The Role of Incretin-Based Therapies: Reconstructing Treatment Approaches in Type 2 Diabetes CME Robert R. Henry, MD Author Information and Disclosures

The effective management of type 2 diabetes mellitus (T2DM) is a constant challenge to physicians. It is an epidemic which places a huge burden on national economies and medical care systems with its acute and chronic complications. The International Diabetes Federation estimates that the global diabetic population is 246 million people and that 7.3% of the world's population, ages 20-79, have diabetes. These numbers are expected to grow significantly in the next few decades. By 2025, the number of people with diabetes is forecast to exceed 380 million.[1] Even with access to numerous hypoglycemic drugs and counseling in life-style changes, it is estimated that 2 of every 3 T2DM patients are unable to reach the hemoglobin A1c (HbA1c) target of less than 7% set by the American Diabetes Association (ADA). The availability of newer drugs such as the incretin mimetics and the dipeptidyl peptidase-IV (DPP-4) inhibitors has grown the therapeutic armamentarium for T2DM, providing the possibility of further improved glycemic control that may eventually lead to a positive impact on the seemingly inevitable complications of T2DM.

The morbidity and mortality associated with diabetic complications contribute to a large proportion of patients with chronic illnesses. T2DM is responsible for 44% of new cases of kidney failure diagnosed each year, cardiac disease and stroke cause 65% of deaths among diabetic patients, more than 60% of lower limb amputations occur in people with diabetes, and diabetes is the leading cause of blindness among adults.[2]

The main objectives in the treatment of diabetes include prevention or slowing of disease progression, including the prevention of microvascular and macrovascular complications, as well as improving mortality. It is now recognized that the onset of T2DM may occur up to 10 years prior to clinical diagnosis.[3] Indeed, it is postulated that nearly one third of all people with diabetes are not yet diagnosed because of the insidious nature of the disease.

Diagnostic criteria for T2DM as defined by the ADA include a fasting plasma glucose ≥ 126 mg/dL, confirmed on repeat testing, or a 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT), or symptoms of hypoglycemia and a casual plasma glucose ≥ 200 mg/dL. Two core defects are known to underlie the pathophysiology of T2DM. Insulin resistance is 1 such defect, occurring in 80-85% of these patients.[4] Obesity and a sedentary lifestyle contribute to the development of insulin resistance, but the inheritance of the genetic potential for insulin resistance does not require obesity to become functional. The second abnormality is impaired pancreatic beta-cell function, which is progressive over time. In type 2 diabetes, insufficient insulin supply occurs in a setting of increased insulin demands, a situation known as chronic insulin resistance. It has been demonstrated that abnormalities in insulin secretion and insulin sensitivity are present long before type 2 diabetes develops. Moreover, both insulin resistance and failing insulin secretion are progressive over the course of many years.[5]

Evidence from studies by Buchanan[6] and Ferrannini and colleagues[7] suggest that the signal provided by circulating plasma glucose levels in relation to the underlying deterioration in beta-cell function is initially low and becomes stronger only when the beta-cell function has deteriorated markedly. The essence of these and other studies clearly shows that, by the time diabetes has been diagnosed, the disease is well under way and the processes leading to the various complications have already begun. Data from the United Kingdom Prospective Diabetes Study (UKPDS) study[3] showed that patients with newly diagnosed type 2 diabetes had only 50% of their beta-cell function. As these patients were followed over a 6-year period, there was a linear reduction in this function. In addition to the decline in beta-cell function, there is also a decline in beta-cell mass caused by increased apoptosis (cell death), although new islet formation and beta-cell replication are normal. The UKPDS study also demonstrated that the addition of metformin, sulfonylureas, or a change to a more healthy diet were not sufficient to arrest the decline in beta-cell function. Treatment that would slow or stop the progression of beta-cell loss, or even reverse it, would dramatically alter the landscape of diabetes management.

Slide 1. ADA/EASD Consensus Algorithm for Type 2 Diabetes Mellitus (2006)The treatment algorithm for the management of individuals with T2DM has been established by opinion leaders on both sides of the Atlantic. The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus algorithm, published in 2006, stresses the need for the rapid additions of medications and transition to new medications when glycemic targets are not met or sustained.

