Pharmacy Drug Class Review November 30, 2009 Disclaimer: Specific agents may have variations Authored By: Kirsten Butterfoss Pharm. D. Candidate 2010; Edited By: Richard J. Kraft, Pharm.D., Type 2 Diabetes Mellitus Focus on DPP-4 inhibitors, Glp-1 Analogs, And Amylin Analogs 1. Introduction: General Drug Class and Dosing Information 2. What role do the incretin hormones play in diabetes? 3. What are the mechanisms of action of these medications? 4. What monitoring parameters are required? 5. Where in the Diabetes GUIDELINES do these classes of medications fit? a. Which patients do they benefit? b. Overview of Diabetic Medications available 6. How do these newer drugs differ in their tolerability and safety? 7. Which drugs in this class are associated with pancreatitis and how serious is the risk? 8. Byetta vs Januvia- which is a better option? 9. Review of Trials a. Byetta b. Januvia c. Onglyza d. Symlin Dipeptidyl Peptidase (DPP-4) Inhibitors: Sitaglipitin (Januvia) Saxagliptin (Onglyza) GLP-1 Analogs: Exenatide (Byetta) Amylin analogs Pramlintide (Symlin) Highlights: The Quick-Read Information 1. Symlin (pramlintide) should be administered? a. [in the same vial as insulin]; b. [only to patients with Type 2 Diabetes Mellitus]; c. [with meals that contain at least 250 calories or 30 gm of carbohydrates] d. [as an adjunct therapy to patients receiving oral diabetic medications] 2. The half-life of endogenous GLP-1 hormone is a. [4 hours]; b. [5 minutes]; c. [1 hour]; d. [2 minutes] Link to Answer Key 3. The incretin hormones, GIP and GLP-1, may be responsible for what percentage of post-prandial insulin secretion? a. [up to 70%]; b. [up to 50%]; c. [less than 50%]; d. [minimal, affects fasting secretion] 4. True or False, data suggests Januvia can decrease systolic blood pressure? a. [True]; b. [False]; 5. According to clinical trials, combining Byetta and Januvia resulted in better control of glucose levels? a. [True]; b. [False]; 6. Which of the medication(s) below has been associated with pancreatitis in current post-marketing surveillance? a. [Onglyza and Januvia] b. [Symlin and Byetta] c. [Byetta and Januvia] d. [only Byetta] 1 P a g e
Generic name (Brand) Sitaglipitin (Januvia) Saxaglipitin (Onglyza) Exenatide (Byetta) Medication Class Dosage Form / Strengths Dipeptidyl peptidase IV (DPP- IV) inhibitor Dipeptidyl peptidase IV (DPP- IV) inhibitor GLP-1 Analog 25, 50, 100 mg tablets 2.5, 5 mg tablets Subcutaneous Solution: 5, 10 mcg Pen for Injection General Class Information Combinations Available Sitaglipitin 50 mg + metformin 500 mg OR Metformin 1000 mg Generic Available? Pregnancy Category No B Tier 2 ** IHA Tier Commercial IHA Tier Medicare Tier 2 ** No No B Tier 3 Tier 3 No No C Tier 2 (ST except endo) Tier 2 ** (ST) Pramlintide (Symlin) Amylin analogue Subcutaneous Solution: Vial: 600 mcg/ml Pen: 1000 mcg/ml No No C Tier 2 (PA except endo, patient must be on insulin therapy) **- 90 day supply can be dispensed (copay for each 30 day supply), ST Step Therapy required, PA Prior Auth Required Tier 2 ** (PA) [Back to Quiz] 2 P a g e
Dosing Information Generic name (Brand) Sitaglipitin (Januvia) Saxaglipitin (Onglyza) Exenatide (Byetta) Pramlintide (Symlin) T2DM Dosing Dose adjustments if used with other Diabetes medications 100 mg/day PO Decrease dose of sulfonylurea if prescribed with sitaglipitin to decrease risk of hypoglycemia 2.5 to 5 mg PO daily Decrease dose of sulfonylurea if prescribed with saxaglipitin to decrease risk of hypoglycemia First Month: 5 mcg SC BID within 60 minutes before a morning and evening meal OR before two main meals of the day approximately 6 hours or more apart (may help with tolerability if patient does not eat large breakfast) After one month: increase to 10 mcg SC BID Type 2 DM: Start 60 mcg SQ before meals, increase to 120 mcg SC before meals in 3-7 days if nausea tolerable Decrease dose of sulfonylurea if prescribed with saxaglipitin to decrease risk of hypoglycemia Renal Dosing Following for ANY point in therapy: CrCl > 50ml/min: No adjustment needed CrCl 30-50 ml/min: 50 mg PO daily CrCl < 30 ml/min: 25 mg PO daily Hemodialysis: 25 mg PO daily Following for ANY point in therapy: CrCl > 50 ml/min: No adjustment needed CrCl < 50 ml/min: 2.5 mg PO daily Hemodialysis: 2.5 mg PO daily after dialysis CrCl>30 ml/min: No dose adjustment needed CrCl 30 to 50 ml/min: Use in caution when increasing dose from 5 to 10 mcg CrCl <30 ml/min: Use is not recommended Hemodialysis: Use is not recommended CrCl 20-50: no adjustment CrCl <20: not studied Comments - Sitaglipitin has NOT been studied with insulin therapy - Weight neutral - dose at 2.5 mg if coadministered with a strong CYP 3A4/5 inhibitor - Saxaglipitin has been studied as an add-on therapy to metformin, glyburide, pioglitazone, or rosiglitazone - Saxaglipitin has NOT been studied with insulin therapy - Weight neutral - Can be used as monotherapy OR in combination with other drugs to treat T2DM - Has NOT been studied with insulin therapy - NON FDA approved administration 2 mg SC once a week - A limited longer duration of 5 mcg dose is reasonable if tolerability continues to be an issue - Clinically significant weight loss as added benefit - do NOT mix with insulin - can be used for Type 1 OR Type 2 - only FDA approved as adjunct therapy with insulin - Should only be used with meals that contain at least 250 calories or 30 gm of carbohydrates - Clinically significant weight loss as added benefit [Back to Quiz] 3 P a g e
