Just a spoonful of medicine helps the sugar go down
... but there's more to it than that
The nation's obesity epidemic has led to an increase in the number of patients with type 2 diabetes and the cardiovascular, renal, and retinal complications it causes.
Recently, new data that rosiglitazone (Avandia) increases the risk of heart disease1 has caused many physicians and patients to re-think their approach to this common condition. Adding to the confusion is the availability of several new varieties of injectable insulin and the withdrawal of inhaled insulin.
Despite the proliferation of therapeutic choices, glycemic control remains inadequate for many patients.2
The good news is that attention to several key principles can increase the safety and effectiveness of diabetes management.
Tighter control: the standard of care
Patients with worse glucose control develop earlier and more severe end-organ complications.3
Weight control: the foundation of treatment for many patients
In randomized trials, weight loss and exercise have proven effective in preventing overweight patients with elevated glucose levels from developing diabetes. In fact, in one large randomized trial, these lifestyle interventions were even more effective than metformin in restoring normal glucose levels - a potent reminder of the important role weight loss and exercise should play in any diabetes regimen, even when drugs are also necessary.4,5
Keeping hemoglobin A1c below 7%
Several key trials have demonstrated that strict glycemic control in patients with diabetes can reduce the risk or severity of end-organ damage.3,6 As a result, maintaining a hemoglobin A1c below 7% has become the goal of therapy for most patients.
When medications are required
The clinical trial evidence favors beginning drug therapy with metformin (multiple generic products and Glucophage).7,8
The focus of management then shifts to effective glycemic control - a hemoglobin A1c at or below 7%. (Individualize this goal in select patients, such as the elderly and pregnant women; see the iDiS monograph on the management of type 2 diabetes for more information.)
Titration of metformin:
- Begin with low-dose metformin (500 mg) taken once or twice per day with meals.
- After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850 or 1,000 mg before breakfast and before dinner.
- If gastrointestinal side effects appear as the dose is advanced, reduce dose and try to increase it later. Such symptoms will resolve in most patients.
- The total maximum effective dose is usually 850 mg twice per day, with modestly greater effectiveness with doses up to a total of 2g per day.
- Generic metformin is the most cost-effective preparation; a more costly longer-acting formulation is available and can be given once per day.
Adapted from American Diabetes Association for the Study of Diabetes Consensus Statement for the Management of Hyperglycemia in Type 2 Diabetes9
Getting to goal
Metformin is usually titrated over 1 to 2 months to its maximum effective dose (usually 850 mg b.i.d.).9
Monotherapy will initially be adequate for many patients to achieve satisfactory glycemic control. After 3 years, about 50% of patients will require addition of another agent. By 9 years, about 75% of patients will need multiple agents to achieve adequate glycemic control.
Adding a second drug
When a new agent is added, it should generally be a sulfonylurea such as glyburide (generics and Diabeta). A short-acting agent in this class, such as glipizide (generics and Glucotrol), is preferable for elderly patients and those with renal impairment.
The decline of the glitazones
Although the 2006 ADA guidelines had suggested that the glitazones might be an alternative choice for a second agent,9 in mid-2007 the FDA added a black-box warning cautioning that both rosiglitazone (Avandia) and pioglitazone (Actos) increase the risk of congestive heart failure. This safety concern, along with an increased risk of fracture, has greatly dampened enthusiasm for use of both drugs in this class.1
Additional clinical trial findings documenting that rosiglitazone increases the risk of myocardial ischemia/infarction by about 40%1,11 have raised the question of what role, if any, this drug should have in the management of diabetes.12
Other agents may be appropriate in select patients; see the iDiS monograph on the management of type 2 diabetes for a full description.
Don't wait to start insulin when regimen intensification is needed
Consider adding insulin for your patients who are...
- on maximal dose of one oral hypoglycemic with A1c levels > 8.5%
- on maximal doses of two oral agents with A1c levels above goal.
The ADA recommends initiating insulin rather than adding a third oral agent in many patients, although adding pioglitazone is another alternative.