Comparison of plasma glucose, insulin, and glucagon levels in non-diabetic and diabetic subjects following administration of an OGTT shows clear differences in response between the 2 groups. The non-diabetic subjects show an increase of plasma glucose of approximately 3 mM, whereas the increase measured in diabetic subjects was approximately 8 mM. This finding was accompanied by a much greater increase in plasma insulin and a decrease in plasma glucagon in the non-diabetic subjects. In the diabetic subjects, plasma insulin did not achieve the same concentration as the non-diabetic group; the rise was much slower, and the consequent return to basal levels was also extended. In contrast to non-diabetics, plasma glucagon levels in the diabetic subjects showed a small transitory increase in response to the OGTT before returning

to basal levels. Using radiolabeled glucose, Mitrakou and colleagues[8] ascertained that the increased systemic glucose delivery in diabetic subjects was primarily due to a reduced suppression of hepatic glucose output and, to a lesser extent, a reduced splanchnic uptake of glucose. Similar changes in plasma glucose, plasma insulin, and plasma glucagon are seen following a carbohydrate meal rather than the standard OGTT when comparing non-diabetic and diabetic subjects.[9]

Glucose homeostasis, in its simplest terms, is the rate at which glucose enters and leaves the circulation. In normal individuals, the plasma concentration of glucose is maintained within a narrow range previously thought to be controlled primarily by insulin and glucagon. However, this concept has now been expanded to include other glucoregulatory hormones including amylin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). It has been known for many years that administration of an oral glucose challenge elicits a stronger insulin response than an equivalent intravenous glucose challenge.[10] This effect has been termed the incretin effect and led to the hypothesis that gut-derived factors are important modulators of insulin secretion and glucose homeostasis. It is now established that 2 gut-derived hormones, GLP-1 and GIP, are responsible for most of the incretin effect. Creutzfeldt introduced the term incretin, which is derived from Intestinal Secretion of Insulin.

Slide 2. Incretin EffectA seminal report by Nauck and colleagues showed that 70% of post-glucose insulin secretion is due to the incretin effect and that the incretin effect is diminished in T2DM.[11] A later study published by Toft-Neilsen and colleagues[12] demonstrated that postprandial GLP-1 levels are decreased in T2DM subjects following an OGTT.

GLP-1 is synthesized and secreted by L cells of the ileum and colon and stimulates glucose-dependent insulin release with a concomitant suppression of hepatic glucose output by inhibiting glucagon secretion. Furthermore, it improves beta-cell responsiveness to glucose by increasing the expression of glucose-transporter-2 and glucokinase together with a decrease in the proinsulin to insulin ratio. It also inhibits gastric emptying and has a central nervous system effect resulting in reduced food intake and a decrease in body weight. In animal models and human islets, it has been shown to enhance beta-cell proliferation and survival. The latter effect is due to a

combination of induction of beta-cell proliferation, neogenesis, and an anti-apoptotic effect.

Slide 3. GLP-1 Modulates Numerous Functions in HumansGIP is produced by K cells in the proximal gut and also stimulates glucose-dependent insulin release. In contrast to GLP-1, it has a little or no effect on gastric emptying and no significant effect on satiety or body weight. It may potentially enhance beta-cell proliferation and survival in islet cell lines.

In patients with T2DM, the incretin effect is either greatly impaired or absent and it is assumed that this finding could be a contributing factor to the inability of these patients to adjust their insulin secretion to their needs. In studies examining the mechanism of this impaired effect, the data show that GIP secretion is unimpaired and levels of intact GIP are actually increased in response to a glucose challenge. In contrast, the secretion of GLP-1 is attenuated. The abnormal incretin effect in T2DM can be described as one of diminished GLP-1 secretion and diminished GIP responsivity. Thus, T2DM patients have a GLP-1 secretory defect, and with a known physiologic defect in the GLP-1 pathway comes the opportunity to leverage its therapeutic potential by correcting it. As T2DM is a progressive disease, there is considerable interest in whether or not incretin-based therapies might be able to prevent the onset of the disease or even reverse its progress by an impact on the transition from normal glucose tolerance, through a state of impaired glucose tolerance to fully developed T2DM.

GLP-1 has been administered to diabetic patients before meals by means of subcutaneous injection causing a significant decrease in postprandial glucose levels.[13] However, the insulin response to the meal was not greatly enhanced and the effect on postprandial glucose concentration was primarily due to a reduction in gastric emptying following the injection of GLP-1. An important finding from a study by Rachman and colleagues[14] where GLP-1 was given by a continuous infusion to T2DM subjects was not only the normalization of postprandial glucose but the normalization of blood glucose during the hours when the patients were asleep. Thus, incretin action is not simply required for the control of postprandial glucose but for 24-hour blood glucose control as well. Zander and co-workers[15] then administered GLP-1 for 6 weeks by

subcutaneous infusion to 10 patients with T2DM. After 1 week's treatment, they observed a marked increase in insulin secretion in response to a 30 mmol/L hyperglycemic clamp, an effect that persisted throughout the 6-week period. In tandem with this increase in insulin secretion, there was a marked reduction in basal plasma glucose levels and a substantial reduction in HbA1c levels. An additional benefit was a mean weight loss of more than 2 kg. This study demonstrated that chronic GLP-1 administration over 6 weeks results in sustained effects on insulin secretion, and A1C. Additionally, it served as proof of concept for the potential therapeutic application of GLP-1 within the diabetic population.