INTRODUCTION Diabetes Mellitus has developed into an epidemic health care issue over the past several years affecting 23.6 million people in the US and is the 7 th leading cause of death. Poorly controlled diabetes is the leading cause of adult blindness, end-stage renal disease, and non-traumatic lower limb amputations. 1 The overall economic costs of diabetes in 2007 was 174 billion dollars; with Type 2 Diabetes Mellitus (T2DM) accounting for most of the expenditure. 1 Diabetes is classified into four major categories: prediabetes, Type 1 diabetes (previously classed insulin-dependent diabetes mellitus or juvenile-onset diabetes), Type 2 diabetes (previously called non-insulin dependent diabetes mellitus or adult onset diabetes), and gestational diabetes. In this drug class review, the focus will be on treatment with DPP4- inhibitors and GLP-1 analogs for T2DM. The figure below depicts the picture of various drugs on blood sugar prior to availability of DPP4 inhibitors and GLP-1 analogs. Role of Incretin Hormones T2DM is typically viewed as a disease that develops due to dysfunction of the beta cells in the pancreas that produce insulin as well as cellular resistance to insulin in the body. However, the ability of the body to maintain a physiologic range of glucose in the blood between 70 to 140 mg/dl is dependent on several factors, not just the production of insulin and the ability to of the body to use the hormone. 2, 3 The gastrointestinal system is also involved in regulating blood glucose levels and abnormalities in the digestive system can also trigger the development of diabetes. Incretin hormones are a group of gastrointestinal hormones that are responsible for augmenting insulin secretion in response to enteral stimulus, with the most important being glucosedependent insulintropic polypeptide (GIP) and glucagon-like peptide (GLP-1). The system was discovered when studies revealed that ORAL administration of glucose caused a two to three fold larger insulin response compared to the intravenous route and play a very important role in maintaining post-prandial glucose (PPG) levels. 4 These 2 incretin hormones may be responsible for up to 70% of postprandial insulin secretion. Other important effects of these hormones and other gut hormones are described in the table below. [Back to Quiz] Endogenous GLP-1 hormone has a half-life of one to two minutes after it is secreted from L cells in the upper ileum and GIP is secreted from K cells in the duodenum and jejunum. Both endogenous hormones are degraded by the enzyme Dipeptidyl Peptidase IV (DPP-IV), which is located on most cells of the body. The effect of these hormones are dependent on the amount of glucose consumed; a small effect on insulin secretion is seen if 25 grams of glucose is ingested; a doubling of insulin secretion is observed with 50 mg of glucose and upwards of a four to five-fold increase with 100 grams of glucose. 5 The effect of GLP-1 predominates at higher glucose levels. Studies have shown that GIP has lost much of its insulinotropic abilities in T2DM, whereas GLP-1 abilities remain intact. Thus, the loss of incretin effects comes from both the function of remaining endogenous hormones AND the amount of hormone present. GLP-1 can restore both first phase and second phase insulin response to glucose, and its levels are decreased in many T2DM and may 4 P a g e
be abnormal in T1DM patients. The discovery of the incretin effect, GLP-1 abilities preserved in T2DM despite reduced levels (vs. GIP), combined with the fact that GLP-1 levels in diabetic patients are generally lower led to the development of medications that target this system. Also, note that the loss of the incretin effect is currently viewed as a consequence of diabetes, rather than a primary cause. Amylin is a peptide that is stored in the beta cells and is co-secreted with insulin and as a complementary action to insulin in regulating nutrient levels in the body. Amylin is deficient in patients with T1DM and can be reduced in T2DM that also require insulin therapy. 6 Endocrine Hormone Insulin Glucagon Glucagon-like Peptide- 1 (GLP-1) Amylin Dipeptidyl Peptidase IV (DPP-IV) Site of Production Pancreatic Beta cells Pancreatic alpha-cells L-cells in the ileum Pancreatic Beta-cells Expressed on most cell surfaces Action of Hormone Binds to receptors throughout the body Inhibits glucagon secretion Promotes glycogenesis Stimulates fat synthesis Promotes storage of triglycerides in fat cells Promotes protein synthesis in liver and muscle cells Promotes glycogenolysis Stimulated by amino acid to convert amino acids into glucose Hormone is inhibited by hyperglycemia, insulin, and somatostatin Enhances insulin secretion Suppresses post-prandial glucagon secretion in a glucose-dependent fashion Potent regulator of gastric emptying rate Reduces food intake Reduces post-prandial glucagon secretion Reduces food intake/enhances satiety Reduces oxidative stress by controlling post-prandial hyperglycemia Degrades endogenous GLP-1 (resulting plasma half-life of GLP-1 of 1-2 minutes) MECHANISM OF ACTION GLP-1 Analogs: Byetta (exenatide) was the first medication approved in a new class of antihyperglycemic agents called incretin mimetics. Exenatide is a GLP-1 agonist that was isolated from the salivary gland venom of a lizard. It results in an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. 7 Exenatide is considered to be as potent as endogenous GLP-1 in stimulating the glucosedependent secretion of insulin that can restore first-phase (release of insulin within 10 minutes of glucose load) and second-phase insulin secretion, suppressing post-prandial glucagon secretion, slowing gastric emptying which can reduce food intake, and promoting beta-cell proliferation. 8 Exenatide does NOT cause hypoglycemia and has been associated with clinically significant weight loss in patients. 7 DPP-IV Inhibitors: Januvia (sitagliptin) is a dipeptidyl peptidase-iv (DPP-IV) inhibitor, which exerts its actions by increasing the half life and the prolonging the effects of the incretin hormones. Incretin hormones are released by the intestine throughout the day, and levels are increased in response to a meal. Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner; GLP-1 does NOT increase insulin secretion when the glucose concentration is < 90 mg/dl. 9 Sitagliptin has also been reported to preserve beta-cell function in rodent models of T2DM. 10 Onglyza (saxagliptin) is the newest approved DPP-IV inhibitor. Saxagliptin increases insulin release and decreases glucagon concentrations in the circulation in a glucose-dependent manner. Similar to sitaglipitin, GLP-1 does NOT increase insulin secretion when the glucose concentration is < 90 mg/dl. Saxaglipitin can reduce both fasting and postprandial serum glucose concentrations in a glucose-dependent manner. 11 5 P a g e