Which insulin to choose
The ADA recommends initiating treatment with a single daily dose of NPH or a long-acting insulin analog.9 By gradually titrating up the insulin dose until the fasting glucose has been normalized (generally ~100 mg/dL), this simple strategy will frequently suffice to manage blood glucose.13
Initiation and titration of insulin
Start with 10 units per day of bedtime long-acting insulin. Adjust insulin every week. To adjust, calculate the mean self-monitored fasting blood glucose values from the previous 2 days.
Insulin initiation and titration
- Start with 10 units per day of bedtime long-acting insulin
- Adjust insulin every week. To adjust, calculate the mean self-monitored fasting blood glucose values (FBG) from the previous 2 days.
Mean FBG Increase insulin by
100-120 mg/dL 2 units
120-140 mg/dL 4 units
140-180 mg/dL 6 units
≥ 180 mg/dL 8 units
The use of biphasic premixed combinations or pre-prandial fact-acting insulin preparations may modestly improve glucose control when compared to single dose regimens.14 However, higher rates of hypoglycemia as well as greater cost and more complex administration mean that single dose regimens will remain the preferred starting medication for most patients. Inhaled insulin has been removed from the market and is no longer used.
Ongoing management
Diabetes requires careful ongoing management by both doctor and patient for years and even decades.
Continue monitoring A1c every three months until it reaches 7%, and then at least every 6 months. This will help reveal how well the regimen is working, and whether intensification is necessary. Reinforce lifestyle intervention at every visit.
Discussing compliance with the patient can be a useful step before simply increasing a dose or adding a new prescription. Poor control may be a symptom of poor medication adherence - a problem far more common with very costly medications.
Older patients and frail patients of any age, may require more flexible goals for glycemic control, since the risk-benefit relationship of very tight A1c control may be less favorable than in otherwise healthy patients with diabetes.
Careful management of both lipids and blood pressure are particularly important in all patients with diabetes, as these risk factors are as important as glucose levels in influencing the likelihood of devastating end-organ damage.
References
1. Nissen SE, Woloski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. The New England Journal of Medicine 2007;356(24):2457-71. 2. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291(3):335-42. 3. Are continuing studies of metabolic control and microvascular complications in insulin-dependent diabetes mellitus justified? The Diabetes Control and Complications Trial. The New England Journal of Medicine 1988;318(4):246-50. 4. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes melllitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England Journal of Medicine 2001;344(18);1343-50. 5. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine 2002;346:393-403. 6. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53. 7. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854-65, 8. Standards if medical care in diabetes - 2007. Diabetes Care 2007;30 Suppl 1:S4-S41. 9. 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(8):1963-72. 10. Rosiglitazone Maleate (marketed as Avandia, Avandamet, and Avandaryl) Information. 2007. (Accessed October 9, 2007, at http://www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm.) 11. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007:298(10):1189-95 12. Solomon DH, Winkelmayer WC. Cardiovascular risk and the thiazolidinediones: deja vu all over again? JAMA 2007;298(10):1216-8 13. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26(11):3080-6. 14. Holman RR, Thorne KI, Farmer AJ, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. The New England Journal of Medicine 2007;357(17):1716-30. 15. McMahon GT, Dluhy RG. Intention to treat - initiating insulin and the 4-T study. The New England Journal of Medicine 2007;357(17):1759-61.
This material was produced by Niteesh K. Choudhry, M.D., Ph.D., Assistant Professor of Medicine, Michael A. Fischer, M.D., M.S., Assistant Professor of Medicine, and William H. Shrank, M.D., M.S.H.S., Instructor of Medicine, Harvard Medical School. Senior editor: Jerry Avorn, M.D., Professor of Medicine, Harvard Medical School. All are physicians at the Brigham and Women's Hospital in Boston. The Independent Drug Information Service (iDiS) is supported by the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania. This program is provided by the Alosa Foundation and is not affiliated in any way with any pharmaceutical company. These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient's clinical condition.
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