A major disadvantage of using GLP-1 to treat T2DM patients is its short half-life (1-2 min) due to rapid catabolism by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-4), thus requiring it be given by continuous intravenous infusion. Clearly, this method of administration is not practical or economical. Therefore, researchers have synthesized GLP-1-based compounds, some currently available and others at various stages of clinical development, which have a more prolonged duration of activity and a more convenient method of administration. These compounds include the GLP-1 receptor agonists with extended biological half-lives such as exenatide and exenatide LAR, GLP-1 analogues such as liraglutide, and DPP-4 inhibitors (incretin enhancers) such as sitagliptin and vildagliptin.

DPP-4 is a glycoprotein consisting of 766 amino acids and is a catalytic enzyme. It is highly concentrated in the capillaries close to the intestinal cells where GLP-1 and GIP are produced, and it is widely distributed throughout the body. The rationale for DPP-4 inhibition as a target for the treatment of T2DM is that the degradation of endogenously released GLP-1 could be attenuated. This would allow prolonged circulating concentrations of the active form of endogenous GLP-1.

Sitagliptin (Januvia, Merck) is an orally administered DPP-4 inhibitor recently approved for use in T2DM. It was approved for use either as monotherapy, or as combination therapy when added to either metformin, a sulfonylurea, or a thiazolidinedione (PPAR-gamma agonist) such as rosiglitazone or pioglitazone. Additionally, The Food and Drug Administration (FDA) has recently approved a fixed-dose combination of sitagliptin and metformin, called Janumet, to be taken twice daily for patients not achieving adequate control on either therapy taken alone or for those patients already taking sitagliptin and metformin. The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥ 5% of patients and more commonly than in patients given placebo was nasopharyngitis.

Sitagliptin is rapidly and almost completely absorbed, with a bioavailability of 87%, and has a half-life of approximately 12.4 hours. In clinical trials, it has been given as monotherapy, comparing it to placebo and in combination when added to other current therapies for T2DM. In all cases, the primary measure of efficacy was the change in HbA1c.

Slide 4. Sitagliptin Studies: SummaryNonaka conducted a 12-week study comparing sitagliptin 100 mg daily to placebo in 151 Japanese patients.[16] There was a 1.05% reduction in HbA1c for patients treated with sitagliptin compared to placebo. Raz studied the effect of 2 doses of sitagliptin versus placebo treated for 18 weeks in 521 T2DM patients.[17] The doses of sitagliptin were 100 mg daily or 200 mg daily, resulting in a decrease in HbA1c, when compared to placebo, of 0.6% and 0.48%, respectively. Both decreases were statistically significant. Aschner and colleagues conducted a study comparing sitagliptin 100 mg and 200 mg daily versus placebo in 741 T2DM when treatment was administered for 24 weeks.[18] The reductions in HbA1c relative to placebo were 0.79% and 0.94% for the 100-mg dose and 200-mg dose of sitagliptin, respectively, and were statistically significant. In all 3 studies, there was a reduction in fasting plasma glucose (FPG) for those patients treated with sitagliptin, whereas all the placebo dose groups had a mean increase in FPG.

Goldstein and colleagues conducted a 24-week randomized, placebo controlled, parallel group study to evaluate the efficacy of sitagliptin when added to metformin in T2DM patients who had inadequate glycemic control with diet and exercise.[19] A total of 1091 patients were randomized to 1 of 6 treatments: sitagliptin 100 mg + metformin 1000 mg, sitagliptin 100 mg + 2000 mg metformin, 1000 mg of metformin, 2000 mg of metformin, 100 mg of sitagliptin, or placebo. At week 24, all active treatments produced significant reductions from baseline (P < .001) in HbA1C relative to placebo. All active treatments also produced significant (P < .001) reductions in FPG from baseline when compared to placebo. The magnitude of FPG reduction by coadministration treatment was additive relative to individual monotherapies. Significant improvement (P < .05) was also observed in other measurements for fasting efficacy such as proinsulin/insulin ratio and homeostasis model assessment beta-cell function (HOMA-B) and HOMA-insulin resistance in the coadministration treatment groups.

In a study reported by Nauck and colleagues,[20] sitagliptin was compared to glipizide in a randomized, parallel group study of 1172 patients with T2DM receiving monotherapy with metformin, but who were considered to have inadequate glycemic control. Subjects were treated for 52 weeks with either sitagliptin 100 mg daily or glipizide 5 mg daily (titrated up to a maximum of 20 mg/day) in addition to their metformin therapy. At

the end of the 52-week period, the mean HbA1c levels between the 2 groups were compared in a non-inferiority analysis. The reduction in HbA1c from baseline was 0.67% in both treatment groups, confirming that sitagliptin was non-inferior to glipizide. There was a significantly higher proportion of glipizide-treated patients who reported at least 1 episode of hypoglycemia (5% sitagliptin, 32% glipizide, P < .001) highlighting the difference in mechanism of action between the sulfonylureas and the DPP-4 inhibitors. There was a mean weight gain of 1.1 kg in the glipizide group compared to a mean weight loss of 1.5 kg in the sitagliptin group. Overall, with the exception of the incidence of hypoglycemia, there was no difference between the groups in drug-related adverse events.

