DPP-4 Inhibitors and the Quest for HbA1c Control

US Pharm. 2007;32(10):HS-24-HS-HS-32.

Currently, there are 20.8 million people, or 7% of the U.S. population, with diabetes. By 2050, this number is projected to more than double to 48.3 million.¹ The majority of these patients are diagnosed with type 2 diabetes, which is characterized by insulin resistance and diminished beta-cell function.² Lifestyle modifications, including medical nutrition therapy, weight management, and physical activity, are the foundations of treatment. In addition to lifestyle interventions, there are now nine classes of antihyperglycemic agents.

Sitagliptin (Januvia), the first in a new class of antihyperglycemic agents, was approved in October 2006. It inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), which causes the degradation of glucagon-like peptide-1 (GLP-1). The only other agent on the market that affects levels of GLP-1 is exen­ atide (Byetta). Exenatide is an injectable GLP-1 agonist, which mimics the action of naturally occurring GLP-1. Indications for sitagliptin include use in type 2 diabetes as monotherapy or in combination with metformin or thiazolidinediones.³

Clinical Effects
The two incretin hormones that have been identified are glucose-dependent insulinotropic polypeptide (GIP) and GLP-1.⁴ Incretin hormones are released by cells in the gastrointestinal tract in response to food, and they stimulate insulin secretion to maintain glucose homeostasis. Research shows a 15% reduction in postprandial levels of GLP-1 in patients with type 2 diabetes.⁵ Circulating levels of GIP are near normal in type 2 diabetes, but the peptide has decreased ability to stimulate insulin secretion levels. The problem is that GLP-1 is rapidly inactivated (half-life of approximately one minute) by the enzyme DPP-4.⁶ Inhibiting the DPP-4 enzyme enhances the action of GLP-1 by prolonging the half-life and increasing circulating GLP-1. GLP-1 causes pancreatic beta-cells to increase insulin secretion when glucose levels are elevated due to a meal; therefore, hypoglycemia is less likely.⁴

DPP-4 inhibitors have actions similar to those of the GLP-1 agonist, such as stimulation of insulin secretion, inhibition of glucagon secretion, and preservation of beta-cell function.⁴ In contrast, DPP-4 inhibitors do not slow gastric emptying or cause weight loss, possibly due to lower concentrations of GLP-1 postprandially compared to the GLP-1 agonist (see Table 1). DPP-4 inhibitors raise incretin levels to normal or slightly above normal levels.⁷ The advantage of DPP-4 inhibitors is oral administration; the GLP-1 receptor agonist is injectable.

Adverse Effects
The most common adverse effects are upper respiratory tract infection, nasopharyngitis, and headache. Nasopharyngitis was reported in 5.2% of patients taking sitagliptin 100 mg as monotherapy versus 3.3% of patients taking placebo.³ When sitagliptin plus pioglitazone was compared with pioglitazone plus placebo, the most common side effects reported  included upper respiratory tract infection (6.3% vs. 3.4%, respectively) and headache (5.1% vs. 3.9%, respectively).⁹ The mechanism for the nasopharyngitis is unknown, but the intensity, duration, and recurrence rate was the same as the placebo group, and this did not cause discontinuation from the clinical trial.³ The DPP-4 enzyme is also found in other tissues, including those from the liver, kidneys, pancreatic duct, and lymphocytes.⁴ Interestingly, early trials suggested DPP-4 may affect the immune system due to inhibition of T-cell activity in vitro.¹¹ It was later determined that higher concentrations were necessary to produce the same effect in vivo. Studies have shown that sitagliptin is a selective and potent inhibitor (greater than 80%) of the DPP-4 enzyme.^3,10 Selectivity is important, because inhibition of two other enzymes, DPP-8 and -9--both in the same family as DPP-4--resulted in serious toxicities and impaired T-cell activation. ^6,7 Long-term trials evaluating the effects on the immune system may be warranted owing to increased reports of nasopharyngitis, urinary tract infection, and small elevations in white blood cell count.^12-14 The overall incidence of hypoglycemia and gastrointestinal adverse events in patients taking sitagliptin 100 mg was similar to that of placebo.¹⁰

Drug Interactions
Sitagliptin does not inhibit or activate the cytochrome P-450 enzyme system, but it is a P-glycoprotein substrate.⁷ After 10 days, sitagliptin 100 mg increased the area under the curve (11%) and the mean peak drug concentration (C_max, 18%) of digoxin.³ Therefore, patients receiving digoxin should be monitored when starting sitagliptin.