Amylin Analogs: Symlin (pramlintide) is the only medication in this class and is approved only as an adjunct therapy with insulin and can be used in T1DM AND T2DM patients. Amylin can decrease post-prandial plasma glucose levels, suppress glucagon secretion, and slow gastric emptying, and decreasing satiety. 12 Alone, pramlintide does NOT cause hypoglycemia, but when it is combined with insulin therapy, the risk of insulin-induced hypoglycemia is INCREASED, with T1DM patients affected more commonly than those with T2DM. What MONITORING parameters are required? As with all diabetic patient monitoring, it is recommended to monitor blood glucose levels as directed by the physician and patients should have their A1c values obtained every 3 to 6 months if they are uncontrolled. (Goal A1c values for T2DM patients are <7% according to the American Diabetes Association, and <6.5% according to the International Diabetes Federation and the American College of Endocrinologists.) Byetta requires additional testing of serum creatinine levels and patients should have a urinalysis preformed periodically. 6 Onglyza also requires serum creatinine/bun levels drawn at the start of therapy and then periodically. 10 In addition to serum creatinine/bun levels drawn, patients on Januvia should be monitored for changes in calcium levels and other electrolyte values and as well as serum amylase levels. 9 No additional routine testing is required with for Symlin. GUIDELINES The initial treatment of patients with T2DM consists of education with emphasis on lifestyle modifications including diet, physical activity levels, and weight reduction. Although these lifestyle changes can lead to remission of the disease, most patients will require therapy with medication in order to maintain normal or near-normal glycemia usually initiated when A1c levels are greater than 8.5%. 11 First line medication that is recommended for typical obese T2DM patients is metformin, mianly based on the United Kingdom Prospective Diabetes Study (UKPDS) since metformin is NOT associated with weight gain, it does NOT provoke a hypoglycemic attack, and is NOT associated with cardiovascular complications. Figure 1 is a consensus algorithm developed from the American Diabetes Association and the European Association for the Study of Diabetes and Figure 2 is a treatment algorithm developed by the International Diabetes Center. 13 The algorithms provide general guidance as to therapeutic options available for patients, but with the increased number of classes of medications, individualized therapy for patients based on side effects, compliance, and response to therapy could provide better control and outcomes for patients with diabetes. Figure 1: Consensus algorithm from the American Diabetes Association and the European Association for the Study of Diabetes (early 2009) 6 P a g e
Figure 2: Treatment of Type 2 DM algorithm developed by the American Association of Clinical Endocrinologists (AACE), newly updated for October 2009. 7 P a g e
Where do they fit in the guidelines, and what patients benefit from therapy? With the advent of new classes of diabetic medications, individualizing therapy to each patient could result in increased patient compliance and better outcomes. It is important to note that four out of six drug classes on the market in 2007 have the potential to cause weight gain (sulfonylurea, meglintinides, thiazolidinediones, and insulin), with alpha-glucosidase inhibitors and biguanides being weight neutral and promoting weight loss, respectively. Since a majority of patients that are diagnosed with T2DM are obese, this side effect can negatively affect a patient s willingness to take the medication. In addition, several of the drug classes can cause hypoglycemia (sulfonlyureas, meglitinides, and insulin) that could lead to hospitalizations and other serious situations especially if patients do not understand what to do if they have low blood sugar. 14 The major reasons to consider using incretin based therapy in patients are low risk of hypoglycemia, no weight gain, low risk of threatening adverse reactions, potential cardiovascular benefits, and possibility of promoting beta-cell health. Exenatide Clinical use of exenatide has been directed towards patients who have failed to achieve glycemic control with metformin, sulfonylureas, and/or thiazolidinediones alone or in combinations. In addition, patients will benefit with add on therapy with exenatide who require weight reduction, especially for patients who gain weight on other diabetic agents, and avoidance of hypoglycemia is a primary consideration. Clinical trials with twice daily exenatide used as an add on therapy to one or greater oral agent demonstrated A1c reductions of 0.6% to 0.9%. 