Slide 5. Sitagliptin and Measures of Beta-Cell FunctionRosenstock and co-workers[21] conducted a study to ascertain the effect of adding sitagliptin or placebo to patients already receiving pioglitazone. The addition of sitagliptin resulted in significant reductions compared with placebo in HbA1c and FPG as well as a significant improvement in the proinsulin/insulin ratio vs. placebo. There was no increased risk of hypoglycemia in the sitagliptin-treated patients compared with placebo.

One potential and hoped for advantage of the DPP-4 inhibitors is that they may be able to modify the progression of type 2 diabetes by maintenance or improvement of beta-cell function. A failing beta-cell is unable to process proinsulin to insulin and C-peptide appropriately. Consequently, the beta-cell secretes an abnormal amount of proinsulin and the ratio of proinsulin/insulin is increased. Another measure of beta-cell function is HOMA-B, a measurement of beta-cell homeostasis. In the study by Aschner and colleagues,[18] sitagliptin improved both indices of beta-cell function when administered to T2DM patients. At a dose of 100 mg daily, sitagliptin significantly reduced the proinsulin/insulin ratio and increased the HOMA-B from baseline compared to placebo. Although sitagliptin reduced FPG, the incidence of hypoglycemia was similar between the 2 groups. These results were confirmed in the study by Raz and co-workers, referred to above,[17] who again demonstrated that sitagliptin reduced HbA1c and improved beta-cell function in patients with T2DM.

Vildagliptin (Galvus, Novartis) is a potent, competitive, and reversible inhibitor of human DPP-4 in vitro and is highly specific relative to other peptidases. It is currently under consideration but it has not yet been approved for marketing by the FDA. In healthy humans, vildagliptin is rapidly and almost completely absorbed (approximately 85% of administered dose) after oral administration with a Tmax of 1-2 hours post-dose and a plasma half-life that ranges from 1.5 to 4.5 hours with doses from 25 to 200 mg.

Slide 6. Vildagliptin Studies: SummaryIn a study of vildagliptin (50 mg twice daily) versus metformin (1000 mg twice daily) in T2DM patients who were drug naive, dosing for 52 weeks showed both drugs to rapidly decrease HbA1c and that the effect was sustained for 52 weeks. The between-group difference did not establish non-inferiority of vildagliptin in drug naive patients, and the incidence of side-effects was similar between the groups, although there were fewer gastrointestinal-related side effects with vildagliptin.[22]

The addition of vildagliptin to metformin was studied for 24 weeks in T2DM patients. When compared to placebo+metformin, vildagliptin (50 mg every day)+metformin significantly reduced HbA1c (P < .001), with a corresponding reduction in FPG.[23] To ascertain the mechanism for this reduction in FPG, Balas and colleagues[24] conducted a meal tolerance test (MTT) and demonstrated that vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of endogenous glucose production.

Rosenstock and colleagues[25] compared vildagliptin to rosiglitazone when each was given as monotherapy and showed them to be equally effective in reducing HbA1c. Body weight increased with rosiglitazone treatment and was unchanged with vildagliptin therapy.

D'Alessio and colleagues[26] compared vildagliptin and placebo for 12 weeks and demonstrated an improvement of beta-cell function in those patients treated with vildagliptin as well as a concomitant attenuation of insulin resistance independent of acute increases in GLP-1. Furthermore, this improvement was sustained for 2-4 weeks after the completion of study therapy, leading to the hypothesis that vildagliptin may exert some disease-modifying effect. Overall, studies with the DPP-4 inhibitors have

demonstrated that, when administered to patients with T2DM, either as monotherapy or in addition to other available treatments for the disease, there is an improvement in glycemic control and beta-cell function.

Inhibiting the breakdown of GLP-1 using DPP-4 inhibitors is 1 way to leverage the therapeutic potential of GLP-1 in T2DM. An alternative approach is to find a substrate that has the same or similar properties to GLP-1 at the receptor site but is resistant to degradation by DPP-4. Several compounds are available or in development that have this capability and have been termed incretin mimetics. Although the incretin mimetics may exhibit glucoregulatory effects similar to GLP-1, their actions may not be mediated solely through the pancreatic GLP-1 receptor. Therefore, the class incretin mimetic is intended to emphasize the glucoregulatory and metabolic effects of these agents, rather than their specific mechanism of action.

