So many new antiglycemic agents have been introduced that clinicians can’t keep up. An endocrinologist/diabetologist provides a refresher.
We all know a diabetes epidemic is upon us, afflicting 21 million Americans and claiming more patients each day. But there’s good news too. Several new diabetes therapies have been introduced recently, including whole new classes of drugs (Table 1). We may be experiencing the biggest revolution in diabetes treatment since insulin arrived on the scene in 1921. This article reviews the new agents.
The most innovative new drug class is the incretin mimetics. Incretins are naturally occurring hormones secreted from the intestines in response to food intake. Exenatide (Byetta), the first incretin mimetic, mimics one of the key hormones deficient in people with type 2 diabetes—glucagon-like peptide 1 (GLP-1).
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Among this peptide’s many actions are (1) a potentiation of glucose-induced insulin secretion at the level of the beta cell, (2) an inhibition of glucagon secretion (and hence glucose production in the liver), (3) an inhibition of GI secretion and motility, two functions that help dampen the typical postprandial glucose spike, and (4) an inhibition of appetite and food intake. Anyone who treats type 2 diabetes can see why deficiency of this hormone is so crucial in worsening glycemic control—and hence can appreciate the value of Byetta, a GLP-1 analog.
Byetta was approved for marketing in 2005 by Eli Lilly and Amylin Pharaceuticals, and has already proved to be a welcome addition to traditional medications. It is usually used as add-on therapy once patients have failed on either metformin or other oral agents.
Byetta is injected subcutaneously (SC) twice a day, with breakfast and dinner, in either 5- or 10-µg doses. The Byetta prefilled pens contain either a 5- or 10-µg dose, so the drug is much simpler to titrate than insulin, doses of which can vary from 1 to 100-plus units.
Each pen contains 60 doses, so I have patients try to increase to the 10-µg pen after using the 5-µg dose for about two weeks. If patients develop nausea—a common side effect—I have them use 5 µg in the morning and 10 µg in the evening until they can tolerate the 10-µg b.i.d. dose. In my practice, about 85% of patients get to the 10-µg dose b.i.d., whereas 10%-15% either stop the medication because of nausea or cannot go beyond the 5-µg dose.
Before approval, Byetta was tested as add-on therapy with a sulfonylurea or metformin, showing an average glycosylated hemoglobin (HbA1c) drop of about one percentage point from the 7%-9% range.1
Weight loss is a major benefit of this drug. For patients, this comes as a welcome contrast to the weight gain that frequently accompanies insulin and other diabetes medicines; the additional weight can eventually worsen the disease. On average, patients lose approximately 10 lb during the first six months of therapy. This can be an effective inducement for patients who are initially hesitant to take this medication because of the injections required.
Dipeptidyl peptidase-4 inhibitors
This is the latest diabetes medication class to become available, represented so far by only one product, sitagliptin, which is sold by Merck under the name Januvia. This class works by inhibiting degradation of endogenous GLP-1.
Januvia is usually prescribed at a dose of 100 mg daily (50 mg in patients with creatinine clearance 30-50 cc/min and 25 mg in those with creatinine clearance <30 cc/min). Studies show that the drug lowers HbA1c by 0.6-1.0 percentage points, so it shouldn’t cause hypoglycemia. Sitagliptin is approved for use with metformin or the thiazolidinediones (Actos and Avandia). Taken as a pill once a day (with or without a meal), it is generally well tolerated with few side effects.
Vildagliptin (Galvus, from Novartis), another drug in this class with efficacy similar to sitagliptin, has been submitted for FDA review. Both drugs appear to be weight-neutral and can serve as an added medication once metformin fails—without the concern of weight gain that accompanies the thiazolidinediones and sulfonylureas. There is also no associated hypoglycemia, as seen with insulin and sulfonylureas.
Pramlintide, an analog of amylin sold as Symlin by Amylin Pharmaceuticals, is another first-in-class agent and is intended for type 1 and type 2 diabetics who use insulin.
The antihyperglycemic effects of amylin have been known for years. Whereas insulin causes an increase in the rate of glucose disappearance from the blood, amylin (and hence Symlin) causes a decrease in the rate of appearance of glucose in the blood. Like exenatide, it decreases appetite, slows gastric emptying, and decreases glucagon secretion.
Amylin is deficient in patients who require insulin treatment for diabetes, and this likely contributes to the high postprandial blood sugars. Symlin is ideal for the motivated patient willing to take an additional injection before meals who has not been able to get the HbA1c and postprandial glucose levels to goal with insulin injections alone. Such patients, despite accurately dosing insulin at meals, may have HbA1c in the 7%-9% range and high postprandial blood sugar levels (above the 150-180 mg/dL goal that most clinicians recommend).
Symlin is not recommended for patients with HbA1c >9% because they are probably not taking enough insulin at mealtime. Patients who inject both Symlin and insulin at meals usually find they require 10%-50% less insulin. Although algorithms exist for prandial insulin-dose adjustments with increasing doses of Symlin, I explain to patients that the goal is to maximize their Symlin dose and minimize their prandial insulin dose. If their postprandial blood sugars are still above goal with 2.5 units of Symlin, they should increase their dose in 2.5-unit increments until they reach 20 units with each meal (10 units for type 1 patients). If they begin to experience low blood sugars postprandially, a reduction of 10%-20% in their premeal insulin dose is recommended.