15 Reports also show that GLP-1 receptors are located on cardiomyocytes and vascular endothelial cells. Combining this with the ability of exenatide to reduce body weight may contribute its ability to decrease cardiovascular risk factors including a reduction in systolic blood pressure. In patients with acute myocardial infarction treated by angioplasty, both T2DM and non-diabetes, an infusion of GLP-1 led to less wall motion abnormality and better overall left-ventricular function. 16 Clinical studies showed exenatide therapy decrease systolic blood pressure by as much as 2.6 mmhg and another analysis of pooled data indicated systolic blood pressure reduction of 1.7 mmhg 17 A 52 week study with once weekly exenatide demonstrated systolic blood pressure reductions of 6 mmhg and improved lipid levels 18 Sitaglipitin and Saxaglipitin Similarly, sitaglipitin and saxaglipitin are usually considered add-on therapy to other treatments, and have been shown to decrease mean A1c levels approximately 0.5% to 0.8%. 19 These medications are generally used in patients who are failing to achieve adequate glucose control and who wish to limit weight gain associated with other diabetic medications. They are most often used in combination with metformin, thiazolidinediones, or sulfonylureas. In a 52-week randomized trial in 1172 patients not well controlled with metformin, the addition of sitagliptin versus glipizide resulted in a similar decrease in A1c of 0.7%. Sitagliptin therapy was also associated with weight loss (mean baseline to end of trial was: -1.5 kg) compared to weight gain (mean baseline to end of trial: +1.1 kg) with glipizide (95% CI: -3.1, -2.0; p < 0.001). 20 Pramlintide Pramlintide is only approved in the US as adjunct therapy to insulin and has been shown to decrease A1c levels by 0.5 to 0.7%. Pramlintide therapy has also been shown to have beneficial effects on body weight: In a 52-week, double-blind, placebo-controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes were enrolled to receive pramlintide or placebo injections in addition to existing insulin therapy with or without a sulfonylurea or metformin. The addition resulted in mean decrease in A1c of 0.62% in patients receiving 120 mcg of pramlintide administered twice daily. 21 Pooled post hoc analyses have shown that reductions in insulin requirements and body weight were greatest in more obese patients. 22 Pramlintide has been associated with reductions in postprandial glucose excursions and in surrogate markers of cardiovascular risk and oxidative stress however, the clinical implications of these findings are unkown. 23 8 P a g e
Table 1: Summary of Key Benefits and Risks of Medications produced by the AACE (Oct 2009) 9 P a g e
Can you combine Byetta and Januvia/Onglyza? [Back to Quiz] Simply put, NO, it would NOT be expected to provide additional efficacy. No data is available on the use of combining a DPP-IV inhibitor with a GLP-1 agonist. Since the mechanisms of these medications ultimately result in increased levels of incretin hormones, clinically the use of both agents in most patients is likely inappropriate. 24 There is also limited data that supports combining Symlin (pramlintide) with Byetta (exenatide) or other GLP-1 based therapies. Although there is a lack of evidence to support combining Byetta (exenatide) with a DPP-4 inhibitor, mechanistically it could be possible to use both since Byetta (exenatide) is NOT degraded by the DPP-4 enzyme, using an inhibitor of the DPP-4 enzyme would NOT affect the half-life of Byetta (exenatide). Note that updated AACE/ACE guidelines concur and do NOT recommend the use of BOTH exenatide and DPP-4 inhibitor. Concerns with prescribing these medications 1. Lack of long-term data for effects/efficacy Since these medications have not been on the market long, it is not known if these medications will decrease the macovascualar or microvascular complications associated with DM. Because these medications have been shown to decrease surrogate markers such as blood glucose levels and A1c, evidence would suggest that these classes of medications would have beneficial effects to reduce severe complications of diabetes. 2. Lack of data for long-term safety The long-term safety of using any of these medications is unknown and prescribing a first-in-class medication can cause concern for the provider and the patient. DPP-4 is responsible for the metabolism of many peptides including peptide YY, neuropeptide Y, growth hormone-releasing hormone, and is involved in activation T-cells, so long term neurological and immunological side effects of inhibiting this enzyme are unknown at this time. 25 3. Treatment Costs Currently, these medications are either a Tier 2 or 3 since there are NO generics available at this time. How do these drugs differ in their tolerability and safety? The common side effects and serious adverse reaction are listed in the table below. The long term side effects and safety of these medications are not known at this time since they are some of the newest medications approved for diabetes treatment. The most common side effects of exenatide are GI related (nausea/vomiting) - tends to DECREASE over time. It is important to note that the medication is prescribed starting at 5 mcg SC BID within 60 minutes before a morning and evening meal OR before two main meals of the day approximately 6 hours or more apart and tapered up to 10 mcg SC BID after one month. This dose regimen is used to decrease the associated adverse GI effects from this medication. Since the DPP-IV enzyme is located on many tissues throughout the body, there are a large number of potential substrates and many processes can be affected. Inhibition of the DPP-IV enzyme interferes with the normal function of the immune system leading to upper respiratory tract infections and lymphopenia. Betta (exenatide) Januvia (sitaglipitin) Onglyza (saxaglipitin) Symlin (pramlintide) Common Adverse Events Injection site reactions Weight loss Dizziness Dyspepsia/GERD/Nausea URI Headache Diarrhea/Vomiting/Abdominal pain Arthralgia URI Headache Diarrhea/Vomiting/Abdominal pain Arthralgia Anorexia/nausea/vomiting abdominal pain headache/fatigue injection site reactions/lipotrophy pharyngitis Serious Adverse Events hypoglycemia with sulfonylurea therapy pancreatitis (acute hemorrhagic and necrotizing) Stevens-Johnson Syndrome hypersensitivity reactions angioedema pancreatitis (acute hemorrhagic and necrotizing) lymphopenia peripheral edema angioedema hypoglycemia 10 P a g e