Liraglutide is a long-acting acylated GLP-1 analogue, currently in phase 3 studies. Studies in healthy subjects and in T2DM after single and multiple dosing[27,28] have reported a half-life of approximately 12 hours. Juhl and colleagues[28] compared the effect of a single subcutaneous dose of liraglutide to placebo when administered at bedtime to 11 T2DM patients. The patients were given a standard mixed meal 12.5 hours later. Profiles of circulating insulin, C-peptide, glucose, and glucagon were then monitored after study treatment was administered. Fasting plasma glucose was significantly reduced by 1.2 mmol/L compared to placebo (P < .01). The hypoglycemic effect in the fasting condition was associated with an increase in insulin secretion, but there was no change in plasma glucagon concentration in the fasting state. This group of investigators then studied the effects of liraglutide when administered for 1 week.[29] This study was a randomized, placebo-controlled, double-blind comparison of liraglutide and placebo when given to T2DM subjects. The study treatment was administered by subcutaneous injection each morning for 9 days. On days 8 and 9, the subjects were admitted to a clinical research unit to allow detailed measurements of pancreatic and metabolic function. Data from 24-hour substrate and hormonal profiles demonstrated a markedly reduced circadian plasma glucose level during liraglutide treatment exhibited by fasting, prandial, and nocturnal concentrations. Basal and prandial insulin secretion rates were unchanged, despite the substantial reduction in glycemia, indicating improved beta-cell function.

A double-blind, randomized, parallel group, placebo-controlled trial with an open-label comparator was conducted in 190 T2DM patients by Madsbad and colleagues.[30] The study examined the effect of 5 doses of liraglutide, placebo, or open-label sulfonylurea on HbA1c after 12 weeks of treatment. HbA1c was decreased in all the liraglutide treatment groups except the lowest dose (0.045 mg). The highest dose of liraglutide (0.75 mg) resulted in a significant decrease of 0.75% in HbA1c (P < .0001), and FPG was also significantly decreased. Body weight was not increased in the liraglutide treatment groups and was observed to decrease in the 0.45-mg liraglutide treatment group. Conversely, although patients treated with glimepiride had a decreased HbA1c and FPG, it was at the cost of a slight increase in body weight. Of 135 patients exposed to liraglutide, 7 experienced hypoglycemia compared to 26 in the glimepiride group. The number of patients with adverse events was comparable across the liraglutide and placebo groups. This study was the first to demonstrate a sustained improvement in glycemic control after long-term treatment with liraglutide. More than half the patients in the 2 higher liraglutide dosage groups (0.60 mg and 0.75 mg) had HbA1c ≤ 7.0% after 12 weeks of treatment.

The clinical effectiveness of liraglutide is being evaluated in a series of clinical trials as part of the Liraglutide Effect and Action in Diabetes, or LEAD program, which consists

of 5 randomized, double-blind controlled studies. These trials will assess the clinical effectiveness of liraglutide in some 3800 patients with T2DM patients whose blood glucose is inadequately controlled with standard oral therapies. The release of data from 3 of the 5 major phase 3 studies suggests that the addition of liraglutide to ongoing oral antidiabetic drugs can significantly improve glycemic control in previously uncontrolled T2DM patients.[31] In LEAD 1, a trial in which 1026 patients receiving maximal dose glimepiride were subsequently randomized to treatment with liraglutide, rosiglitazone. or placebo, liraglutide achieved statistically significantly better glucose control (HbA1c < 7%) than rosiglitazone. In LEAD 2, in which 1026 patients receiving the maximal dose of metformin were subsequently randomized to treatment with liraglutide, glimepiride, or placebo, the improvement in HbA1c was similar in the liraglutide and glimepiride treatment arms. In LEAD 5, a 581-patient study, the addition of liraglutide to metformin and glimepiride saw over 50% of patients achieving good glycemic control (HbA1c < 7%) with over 35% achieving an HbA1c of < 6.5%. The reduction in HbA1c achieved with liraglutide was >0.2% better than that achieved in the active comparator arm (insulin glargine), a statistically significant difference.

Slide 7. Once-Daily Injection Covers 24 Hours in Type 2 DiabetesExenatide (Byetta, Amylin Pharmaceuticals, Inc), a GLP-1 receptor agonist, is the first drug in this class to be approved by the FDA and marketed in the United States. It has been approved as an adjunctive therapy for use in patients with T2DM who take metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea or a combination of metformin and a thiazolidinedione. In contrast to sitagliptin and vildagliptin, which are administered orally, exenatide is given by twice daily subcutaneous injection.

Exenatide is the synthetic version of exendin-4, originally isolated from the salivary secretions of the lizard Heloderma suspectum, otherwise known as the Gila monster. The venom contains a number of highly bioactive peptides including the peptides exendin-3 and exendin-4. These peptides were named exendins by Eng and Raufman in that they were isolated from an exocrine gland and were subsequently shown to have endocrine actions. This animal is 1 of the 2 most venomous lizards in the world, and its venom is secreted as it bites down on its prey (ingestion of a meal) thus representing the first example of an endocrine hormone secreted from the salivary

glands. Exendin-4 is a naturally occurring 39-amino acid peptide. Exenatide has 53% homology overlap with exendin-4. As an agonist at the GLP-1 receptor, it has a longer duration of action than GLP-1 largely due to its resistance to DDP-4-mediated catabolism.