Dosage
The recommended dosage of sitagliptin is 100 mg once daily with or without food. The majority of sitagliptin (79%) is excreted unchanged in the urine. For patients with moderate, severe, and end-stage renal disease, a dosage adjustment is required (see Table 2).

Sitagliptin is available in 25-, 50-, and 100-mg tablets. The different strengths are available for dosage adjustment in renal insufficiency and should not be used for dosage titration.

Place In Therapy
In type 2 diabetes, there is a progressive loss of beta-cell mass and function. GLP-1 increases endogenous insulin secretion, which supports the use of DPP-4 inhibitors early in the disease process.

To date, there are few head-to-head trials comparing DPP-4 inhibitors to other antihyperglycemic agents. A noninferiority trial compared sitagliptin to glipizide as add-on therapy in 1,172 patients inadequately controlled using metformin alone. After 52 weeks of treatment, the change in the glycosylated hemoglobin A1c (HbA1c) level from baseline was –0.67% for both groups. There was more hypoglycemia and weight gain (+1.1 kg) in the glipizide group, whereas the sitagliptin group had weight loss (-1.5 kg).¹²

Sitagliptin is not as potent in lowering HbA1c levels (0.6%-0.85%) as metformin (1%-2%).¹⁵ However, the recent FDA approval of sitagliptin/metformin (Janumet) may make sitagliptin a more reasonable first-line choice. The combination of sitagliptin and metformin is indicated in patients who are not adequately controlled on metformin or sitagliptin alone or in patients already taking both agents. ¹⁶ This approval was based on a randomized, double-blind, placebo-controlled trial of 701 patients inadequately controlled on metformin alone. The average duration of diabetes was 6.2 years, and patients were on at least 1,500 mg of metformin with a mean HbA1c of 8%. The HbA1c level decreased by an additional 0.7% using sitagliptin. Fasting plasma glucose decreased by 16.2 mg/dL, compared to 9.0 mg/dL with placebo. Two-hour postprandial glucose decreased by 61.3 mg/dL using the combination drug versus 10.8 mg/dL with placebo. Most impressive was that more patients taking the combination drug (47%) reached an HbA1c level of less than 7% during the 24 week study than did those taking placebo (18%).¹⁴ Pairing sitagliptin with metformin is a good combination, because metformin is commonly used as initial therapy due to the absence of weight gain and hypoglycemia.

Most patients will require more than one agent to control diabetes. Many of the antihyperglycemic therapies currently available are associated with weight gain (i.e., sulfonylureas, nonsulfonylureas, thiazolidinediones, and insulin). The DPP-4 inhibitors offer the advantage of no weight gain.^7,11 It is unknown if DPP-4 inhibitors can prevent weight gain in the long term. DPP-4 inhibitors may be a treatment option for patients in whom metformin is contraindicated due to decreased renal function or intolerable gastrointestinal side effects. The biggest disadvantage is cost, since sitagliptin is approximately three times more expensive than metformin and about ten times more expensive than the sulfonylureas.¹⁷

Long-term effects of GLP-1 in animal studies demonstrated increases in beta-cell mass and beta-cell efficiency.⁴ Can these agents that increase the levels of GLP-1 alter the course of type 2 diabetes in humans? Some of the clinical studies did document improvement in the markers of alpha- and beta-cell function (glucagon suppression, indices of insulin secretion, measures of beta-cell sensitivity, proinsulin–insulin ratios, and Hemeostatis Model Assessment of beta cell function [HOMA-beta]) in patients taking a DPP-4 inhibitor.⁷ However, long-term studies are needed to confirm these findings and document a delay in disease progression.

The mechanism of action of the DPP-4 inhibitors raises the question: Will these agents be effective in patients who have had diabetes for 10 to 15 years and who may no longer have any beta-cell function? In clinical practice, sitagliptin is often used as add-on therapy to delay insulin therapy. The fasting and postprandial reductions are not as impressive. To date, there are no trials assessing patients who have had diabetes for more than 6.2 years.¹⁴ Long-term studies and postmarketing data may help answer this question.