Drugs associated with Pancreatitis At this time, Byetta and Junuvia are the only two medications that have pancreatitis listed as a serious adverse reaction in their package insert. Acute pancreatitis has occurred post-marketing in 88 patients treated with Januvia, including 2 cases of hemorrhagic or necrotizing. Januvia has not been studied in patients with a history of pancreatitis, so it is not known whether these patients are at an increased risk for developing pancreatitis and so far no deaths have been reported. At this time the FDA recommends that healthcare providers should monitor patients carefully for the development of pancreatitis and discontinue therapy if patients are suspected of developing this adverse reaction while on Januvia (sitagliptin) or Janumet (sitaglipitin/metformin). 26 There have been 36 postmarketing reports of acute pancreatitis in patients taking Byetta including a few cases of necrotizing or hemorrhagic pancreatitis; fatalities have occurred. 27 The overall reporting rate for pancreatitis in exenatide users is 1 in 3000 and for necrotizing or hemorrhagic pancreatitis, and less than 1 in 10,000 for other forms of pancreatitis (which is similar to the risk of developing pancreatitis for any diabetic patient). Patients with persistent severe abdominal pain (with or without nausea), should be examined for pancreatitis and Byetta should be discontinued. If pancreatitis is confirmed, Byetta should NOT be restarted. Byetta vs Januvia: which is a better option? Byetta and Januvia both augment incretin hormone actions, but these medications had NOT been compared in a head-to-head clinical trial until the DeFronzo group preformed the following randomized clinical trial OBJECTIVE: To evaluate the effects of exenatide and sitaglipitin on the effects of 2 hour postparandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in type 2 diabetic patients. STUDY DESIGN: Double blind, randomized cross-over, multi-center study was conducted in metformin-treated T2DM patients. Patients received exenatide (5 mcg BID for one week, than 10 mcg BID for 1 week) or sitaglipitin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed over to the alternative therapy. RESULTS: After 2 weeks of therapy 2h PPG was lower with exenatide vs sitagliptin: 133 6mg/dl vs 208 6 mg/dl, p<0.0001). Switching from exenatide to sitagliptin increased 2 hour PPG by +73 11mg/dl, while switching from sitagliptin to exenatide reduced 2 hour PPG by -76 10mg/dl. Exenatide also slowed gastric emptying and reduced total caloric intake compared to sitagliptin. Common adverse reactions with both treatments were mild to moderate in intensity and gastrointestinal in nature. (Of note this study was funded by Amylin Pharmaceuticals.) Interpretation of Study: Administering Byetta is comparable to using insulin therapy in patients with T2DM since both insulin and GLP-1 hormones are low in patients with T2DM. Using a DPP-4 inhibitor can increase GLP-1 hormones but it does it in a way that can have additional side effects since the DPP-4 enzyme inhibits other hormones besides GLP-1. Aside for the fact that Byetta must be injected, it most likely will be a better option for most patients who are not controlled with their current diabetic regimen, and Byetta is associated with weight loss whereas DPP-4 inhibitors are weight neutral. Reivew of Trials Byetta (Exenatide) Study 1 29 (exenatide) OBJECTIVE: To determine if exenatide can improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS: A triple-blind, placebo-controlled, 30-week study at 82 US sites. 336 patients were randomized to be enrolled in the trial, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m 2 and A1c of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 mcg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 mcg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. 11 P a g e
RESULTS: At week 30, A1c changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 mcg), -0.40 +/- 0.11% (5 mcg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P<0.002). Of evaluable subjects, 46% (10 mcg), 32% (5 mcg), and 13% (placebo) achieved A1c goal Study 2 30 (exenatide) OBJECTIVE: Study was looking to determine the ability of exentide to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. RESEARCH DESIGN AND METHODS: This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m 2, A1c 8.6 +/- 1.2% [SD]) and began 4 weeks at 5 mcg SQ exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. After this period, patients in arm B were escalated to 10 mcg SQ exenatide twice daily. All subjects continued sulfonylurea therapy. RESULTS: At week 30, A1c changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% [+/-SE] in the 10-mcg, 5- mcg, and placebo arms, respectively (adjusted P<0.001). Of evaluable subjects with baseline A1c>7% (n = 237), 41% (10 mcg), 33% (5 mcg), and 9% (placebo) achieved Hb1c target levels. Fasting plasma glucose concentrations were significantly decreased in the 10- mcg arm compared with placebo (P<0.05). Dose-dependent weight loss at the end of the trial resulted in -1.6 +/- 0.3 kg from baseline in the 10-mcg exenatide arm (P<0.05 vs. placebo). No hypoglycemia was observed and the most serious adverse events were gastrointestinal related (nausea/vomiting) CONCLUSIONS: Exenatide reduced A1c in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss. Study 3 31 (exenatide) OBJECTIVE: To compare the effects of exenatide versus placebo on glycemic control and determine the change from baseline in hemoglobin A1c level. DESIGN: Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005 conducted in 49 sites in Canada, Spain, and the United States. 