Data from animal models demonstrate a number of acute and longer term actions with administration of exenatide. The primary acute actions are enhancement of glucose-dependent insulin secretion, glucose-dependent suppression of inappropriately high postprandial glucagon secretion, and slowing of gastric emptying. The longer term actions include reduction of food intake with subsequent weight reduction, enhanced insulin sensitivity, and an increase in beta-cell mass. To determine whether these actions are also seen in humans, Koltermann and colleagues[32] reported the results from 2 studies designed to explore the postprandial and fasting glucose-lowering effect of exenatide in subjects with T2DM. The plasma glucose response to a Sustacal meal was significantly reduced by the administration of exenatide. In addition, exenatide caused reductions in postprandial insulin concentrations and attenuation of the glucagon response. These effects were shown to be a result of delayed gastric emptying. In the second part of the study, the investigators evaluated the effects of 3 doses of exenatide on fasting glucose concentrations. All 3 doses markedly reduced plasma glucose concentrations compared to the fasting state during an 8-hour observation period. Exenatide also impacted serum insulin concentrations within the first 3 hours post-dose compared to placebo. There was a statistically significant dose-dependent increase in fasting insulin for AUC0-3h (P < .0001). In contrast, there was a relatively stable response to placebo administration. The rise and peak serum insulin concentrations coincided with the rapid decline of fasting glucose concentrations. The most frequent study-related adverse events for subjects administered exenatide were headache, vomiting, and nausea. The findings of these 2 studies would suggest that exenatide can acutely reduce both fasting and postprandial glucose concentrations in patients with T2DM. The overall acute effect is mediated by several mechanisms. In the fasting state, both glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are predominant, whereas in the postprandial period, slowing of gastric emptying also plays a significant role.

Treatment with exenatide was then evaluated in 3 phase 3 trials when it was administered to patients with T2DM. The studies have been labeled the AC2993:Diabetes Management for Improving Glucose Outcome (AMIGO) development program. The 3 studies were very similar in design; all were randomized, double-blind, placebo-controlled, add-on therapy, multicenter studies with change in HbA1c as the primary outcome variable. Following a 4-week placebo run-in period, subjects were randomized to receive either exenatide 5 mcg twice daily, exenatide 10 mcg twice daily, or placebo to match both exenatide treatment arms. The 10-mcg group and the matched placebo group were initiated at the 5-mcg dose and volume, with a forced titration to the higher dose and volume after 4 weeks. All subjects were then followed for a subsequent 26 weeks.

The 3 studies are distinguished by the entry criteria of the individual study. The first study, AMIGO I, examined exenatide treatment in T2DM patients inadequately controlled on metformin monotherapy. The second study, AMIGO II, enrolled subjects inadequately controlled on sulfonylurea monotherapy; the third study, AMIGO III, enrolled subjects inadequately controlled on the combination of metformin and sulfonylurea. In all 3 studies, the patients continued their concurrent medication. However, in AMIGO III, to explore the risk of hypoglycemia, all patients continued their current dose of metformin but were randomized to either a maximally effective or minimum recommended dose of their sulfonylurea. No dietary intervention was

included in the studies, and subjects were instructed to maintain their previously prescribed dietary regimens. Data were reported for the 3 individual studies.[33,34,35]

Slide 8. Exenatide: Effects on Glycemic Control in Combination With Current Oral TherapiesAMIGO I recruited 336 patients with an average HbA1c of 8.2 =/- 1.1% and a mean disease duration of 6 years. Amigo II recruited 377 patients with an average HbA1c of 8.6 ± 1.2% and a mean duration of disease of 6 years. Amigo III recruited 734 patients with a mean HbA1c of 8.5 ± 1.0% HbA1c and a mean duration of disease of 9 years. Minorities were well represented throughout all study cohorts.

In all 3 studies, the addition of exenatide to the patient's concurrent therapy resulted in a significantly greater proportion achieving an HbA1c ≤ 7%. In addition, each respective group of patients treated with exenatide had significant reductions in mean HbA1c when compared to placebo (P < .001). Because of the identical study design between the 3 studies, it is acceptable to pool the data and make comparisons of exenatide versus placebo. In the measurement of HbA1c, pooled data show an increase of 0.1% for those subjects randomized to placebo, whereas 5 mcg of exenatide twice daily led to a mean reduction of 0.6% and 10 mcg twice daily exenatide led to a mean reduction of 0.9%, and both decreases were statistically significant when compared to placebo twice daily .

