TZD) are particularly effective in lowering glycemia.1
Initiation and intensification of basal insulin in patients who fail on oral agents1
The ADA/EASD recommends basal insulin either as second-line therapy if metformin fails, or as third-line therapy if metformin plus a second oral agent fails to meet A1C targets. As stated in the guidelines: “Although 3 oral agents can be used in patients who fail to reach target A1C, the initiation and intensification of insulin therapy is preferred based on effectiveness and expense.”1
For patients with T2 DM, initial insulin therapy is aimed at lowering fasting blood glucose, typically with long- or intermediate-acting insulins. Some patients may also require preprandial rapid- or short-acting insulin therapy.1
Current options in basal insulin therapy
Among the currently available basal insulin therapies to choose from are the insulin analogs and NPH insulin:
Insulin analogs: The newer long-acting insulin analogs, such as Lantus® (insulin glargine [rDNA origin]), and Levemir® (insulin detemir [rDNA origin]) are preferred by many physicians and patients due to their lack of pronounced peak and approximate 24-hour duration of action. Both agents were created by recombinant DNA modification of human insulin, and have the advantage of providing a steady, consistent level of basal insulin coverage.2,3 The physio/chemical structure of LANTUS enables slow release of drug, allowing it to be dosed once-daily.2 Levemir can be dosed once- or twice-daily.3 Treatment with a single-dose of long-acting insulin analog can minimize the complexity of insulin therapy, and decrease the risk of hypoglycemia and weight gain seen with NPH insulin.4 It also compares favorably to adding a third oral agent (a TZD) for impact on health-related quality of life.5
NPH insulin: Neutral protamine Hagedorn, or NPH, insulin has an intermediate duration of action and typically requires twice-daily injection to achieve required basal insulin levels over 24 hours. NPH insulin is lower in cost than the analogs.1,6 So, in patients for whom cost is a consideration, physicians may want to prescribe NPH beginning at bedtime (not dinner) to lower fasting blood glucose (FBG). Target FBG levels in T2 DM are generally 100 mg/dL or slightly less.
Both long-acting analogs and bedtime NPH as basal insulin can be added to oral or other diabetes medications. They can also be started as initial antihyperglycemic therapy when patients have greater hyperglycemia (eg, FBG >300 mg/dL and/or A1C >10%; these patients almost always require insulin treatment to control their glucose intolerance).
BD Ultra-Fine™ Insulin Syringes and Pen Needles: Quality, Comfort and Convenience
MYTH: Taking injections of insulin and other diabetes medications will be painful.
REALITY: Many patients have no idea just how small and thin an insulin needle actually is, and are pleasantly surprised when they finally see and use one for the first time. Also, many are benefiting from the increasing range and availability of insulin pens, since they find it easier and more convenient to dial and administer their dose with this delivery device. Both the insulin analogs and NPH insulin are available in pens.
BD Ultra-Fine Insulin Syringes and Pen Needles are an excellent choice for patients on, or transitioning to, insulin therapy:
No insulin syringe needle is shorter or thinner than BD Ultra-Fine
BD pen needles are universally compatible with all makes of diabetes pens and dosers in the US
BD pen needles come in a variety of lengths, including the shortest pen needle available (5mm) to meet the needs of all patients
BD Getting Started™ Take Home Kits are available to help your patients effectively transition to injection therapy
For more information on BD Ultra-Fine injection products and how to access complimentary BD Getting Started™ kits for your medical practice, visit www.bddiabetes.com/us/
REFERENCES
1. Nathan DM, Buse JB, Davidson MB, et al. Management of Hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963-1972.
2. Lantus [prescribing information]. February 2006. Bridgewater, NJ, sanofi-aventis, U.S., LLC.
3. Levemir [prescribing information]. 2005. Princeton, NJ, NovoNordisk, Inc.
4. Bethel MA, Feinglos MN. Basal insulin therapy in type 2 diabetes. J Am Board Fam Med. 2005;18:199-204.
5. Vinik AI, Zhang Q: Adding Insulin glargine versus rosiglitazone: health-related quality-of-life impact in type 2 diabetes. Diabetes Care. 2007;30(4):795-800.
6. Goldman-Levine JD. Insulin detemir (Levemir) for diabetes mellitus. STEPS: New drug reviews. Am Fam Physician. 2006;74(2). Available at: http://www.aafp.org/afp/20060715/steps.html.
The ADA/EASD consensus guidelines and algorithm emphasize:1
Achievement and maintenance of normal glycemic goals
Initial therapy with lifestyle intervention and (usually) metformin
Rapid addition of medications, and/or transition to new interventions/regimens as rapidly as possible — when target glycemic goals are not achieved or sustained
Early addition of insulin therapy in patients who do not meet target goals using other medications, or promptly in patients with greater hyperglycemia
Selecting antihyperglycemic interventions
As seen in algorithm below, the ADA/EASD consensus is that metformin therapy should be initiated concurrently with lifestyle intervention at diagnosis in all but the mildest patients with T2 DM (without contraindications). However, given the progressive nature of T2 DM, more than one medication will be necessary for the majority of patients over time.1 The goal is “to achieve and maintain glycemic levels as close to the nondiabetic range as possible and to change interventions at as rapid a pace as titration of medication allows.” 1
Note that the ADA/EASD algorithm above does not include the incretin mimetics, synthetic amylin, or DPP-4 inhibitors, as limited clinical data were available on these relatively new classes of medication at the time of the guideline publication. However, these drugs may be appropriate choices in selected patients.