233 patients with T2DM that were suboptimally controlled with TZD treatment (with or without metformin) were enrolled; 121 received 10 mcg exenatide twice daily, 112 received placebo twice daily. Mean baseline A1c level was 7.9% +/- 0.1%. Patients remained on TZD therapy and study was conducted over a 16 week period. RESULTS: Exenatide treatment reduced A1c level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -30.5 mg/dl, [CI, -40.0 to -21.1 mg/dl], and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). 16% of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. The most common adverse events reported were: nausea: 40% exentide group, 15% placebo; vomiting: 13% exenatide group, 1% placebo; vomiting, hypoglycemia: 11% exenatide group, 7% placebo. CONCLUSIONS: Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy LIMITATIONS: Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study. Study 4 32 (exenatide) OBJECTIVE: To assess the efficacy and safety of Byetta in adults with T2DM based on randomized controlled trials published in peer-reviewed journals or as abstracts. DATA SOURCES: MEDLINE (1966-2007) and the Cochrane Central Register of Controlled Trials (second quarter, 2007) for English-language randomized controlled trials involving an GLP-1 analog or DPP4-inhibitor. STUDY SELECTION: Randomized controlled trials were selected if they were at least 12 weeks in duration, compared incretin therapy with placebo or other diabetes medication, and reported hemoglobin A1c data in nonpregnant adults with T2DM. RESULTS: 29 articles were included and results showed incretins lowered hemoglobin A1c compared with placebo (weighted mean difference, -0.97% [95% confidence interval -1.13% to -0.81%] for GLP-1 analogues and -0.74% [95% CI, -0.85% to -0.62%] for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. GLP-1 analogues resulted in weight loss while DPP4 inhibitors were weight neutral. GLP-1 analogues had more gastrointestinal side effects (risk ratio for Nausea, 2.9 [95% CI, 2.0-4.2]; and 3.2 for vomiting [95% CI, 2.5-4.4]). DPP-4 4 inhibitors had an increased risk of infection (risk ratio, 1.2 for nasopharyngitis [95% CI, 1.0-1.4], and 1.5 for urinary tract infection [95% CI, 1.0-2.2]). CONCLUSIONS: Incretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with T2DM, with modest efficacy and a favorable weight-change profile. LIMITATIONS: All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated 12 P a g e
Table 2. Outcomes from several clinical trials of exenatide. 33 DPP-4 Inhibitors: Januvia Study 1 34 OBJECTIVE: To determine the efficacy of sitagliptin as a once daily monotherapy for T2DM patients STUDY DESIGN: A multinational, 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. 555 patients were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100 mg once-daily, or sitagliptin 50 mg twicedaily. RESULTS: Mean baseline A1c ranged from 7.6 to 7.8% across treatment groups. After 12 weeks, treatment with all doses of sitagliptin significantly reduced A1c by -0.39 to -0.56% (p < 0.05) and fasting plasma glucose by -11.0 to -17.2 mg/dl relative to placebo, with the greatest reduction observed in the 100-mg once-daily group. The incidence of adverse events of hypoglycemia was low, with one event in each of the 25 and 50 mg once-daily and 50-mg twice-daily treatment groups; two events occurred in the 100 mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. CONCLUSION: Sitagliptin monotherapy improved A1c values (-0.39 to -0.59% decrease in A1c) and fasting plasma glucose compared to placebo and was generally well-tolerated LIMITATIONS: Study duration was only 12 weeks; safety and tolerability could change during a longer duration of therapy. In addition, the full effect of sitagliptin could change with a longer duration of use. Januvia Study 2 9 OBJECTIVE: Determine how the addition of sitagliptin, added to ongoing metformin therapy would impact A1c values in T2DM patients who had inadequate glycemic control on metformin alone. RESEARCH DESIGN: Double blind, randomized control trial enrolled 701 patients (mean A1C 8.0%) who were receiving metformin ( 1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. RESULTS: At week 24, sitalipitin had reduced A1c (-0.65%), fasting plasma glucose, and 2-h postmeal glucose; and a greater proportion of patients achieved an A1C <7% with sitagliptin (47.0%) than with placebo (18.3%). The only reported adverse reactions were hypoglycemia and gastrointestinal reactions that were similar in the sitagliptin group and placebo group. 13 P a g e