Pooled data from the AMIGO studies also demonstrated a beneficial effect of exenatide on FPG and postprandial glucose levels. Both were significantly reduced by exenatide after 30 weeks of treatment.

Slide 9. Exenatide Reduced Weight: Large Phase 3 Clinical StudiesAllied with the reduction of FPG and the improved control of postprandial glucose levels was a progressive weight loss, predefined in the protocols as a secondary outcome, for those subjects treated with exenatide. Pooling the data showed that subjects treated with exenatide 10 mcg twice daily had an end of study loss of 1.8 kg from baseline; subjects randomized to the lower dose of exenatide had a weight loss of 1.4 kg, whereas the placebo group showed a 0.1-kg weight loss from baseline.

In general, across the 3 studies, exenatide was well tolerated and the adverse event profile was also similar with the exception of hypoglycemia risk. A modest increase in hypoglycemia risk was seen with the addition of exenatide to sulfonylurea or the combination of metformin plus sulfonylurea. Combination of exenatide with metformin did not demonstrate any appreciable increase in the incidence of hypoglycemia, which would suggest that, in the absence of an insulin secretogogue or exogenous insulin, exenatide does not cause hypoglycemia. The most commonly reported adverse event was mild-moderate nausea, which more often than not occurred early after the initiation of exenatide treatment. In AMIGO I, 45% of patients in the group receiving exenatide 10 mcg twice daily reported nausea compared to 23% in the placebo group. There was a 3% dropout for the exenatide group and 0% for the placebo group. In the AMIGO III study, 49% of patients taking 10 mcg of exenatide twice daily reported nausea compared with 21% for placebo. However, the nausea seemed to be minimized by gradual dose titration. A partial coefficient and subgroup analysis indicate that nausea had a negligible effect on HbA1c or the reduction in body weight seen with exenatide treatment.

On completion of the treatment period in their respective study, patients were given the opportunity to continue with open-label exenatide treatment at a dose of 10 mcg twice daily. Results reported by Webb and co-workers[36] from 314 overweight patients that used exenatide twice daily for 82 continuous weeks demonstrated that patients continued to lose weight, with a mean loss of 4.4 kg. Ratner and colleagues[37] reported the data from the patients also taking metformin and in addition to the continued loss of body weight, there was a durable and continued decrease in HbA1c of 1.3% from baseline compared to a decrease of 1.0% after 30 weeks dosing. Another benefit from long-term dosing with exenatide was an improvement in cardiovascular risk factors

when compared to baseline. A variety of risk factors were measured, and the data are presented in Table 1.

Parameter Mean Baseline Mean ∆ From Baseline 95% CI

Total cholesterol (mg/dL) 188.2 -2.4 -6.3 to +1.5

LDL-C (mg/dL) 116.7 -1.6 -5.2 to +1.9

HDL-C (mg/dL) 38.6 +4.6 +3.7 to +5.4

Apo B (mg/dL) 92.6 -1.1 -3.5 to +1.3

Triglycerides (mg/dL) 243.1 -38.6 -55.5 to -21.6

Systolic BP (mm Hg) 129.0 -1.3 -3.1 to +0.5

Diastolic BP (mm Hg) 78.8 -2.7 -3.8 to -1.7

Table 1: Exenatide Improved Cardiovascular Risk Factors at Week 82For 82-week completers, N = 314. Data from Blonde et al. Diabetes Obes Metab. 2006;8:436-447.CI, confidence interval; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; Apo B, apolipoprotein B; BP, blood pressure.Another beneficial feature of long-term treatment with exenatide was an observed improvement in hepatic injury biomarkers when followed over 2 years. Buse and colleagues[38] reported that patients with normal levels of alanine transferase (ALT) at baseline had no significant change after 2 years of treatment with exenatide. However, patients with elevated ALT at baseline (38 ± 1 IU/L, N = 151) had a mean reduction of 11 ± 1 IU/L (P < .05), and 39% of these subjects achieved a normal ALT by the end of 2 years treatment. Aspartate amino transferase was also improved over the same period. The same authors also reported an improvement in HOMA-B with an almost 50% increase from baseline.

The AMIGO studies clearly demonstrated a benefit of adding exenatide to ongoing metformin or sulfonylurea therapy in the treatment of T2DM, and for most patients the effect persisted during long-term therapy. Zinman and colleagues[39] reported the results of a randomized, placebo-controlled, double-blind study where the objective was to examine the effect of adding exenatide to thiazolidinediones (TZD), another class of drug also used in the treatment of T2DM. Patients considered for the study were suboptimally controlled on their current therapy and were to have been on a stable dose of either rosiglitazone (≥ 4 mg/day) or pioglitazone (≥ 30 mg/day) for at least 30 days. The primary outcome was the change in HbA1c from baseline; secondary outcomes included FSG, body weight, and self-monitored blood glucose levels.