Patients who use Symlin may experience some nausea initially and when they up-titrate. Some may say they cannot tolerate more than “X” units but will report benefits in postprandial control, HbA1c, and weight loss. Since most patients who use Symlin are on basal-bolus insulin therapy (i.e., four injections a day), I prescribe Symlin at their largest meal. This often helps with food intake, weight loss, and blood sugar control since the greatest amount of calories and carbohydrates, and the highest blood sugars, are often associated with this meal. Many patients will then use Symlin at other meals once they have learned how to best use it at one meal.
I have several patients who use an insulin pump and benefit from Symlin. Because they are not injecting insulin on a regular basis, they find Symlin injections more tolerable. Pump patients can also adjust the rate at which the prandial insulin is given which, along with Symlin, most closely resembles the physiologic rise in insulin and amylin levels after a meal.
New forms of insulin
Levemir: New insulin therapies have also been added to the arsenal of treatments. Levemir (insulin detemir) is a basal insulin from Novo Nordisk prescribed either once or twice a day. It does not appear to last quite as long as insulin glargine (Lantus), so type 1 patients who are not on high doses (<0.6 units basal insulin/kg body weight daily) need to split the dose to b.i.d. to ensure their basal insulin will cover them throughout the day.
Levemir may have less variability day to day in a given patient, compared with other long-acting insulins. For instance, I have had good results with Levemir in the patient who has varying blood sugars despite eating the same or similar meals day to day and participating in the same physical activities. Convincing clinical data have shown that the coefficient of variability of Levemir (i.e., the variable insulin concentrations seen after an injection of insulin on one day compared with the same injection the next day) is less than with isophane insulin (neutral protamine Hagedorn) and even insulin glargine.2
Apidra: Insulin glulisine is a new rapid-acting insulin approved for use within 15 minutes before or 20 minutes after starting a meal. Manufactured by Sanofi Aventis, it is for both types of diabetes and should be used as a supplement to longer-lasting insulin.
Exubera: Inhaled insulin was introduced last year by Pfizer as Exubera. Available in 1- and 3-mg packets, it is dosed before meals. It should not be used by anyone who has smoked or given up smoking within the previous six months or who has asthma, chronic obstructive pulmonary disease, or any other active lung disease.
The 1-mg blister pack delivers the equivalent of 3 units of rapid-acting SC insulin, and the 3-mg blister pack delivers the equivalent of 8 units. Baseline pulmonary function testing should be done (e.g., carbon monoxide diffusing capacity and forced expiratory volume in one second [FEV1]). Follow-up testing needs to be done at six months, and if there is a decline in FEV1 of >20%, Exubera should be stopped.
Overall, Exubera’s use since its release has fallen below expectations. The need to measure and monitor pulmonary function has likely discouraged many clinicians. Also, since only 1- and 3-mg blister packs are available, patients are limited in their ability to closely match their insulin doses to carbohydrate intake.
Moreover, even though there are no specific safety issues or warnings involved with Exubera, the long-term effects of insulin exposure to the lung are not known (although a two-year study published earlier this year found no differences in lung function between Exubera and insulin patients).3 Finally, the realization that glycemic control is likely no better in most patients with inhaled insulin versus SC insulin discourages switching from the tried-and-true injection method.
But for the patient who needs prandial insulin and will not take an injection (and anyone who has treated diabetics has had to deal with such patients), Exubera is a major plus. For insulin-resistant patients who require larger doses of prandial insulin, the dosing limitations described above may not be as significant as it is in more insulin-sensitive patients, for whom an extra unit or two can affect control significantly. Your more insulin-resistant patients may be good ones to try on Exubera, especially if they are hesistant to start injection therapy.
New form of metformin
Glumetza is the latest extended-release form of metformin and shows fewer GI side effects than immediate-release formulations. It is available in 500-mg tablets, which are taken once daily with the evening meal. To date, no head-to-head comparison study between Glumetza and its competitors has been published.
Three new combination medications enable clinicians to write one prescription for two agents with separate but complementary modes of action.
Avandaryl, from GlaxoSmithKline, combines rosiglitazone (Avandia) and glimepiride (Amaryl) in 1-mg/4-mg, 2-mg/4-mg, and 4-mg/4-mg tablets. Avandaryl is given once daily and should have the same therapeutic and side effects as taking the two drugs separately and simultaneously. The patient benefits from both convenience and having just one co-payment at the pharmacy instead of two.
Duetact (pronounced “duet act”), from Takeda Pharmaceuticals, combines pioglitazone and glimepiride and is available in 2-mg/30-mg and 4-mg/30-mg pills.It is taken once daily with the first main meal.
Janumet, from Merck, combines Januvia (sitagliptin) and metformin. Merck says the combination targets all three key defects of type 2 diabetes: diminished insulin release, uncontrolled production of glucose, and insulin resistance. Premarketing clinical trials showed that patients using the combination agent experienced weight loss comparable with metformin alone and experienced no increased risk of hypoglycemia, edema, or GI disturbances beyond metformin alone.
Janumet comes in a tablet combining 50 mg Januvia with either 500 or 1,000 mg metformin.
Dr. Mitzner is an endocrinologist at the Joslin Clinic and an instructor in medicine at Harvard Medical School, both in Boston.
1. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1083-1091 and 1092-1111.
2. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-1620.
3. Skyler JS, Jovanovic L, Klioze S, et al. Two-year safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 1 diabetes. Diabetes Care. 2007;30:579-585.