HbA1cGoals

The United Kingdom Prospective Diabetes Study demonstrated that for every percentage point reduction in HbA1c, there was a 35% reduction in the risk of complications in patients with type 2 diabetes. ¹⁸ For type 1 diabetes, the Diabetes Complications and Control Trial showed that complications--including retinopathy, nephropathy and neuropathy--can be delayed or prevented with intensive insulin therapy. ¹⁹ These large, controlled clinical trials have been the basis for recommendations aimed at preventing long-term complications. Extensive research supports tighter glucose control to reduce complications. Despite our best efforts, the treatment of diabetes remains suboptimal. The National Health and Nutrition Examination Survey 2001–2002 sample data indicate that only half (49.8%) of diabetic adults aged 18 years or older met the recommended HbA1c level of less than 7%.²⁰

It is important to remember that both fasting and postprandial glucose contribute to HbA1c. In patients with near-normal fasting glucose who are unable to reach an HbA1c level of less than 7%, postprandial glucose should be the target.²¹ Fasting hyperglycemia is the dominant contributor when the HbA1c level rises above 8.4%.²² Clinical trials for sitagliptin reflect a more dramatic reduction in postprandial glucose (–49 to –62 mg/dL) compared to fasting glucose (–10 to –25 mg/dL).^7,10

The American Diabetes Association (ADA) continues to recommend an HbA1c level of less than 7%, but in 2006, it stated that the HbA1c level should be "as close to normal (<6%) as possible without significant hypoglycemia."²³ On the other hand, the American Association of Clinical Endocrinologists (AACE) recommends an HbA1c level of less than 6.5%.²⁴ Recommendations for glycemic control from both organizations are listed in Table 3. Both the ADA and the AACE agree that the HbA1c goals should be individualized, but despite all the treatment options available, good glycemic control is not always attainable.

Barriers

Glycemic control in patients with type 2 diabetes remains poor despite the use of old and new medications available for the treatment of diabetes. There are numerous factors that affect adherence, including patient and/or physician resistance to intensifying treatment regimens, financial burden, and the complexity of the medication regimen. ²⁵ Many times, pharmacotherapy is postponed at the time of diagnosis in the hopes that diet and exercise therapy will be successful. A retrospective analysis of 9,416 patients over a three-year period showed the mean HbA1c level was 8.4% when antihyperglycemic therapy was started.²⁶ The majority (67%) of the patients reviewed had a mean baseline HbA1c of 9.5% when therapy was initiated, which supports the theory of lack of action in response to abnormal findings. Infrequent monitoring of HbA1c was another reason identified for not intensifying treatment regimens. Data showed that patients had, on average, one HbA1c test annually.²⁶ The ADA recommends monitoring HbA1c levels twice a year for patients at goal and four times a year for patients not at goal.² Data show that more than 50% of patients started on monotherapy will require a second medication to control diabetes after three years.²⁷ Also, studies have concluded that it is very difficult and expensive to treat patients to an HbA1c level of less than 7%.²⁸ The combination of multiple medications and/or the financial burden may be too much for some patients.

Other reasons associated with poor glycemic control include physicians' lack of knowledge about diabetes treatment guidelines or their choice not to follow them.

What's Next?
Development of new therapies for the treatment of diabetes continues to focus on enhancing the positive effects of GLP-1. In February 2007, Novartis received an approval letter from the FDA for vildagliptin (Galvus), another DPP-4 inhibitor.²⁹ One study of interest looked at vildagliptin in patients with type 2 diabetes who required insulin. Findings revealed that patients were able to take lower dosages of insuline and had fewer episodes of hypoglycemia.³⁰ The side-effect profile of vildagliptin is similar to that of sitagliptin. In addition, the rate of hypoglycemia in patients taking vildagliptin is similar to that of patients taking placebo. There is no anticipated dosage adjustment for renal insufficiency.³⁰ So far, the studies show a mixed effect on cholesterol, with one study showing a small increase in total cholesterol and another study producing a decrease in HDL cholesterol.²⁹ Two other DPP-4 inhibitors, saxagliptin and denagliptin, are in development.³¹

Currently, clinical trials are evaluating the effects of a long-acting-release form of exenatide. Preliminary data show greater reductions in fasting glucose and HbA1c with a weekly injection.³¹

Lastly, a longer-acting synthetic derivative of GLP-1, liraglutide, is in the pipeline. Liraglutide is more like human GLP-1 than exenatide and is injected once daily. Disadvantages, compared to sitagliptin, include an injectable dosage form and gastrointestinal side effects. The most frequent side effects are nausea and diarrhea. Liraglutide increases insulin secretion, suppresses postprandial glucagon secretion, and decreases weight and HbA1c.³²

Summary
DPP-4 inhibitors may have the greatest impact in patients who are early in the disease process. Sitagliptin is another weapon in the arsenal of oral antihyperglycemic agents; however, whether it will be enough to get more patients to reach their goal HbA1c level or whether it will simply delay the start of insulin therapy remains in question. The pharmacist can have a key role in educating patients and providers about the importance of regular diabetes follow-up, home glucose monitoring, frequent HbA1c testing, and why multiple medications are needed. The ultimate objective is to increase the number of people with diabetes with an HbA1c level of less than 7%, but it will take a team effort.

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