CONCLUSIONS: The addition of sitagliptin 100 mg once-daily to metformin therapy was well tolerated and reduced A1c values in patients with T2DM who had inadequate glycemic control with metformin alone. Table 3. Review of clinical trials involving Januvia (sitaglipitin). 32 Onglyza Study 1 27 OBJECTIVE: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with T2DM and inadequate glycemic control. Primary endpoint to this study was change in A1c from baseline; secondary endpoints included fasting plasma glucose (FPG) among others. STUDY DESIGN: Study included a main treatment cohort (MTC) with 401 patients (A1c 7% and 10%) randomized and treated with oral saxagliptin 2.5, 5, or 10 mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (A1c > 10% and 12%) who received saxagliptin 10 mg once daily for 24 weeks. RESULTS: In the MTC, saxagliptin resulted in a decrease adjusted mean A1c from baseline (mean, 7.9%) to week 24 ( 0.43%, 0.46%, 0.54%) for saxagliptin 2.5, 5, and 10 mg, respectively, vs. +0.19% for placebo (all p < 0.0001). Adjusted mean FPG was reduced from baseline ( 15, 9, 17 mg/dl) for saxagliptin 2.5, 5, and 10 mg, respectively, vs. +6 mg/dl for placebo. The amount of saxagliptin-treated patients achieving A1c < 7% at week 24 were (35%, 38% [p = 0.0443], 41% [p = 0.0133]) for saxagliptin 2.5, 5, and 10 mg, respectively. 24% of patients in the placebo achieved A1c values <7%. A1c and FPG reductions were also observed in the OLC at 24 weeks. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose 50 mg/dl) were observed in either cohort and saxagliptin was not associated with weight gain. CONCLUSIONS: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and decreased A1c and FPG vs. placebo. 14 P a g e
LIMITATIONS: Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment. Onglyza Study 2 35 OBJECTIVE: To evaluate the efficacy and safety of initial combination therapy with saxagliptin with metformin vs. saxagliptin or metformin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycaemic control. The main outcome measure was change in A1c from baseline to week 24 secondary outcomes included change from baseline to week 24 in fasting plasma glucose (FPG), and proportion of patients achieving HbA1c <7%. STUDY DESIGN: Multicentre, randomized, double-blind, active-controlled phase 3 trial, 1306 treatment-naïve patients with A1c >8 to or<12%, BMI, <40 kg/m 2 were randomized to receive saxagliptin 5 mg with metformin 500 mg, saxagliptin 10 mg plus metformin 500 mg, saxagliptin 10 mg plus placebo, or metformin 500 mg plus placebo for 24 weeks. RESULTS: At 24 weeks, saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin demonstrated significant adjusted mean decreases vs. saxagliptin 10 mg and metformin monotherapies in HbA1c (-2.5 and -2.5% vs. -1.7 and -2.0%, all p < 0.0001 vs. monotherapy) and FPG (-60 and -62 mg/dl vs. -31 and -47 mg/dl, both p < 0.0001 vs. saxagliptin 10 mg; p = 0.0002 saxagliptin 5 mg + metformin vs. metformin; p < 0.0001 saxagliptin 10 mg + metformin vs. metformin). Proportion of patients achieving an HbA1c <7% was 60.3 and 59.7% for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin (all p < 0.0001 vs. monotherapy). Adverse event occurrence was similar across all groups including hypoglycemic events. CONCLUSION: Saxagliptin + metformin as initial therapy led to statistically significant improvements compared with either treatment alone across key glycemic parameters with a tolerability profile similar to the monotherapy components. LIMITATIONS: Study duration was only 24 weeks; safety and tolerability could change during a longer duration of therapy. In addition, the full effect of saxaglipitin could change with a longer duration of use. Pramlintide Studies: Symlin Study 1 36 OBJECTIVE: To assess the efficacy and safety of pramlintide in patients with type 2 diabetes patients who are uncontrolled with basal insulin therapy. The primary endpoints were the change in A1c at week 16, and a composite measure of overall diabetes control comprising A1c 7.0% or reduction 0.5%, mean daily postprandial glucose (PPG) increments 40 mg/dl, no increase in body weight, and no severe hypoglycemia. STUDY DESIGN: A 16-week, double-blind, placebo-controlled study, 212 patients using insulin glargine with or without oral antidiabetes agents (OAs) were randomized to receive the addition of pramlintide (60 or 120 μg bid/tid) or placebo. Insulin glargine was adjusted to target a fasting plasma glucose concentration of 70-100 mg/dl. RESULTS: Patients receiving pramlintide achieved the composite end points than those receiving placebo (25% vs. 7%; P < 0.001). Reductions (means ± SE) in A1c ( 0.70 ± 0.11% vs. 0.36 ± 0.08%; P < 0.05) and PPG increments ( 24.4 ± 3.6 mg/dl vs. 0.4 ± 3.0 mg/dl; P < 0.0001) were greater in pramlintide versus placebo treated patients, respectively. Glycemic improvements were accompanied by weight loss with pramlintide and weight gain with placebo ( 1.6 ± 0.3 kg vs. +0.7 ± 0.3 kg; P < 0.0001). No treatment-related severe hypoglycemia occurred. CONCLUSIONS: Pramlintide improved multiple glycemic parameters and reduced weight with no increase in hypoglycemia in patients with type 2 diabetes who were not achieving glycemic targets with basal insulin with or without OAs. Symlin Study 2 37 OBJECTIVE: To determine the weight lowering effect of pramlintide in patients with T2DM RESEARCH DESIGN: Pooled post hoc analysis of two long-term trials included patients who were overweight/obese at baseline (BMI > 25 kg/m2), and who were treated with either 120 mcg pramlintide BID (n = 254; HbA1c 9.2%; weight, 96.1 kg) or placebo (n = 244; HbA1c 9.4%; weight, 95.0 kg). Statistical endpoints included changes from baseline to week 26 in HbA1c, body weight, and insulin use. RESULTS: Pramlintide treatment resulted in significant reductions from baseline to week 26, compared with placebo, in HbA1c and body weight (both, p < 0.0001), for placebo-corrected reductions of -0.41% and -1.8 kg, respectively. Approximately three times the number of patients using pramlintide experienced a > 5% reduction of body weight than with placebo (9% vs. 3%, p = 0.0005). Patients using pramlintide also experienced a decrease in total daily insulin use (r = 0.39, p < 0.0001). The greatest placebo-corrected reductions in weight at week 26 were observed in pramlintide-treated patients with a BMI >40 kg/m2 and in those concomitantly treated with metformin (both, p < 0.001), for placebo-corrected reductions of -3.2 kg and -2.5 kg, respectively. 15 P a g e
