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Current diabetes treatment algorithms do not address the physiology of the disease, according to Kathleen L. Wyne, MD, PhD, of the Division of Endocrinology and Metabolism, The University of Texas Southwestern Medical School at Dallas.
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During the session, "When to Advance From Oral Agents to Insulin," at the American Association of Diabetes Educators (AADE) annual meeting, Wyne stressed that therapy should be oriented toward the disease process and not just the end of the process, blood glucose.
"When I look at type 2 diabetes, I take the traditional schematic which starts with the pancreas on the top and flip it over," says Wyne. "The pancreas is an innocent bystander in this whole process."
Unlike the other organs, the pancreas cannot store large amount of fats. The only way for beta-cells to get rid of the extra fat is nonoxidative metabolism, which kills the beta-cells.
"We don't normally recognize diabetes until very late in the progression and once we do, our therapies are typically oriented toward reacting to the glucose," says Wyne. "The goal for therapy should be a normal glycated hemoglobin (A1C), the same as a person without diabetes."
The importance of keeping A1C as low as possible was shown by results from the U.K. Prospective Diabetes Study (UKPDS). The researchers looked at the composite incidence of any diabetes-related endpoint compared with the mean A1C and mean systolic blood pressure. They found that every 1% lowering of A1C resulted in a 21% decrease in complications that continued to 6% A1C, or normal.
However, UKPDS results show that maintaining A1C levels is difficult to do over time.
The researchers in the U.K. found that 50% of normal beta-cell function is present when a diabetes diagnosis is initially made. That is stabilized for around a year with diet and exercise alone, but progressive loss of beta-cell function continues. Similar results are seen with metformin and sulfonylurea use. This indicates that there is some process causing the loss of beta-cell function that is already established by the time of diagnosis.
Wyne suggests a stratified approach to initiating therapy in patients who are nonketotic, not dehydrated, and not acutely ill; have no significant weight loss; and have fasting plasma glucose (FPG) under 350 mg/dl. The three strata for FPG are as follows: less than 160 mg/dl, between 160 and 240 mg/dl, and between 240 and 350 mg/dl.
"We set an arbitrary top level of 350 mg/dl with the idea that if you are above that, especially if you are dehydrated and have significant weight loss, insulin should begin immediately and oral agents can be added later," says Wyne. "These are all indications that very little beta-cell reserve is left."
For those with fasting glucose levels between 126 and 160 mg/dl, the suggested initial treatment is to begin with biguanide, a thiazolidinedione, or a combination of the two. If there is still not enough insulin after advancing to the maximal suggested dose, a secretagogue could be added. In those patients where this still does not get blood glucose to target, a bedtime insulin could be added or the secretagogue could be stopped and a basal/bolus insulin regimen begun. Reassessments should be made every 3 months.
For those patients with fasting glucose levels between 160 and 240 mg/dl, the suggestion is to start with any two-drug combination. If the patient is that far from goal, the likelihood that one drug is going to get them there is small. This method allows the practitioner to tailor the medication to the needs of the patient.
For example, if the patient has high postprandial levels, a secretagogue might be used. For another patient with high fasting blood glucose, biguanide may be the better choice. As with the other strategy, those who do not respond can have a secretagogue or a basal/bolus insulin regimen added. The patient's response should be reassessed every 2 months.
For those in the highest strata, a two- or even three-drug combination is suggested to start. The next step is increasing the metformin or secretagogue while keeping the thiazolidinedione dose low for 3 to 6 months to avoid weight gain and edema. If maximal doses of two or three agents do not reduce A1C to goal, adding insulin or stopping the secretagogue and adding insulin is the next step.
The only time a switch is suggested is when going from secretagogue to basal/bolus insulin.
The practitioner should always continue the metformin and thiazolidinedione at that point.
Another issue is the point at which a patient should be started on insulin therapy. Wyne suggests that everyone who is in diabetic ketoacidosis or unprovoked ketosis, has had a significant weight loss, or has an A1C over 10% should be considered for immediate insulin therapy.
According to Wyne, one of the main problems with insulin therapy in the U.S. is that we don't give enough. Both doctors and patients are afraid of insulin.
"Health professionals perpetuate that fear by using insulin as a punishment such as telling the patients that if they don't take the other medications, we'll make them take insulin," says Wyne.
Overall, the idea is to progressively and aggressively treat diabetes beginning with low-dose combinations of each of the agents, to treat as many components of the disease as possible. The goal is to get A1C down to at least 7% and preferably 6.5% or lower.
Wyne suggests monitoring both fasting and 2-hour postprandial blood glucose. If the postprandial, but not the fasting, blood glucose is increasing, the patient may need prandial insulin.
For more information, visit AADE at
www.aadenet.org.
Footnotes
U.K. Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 352:837-853, 1998[Medline].
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