Slide 10. Seven-Point Self-monitored Blood Glucose ProfilesThe addition of exenatide for 16 weeks reduced mean HbA1c by 0.98% (P < .001), whereas there was a marginal increase in HbA1c with placebo treatment. Within the exenatide treatment population, 62% of patients were able to achieve the ADA target of an HbA1c ≤ 7% compared to only 16% in the placebo group (P < .001). Also of note is the finding that 30% of exenatide patients achieved an HbA1c level of ≤6.5% compared to 8% in the placebo group (P < .001). Exenatide also improved FPG level with a mean reduction of 1.69 mmol/L compared to the reduction of 1.17 mmol/L observed with placebo (confidence interval, -2.22 to -1.17 mmol/L). The administration of exenatide also reduced body weight by an average of 1.51 kg.

Patients were encouraged to self-monitor their blood glucose at 7 specified daily events to allow blood glucose profiles to be built. The profiles at baseline and post-treatment were almost identical and superimposable upon the placebo group profiles. In the exenatide treatment group, there were clear reductions in blood glucose throughout the day and the postprandial excursions were also attenuated. Overall, it can be concluded that the addition of exenatide to TZD improved glycemic control and reduced body weight, with a slight increase in the reporting of gastrointestinal side effects, primarily nausea, when compared to placebo.

Recently, data from 217 subjects who have received exenatide 10 mcg twice daily for 3 years were presented.[40] There was a sustained reduction in HbA1c and FPG. A total of 46% of the study participants achieved the ADA goal of an HbA1c below 7%, and 36% achieved an HbA1c of 6.5% or less. Weight loss was progressive with study subjects losing a mean 5.3 ± 0.4 kg at 3 years. In a subset of 92 subjects, 3 years of treatment with exenatide resulted in a 17% improvement from baseline in beta-cell function as determined by HOMA-B.

Pharmacokinetic studies with exenatide show its half-life to be 2.4 hours with effects lasting up to 8 hours. This is 20-30 times longer than GLP-1 when compared in preclinical studies. However, as exenatide is administered in the morning and evening, the possibility exists that it may not provide complete coverage after midday meals or overnight. Therefore, an extended release formulation was developed with the objective of providing once weekly subcutaneous administration of exenatide. This new

formulation, referred to as exenatide LAR (long-acting release), was compared at 2 dose levels to placebo in a 15-week double-blind, randomized study in T2DM patients.[41] The dose levels of exenatide were 0.8 mg and 2.0 mg, which were targeted to result in blood levels previously found to be therapeutic with twice daily exenatide. Plasma concentrations of exenatide rose steadily and reached steady state levels by weeks 6-7. After about 6 weeks of treatment with 2.0 mg of exenatide LAR, plasma exenatide concentrations were maintained at levels similar to the maximum concentration achieved with a single injection of 10 mcg of exenatide.

Slide 11. Exenatide LAR Reduced FPGExenatide LAR reduced HbA1c by week 3 in both active treatment groups, and HbA1c decreased progressively throughout the remainder of the treatment period. Fasting plasma glucose was rapidly and significantly reduced in both exenatide groups. All 3 groups had similar self-monitored glucose profiles at baseline. After 15 weeks of study treatment, the average daily blood glucose concentration decreased for both LAR treatment groups and increased for the placebo treatment group. Exenatide LAR also decreased preprandial and postprandial glucose excursions. Body weight decreased progressively in the 2.0-mg exenatide LAR group (P < .05 vs placebo). Body weight was unchanged for the 0.8-mg exenatide LAR and the placebo groups.

Slide 12. Exenatide LAR Reduced Overall Daily GlucoseAs in studies with conventional exenatide, the most frequently reported adverse event was nausea (exenatide LAR 0.8 mg 19%, exenatide LAR 2 mg 13% vs placebo LAR 15%) followed by gastroenteritis and hypoglycemia. Most treatment emergent adverse events were reported as mild or moderate.

In summary, the incretin mimetics have been shown to be effective in sustaining glycemic control together with gradual but continuous reductions in body weight and improvements in beta-cell function. In the case of exenatide, data are now available, showing that the efficacy persists for up to 3 years. Side effects are generally mild to moderate in severity. With exenatide, there is a noticeable increase in the number of reports of nausea, although these reports do seem to decrease over time.

Although the ADA treatment algorithm was published only recently, the availability, safety, and proven effects of these newer agents, the DPP-4 inhibitors and the incretin mimetics, would suggest that they should be incorporated into a revised treatment algorithm in the near future. Both classes represent a novel strategy for improving the imbalance of glucose homeostasis that occurs in T2DM and for restoring normal physiology. The introduction of these new agents may have a dramatic impact and unprecedented impact on T2DM as true disease-modifying agents, perhaps improving or preventing complications and ultimately improving mortality as the progression of the disease is delayed or potentially reversed.

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