CONCLUSION: These findings support further evaluation of the weight-lowering potential of pramlintide in obese patients with type 2 diabetes. LIMITATIONS: this was a retrospective trial so control of entry criteria was limited to trials that have already been completed. Wrong answer try again or read on. [Back to quick-read info and quiz question] Some Key references: IHA Provider formulary. www.independenthealth.com. user: partners, pass: partners Individual product information sheets for each drug were also utilized. Links to each provided in first chart. 1. ADA. Standards of Medical Care in Diabetes-2009. Diabetes Care 2009. 2. Knop F, Aaboe K, Vilsboll T, Madsbad S, Holst J, Krarup T. Reduced incretin effect in obese subject with normal glucose tolerance as compared to lean control subjects. Diabetes 2008;57. 3. Perley M, Kipnis D. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 1967;46:1954-62. 4. McIntyre N, Holdsworth C, Turner D. New interpretation of oral glucose tolerance. Lancet II 1964;20. 5. Nauck M, Homberger E, Siegel A, Eaton R, Ebert R. Incretin effects of increasing glucose loads inmancalculated fromvenous insulin and C-peptide responses. J Clin Endocrinol Metab 1986;63:492-8. 6. Buse J, Weyer C, Maggs D. Amylin replacement with Pramlintide in type 1 and type 2 diabetes: a physiological approach to overcome barriers with insulin therapy. Clinical Diabetes 2002;20:137. 7. Byetta (exenatide) injection prescribing information. 2008. 8. Stonehouse A, Okerson T, Kendell D. Emerging incretin-based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Curr Diabetes Rev 2008;4:101-9. 9. Raz I, Hanefeld M, Xu L. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus.. Diabetologia 2006;49:2564 71. 10. Mu J, Woods J, Zhou Y. Chronic inhibition of dipeptidyl peptidase-4 with sitaglipitin analog preseves pancreatic B-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006;55:1695-704. 11. Onglyza (saxagliptin)tablets prescribing information. 2009. 12. Symlin (pramlintide) prescribing information. 2006. 13. Nathan D, Buse J, Davidson M, et al. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009 32:193-203. 14. Nauck M, Smith U. Incretin-based therapy: how do incretin mimetics adn DPP-4 inhibitors fit into treatment algorithms for type 2 diabetec patients?. Best Practive & Research Clinical Endocrinology & Metabolism 2009;23:523-. 15. Buse J, Henry R, Han J. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes. Diabetes Care 2004;27:2628 35. 16. Nikolaidis L, Mankad S, Sokos G. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004;109:962 5. 17. Okerson T, Yan P, Stonehouse A. Exenatide improved systolic blood pressure compared to insulin or placebo in patients with type 2 diabetes. Program and Abstracts of the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD). 2008. 18. Bergenstal R, Kim T, Trautmann M. Exenatide once weekly elicited improvements in blood pressure and lipid profile over 52 weeks in patients with type 2 diabetes. Program and Abstracts of the American Heart Association Scientific Sessions; November 9 New Orleans, Louisiana. 2008. 19. Aschner P, Kipnes M, Lunceford J. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29:2632-37. 20. Nauck M, Meininger G, Sheng D, Terranella L, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, doubleblind, non-inferiority trial. Diabetes Obes Metab 2007 9:194-205. 21. Hollander P, Levy P, Fineman M, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2003;26 :784-90. 22. Hollander P, Maggs D, Ruggles J. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res 2004;12:661 68. 23. Ceriello A, Lush C, Darsow T, et al. Pramlintide reduced markers of oxidative stress in the postprandial period in patients with type 2 diabetes. Diabetes Metab Res Rev 2008;24:103-8. 24. DeFronzo R, Okerson T, Viswanathan P. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin 2008;24:2943-52. 16 P a g e
25. Miller S, St. Onge E. Sitaglipitin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336-43. 26. FDA. Information for Healthcare Professionals- Acute pancreattis and sitagliptin (Marketed as Juauvia and Janumet) 2009. 27. Rosenstock J, Sankoh S, List J. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naıve patients with type 2 diabetes. Diabetes, Obesity & Metabolism 2008;10:376 86. 28. DeFonzo R, Okerson T, Viswanathan P, Guan X, Holcombe J, MacConell L. Effects of exenatide versus stiagliptin on postparandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Current Medical Research and Opinion 2008;24:2943-52. 29. Defronzo R, Ratner R, Han J, Kim D, Fineman M, Baron A. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1092-100. 30. Buse J, Henry R, Han J, Kim D, Fineman M, Baron A. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628-35. 31. Zinman B, Hoogwerf B, Duran Garcia S, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2007;146:477-85. 32. Amori R, Lau J, Pittas A. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007;11:194-206. 33. Madsbad S, Thure K, Deacon C, Holst J. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials. Current Opinion in Clinical Nutrition and Metabolic Care 2008;11:491-9. 34. Hanefeld M, Herman G, Wu M. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Current Medical Research and Opinion 2007;23:1329 39. 35. Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab 2009;11:611-22. 36. Riddle M, Frias J, Zhang B, et al. Pramlintide Improved Glycemic Control and Reduced Weight in Patients With Type 2 Diabetes Using Basal Insulin Diabetes Care 2007;30:2794-9. 37. Hollander P, Maggs D, Ruggles J, et al. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients Obes Res 2004;12:661-8. [Back to Quiz] Quiz Answers: 1) C 2) D 3) A 4) B 5) B 6) C 17 P a g e