Per the guidelines, a number of factors influence the selection of antihyperglycemic medications: their effectiveness in lowering glucose, their extraglycemic effects that may reduce long-term complications, safety profiles, tolerability, and cost.1
When adding a second and potentially third antihyperglycemic medication, the physician should consider potential synergy and other interactions of particular combinations. Generally, agents with different mechanisms of action have greater synergy. For example, insulin plus metformin or insulin plus a thiazolidinedione (TZD) are particularly effective in lowering glycemia.1
Initiation and intensification of basal insulin in patients who fail on oral agents1
The ADA/EASD recommends basal insulin either as second-line therapy if metformin fails, or as third-line therapy if metformin plus a second oral agent fails to meet A1C targets. As stated in the guidelines: “Although 3 oral agents can be used in patients who fail to reach target A1C, the initiation and intensification of insulin therapy is preferred based on effectiveness and expense.”1
For patients with T2 DM, initial insulin therapy is aimed at lowering fasting blood glucose, typically with long- or intermediate-acting insulins. Some patients may also require preprandial rapid- or short-acting insulin therapy.1
Current options in basal insulin therapy
Among the currently available basal insulin therapies to choose from are the insulin analogs and NPH insulin:
Insulin analogs: The newer long-acting insulin analogs, such as Lantus® (insulin glargine [rDNA origin]), and Levemir® (insulin detemir [rDNA origin]) are preferred by many physicians and patients due to their lack of pronounced peak and approximate 24-hour duration of action. Both agents were created by recombinant DNA modification of human insulin, and have the advantage of providing a steady, consistent level of basal insulin coverage.2,3 The physio/chemical structure of LANTUS enables slow release of drug, allowing it to be dosed once-daily.2 Levemir can be dosed once- or twice-daily.3 Treatment with a single-dose of long-acting insulin analog can minimize the complexity of insulin therapy, and decrease the risk of hypoglycemia and weight gain seen with NPH insulin.4 It also compares favorably to adding a third oral agent (a TZD) for impact on health-related quality of life.5
NPH insulin: Neutral protamine Hagedorn, or NPH, insulin has an intermediate duration of action and typically requires twice-daily injection to achieve required basal insulin levels over 24 hours. NPH insulin is lower in cost than the analogs.1,6 So, in patients for whom cost is a consideration, physicians may want to prescribe NPH beginning at bedtime (not dinner) to lower fasting blood glucose (FBG). Target FBG levels in T2 DM are generally 100 mg/dL or slightly less.
Both long-acting analogs and bedtime NPH as basal insulin can be added to oral or other diabetes medications. They can also be started as initial antihyperglycemic therapy when patients have greater hyperglycemia (eg, FBG >300 mg/dL and/or A1C >10%; these patients almost always require insulin treatment to control their glucose intolerance).
BD Ultra-Fine™ Insulin Syringes and Pen Needles: Quality, Comfort and Convenience
MYTH: Taking injections of insulin and other diabetes medications will be painful.
REALITY: Many patients have no idea just how small and thin an insulin needle actually is, and are pleasantly surprised when they finally see and use one for the first time. Also, many are benefiting from the increasing range and availability of insulin pens, since they find it easier and more convenient to dial and administer their dose with this delivery device. Both the insulin analogs and NPH insulin are available in pens.
BD Ultra-Fine Insulin Syringes and Pen Needles are an excellent choice for patients on, or transitioning to, insulin therapy:
No insulin syringe needle is shorter or thinner than BD Ultra-Fine
BD pen needles are universally compatible with all makes of diabetes pens and dosers in the US
BD pen needles come in a variety of lengths, including the shortest pen needle available (5mm) to meet the needs of all patients
BD Getting Started™ Take Home Kits are available to help your patients effectively transition to injection therapy
For more information on BD Ultra-Fine injection products and how to access complimentary BD Getting Started™ kits for your medical practice, visit www.bddiabetes.com/us/
REFERENCES
1. Nathan DM, Buse JB, Davidson MB, et al. Management of Hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963-1972.
2. Lantus [prescribing information]. February 2006. Bridgewater, NJ, sanofi-aventis, U.S., LLC.
3. Levemir [prescribing information]. 2005. Princeton, NJ, NovoNordisk, Inc.
4. Bethel MA, Feinglos MN. Basal insulin therapy in type 2 diabetes. J Am Board Fam Med. 2005;18:199-204.
5. Vinik AI, Zhang Q: Adding Insulin glargine versus rosiglitazone: health-related quality-of-life impact in type 2 diabetes. Diabetes Care. 2007;30(4):795-800.
6. Goldman-Levine JD. Insulin detemir (Levemir) for diabetes mellitus. STEPS: New drug reviews. Am Fam Physician. 2006;74(2). Available at: http://www.aafp.org/afp/20060715/steps.html.
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