Oral Antidiabetic Agents in Type 2 Diabetes

By Levetan, Claresa

Key words: Dipeptidyl peptidase-4 inhibitors – Glucagon-like peptide 1 – Type 2 diabetes

ABSTRACT

Background: Oral antidiabetic agents differ with regard to mechanisms of action, hemoglobin A^sub 1c^-lowering efficacy, safety, and tolerability. Traditional agents consist of those that enhance insulin secretion (i.e., sulfonylureas and glinides), those that enhance insulin sensitivity (i.e., metformin and the thiazolidinediones), and those that inhibit intestinal carbohydrate absorption (i.e., the α-glucosidase inhibitors). New oral agents include the dipeptidyl peptidase-4 (DPP-4) inhibitors, which potentiate the activity of the incretin glucagon-like peptide 1 and enhance glucose-dependent insulin secretion.

Scope: We review the characteristics of the traditional oral agents and these newer additions to the pharmaceutical armamentarium. Abstracts and original clinical and preclinical reports in the English language were identified for review based on MEDLINE literature searches (1970-2006) and abstract collections from major diabetes meetings.

Conclusions: Traditional oral agents provide significant treatment benefits for diabetic patients, including reduction in risk of microvascular complications. However, most patients with type 2 diabetes do not achieve target glycemic levels with traditional therapies, and these agents are also associated with hypoglycemia, weight gain, and poor tolerabillty. Oral DPP-4 inhibitors offer the potential for significant improvement in glycemic control without hypoglycemic or weight gain, although long- term durability of glycemic control (>52 weeks) has not been established.

Introduction

Pancreatic islet dysfunction in the face of insulin resistance is the underlying cause of type 2 diabetes. Islet (α and β cells) dysfunction plays a crucial role in disrupting the physiologic balance between glucagon and insulin, leading to hyperglycemic. Although insulin resistance is a pre-existing state in most patients with type 2 diabetes, euglycemia can be maintained as long as insulin secretion increases to meet elevated requirements’. However, when insulin secretion can no longer keep up with the demands of insulin resistance and there is inadequate first- phase insulin release by the pancreas, postprandial and fasting glucose levels become elevated. In the further progression to diabetes, inadequate insulin secretion is exacerbated by a progressive loss of -cell function, mass, and number due to accelerated apoptosis and insufficient replication and neogenesis. This leads to progressive hyperglycemia and an increased risk of vascular disease1.

Despite the availability of therapies and interventions to prevent both diabetes and reduce the risks for microvascular and macrovascular disease associated with diabetes, this disease remains the leading cause of cardiovascular disease, blindness, lower extremity amputations, and renal failure necessitating dialysis and transplantation. This may in part be due to failure of current therapies to provide adequate glucose control, and it is likely that other factors such as patient lifestyle choices and lack of adherence to therapy are responsible as well. A recent American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus statement stresses the need to rapidly add antidiabetic agents and to change ineffective regimens to avoid the prolonged periods of inadequate glycemic control that are associated with increased risk of complications2. There are a number of oral agents at our disposal for use in achieving and maintaining tight glycemic control that differ with regard to hemoglobin A^sub 1c^ (A1C)-lowering efficacy, mechanisms of action, and safety and tolerability. The major traditional categories include medications that stimulate insulin secretion (e.g., sulfonylureas (SUs) and glinides), improve insulin sensitivity (e.g., metformin and the thiazolidinediones (TZDs)), and reduce intestinal carbohydrate absorption (e.g., α-glucosidase inhibitors (AGIs)). The oral dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of medications that improve glucose homeostasis by augmenting the action of the incretin hormone glucagon-like peptide 1 (GLP-I), an activity that results in improved insulin secretion from α cells and a reduction in hepatic glucose production via inhibition of inappropriate glucagon release from α cells3-6. This approach to improving glucose metabolism is also reflected in the new injectable GLP-I mimetics.

Characteristics of the traditional oral agents and these newer additions to the armamentarium are reviewed herein. Abstracts and original clinical and preclinical reports in the English language were identified for review based on MEDLINE literature searches (1970-2006) and abstract collections from major diabetes meetings. Search terms for the literature search included ‘α-glucosidase inhibitor’, ‘dipeptidyl peptidase-4 (DPP-4) inhibitor’, ‘glucagon- like peptide 1 (GLP-1) receptor agonist’, ‘meglitinide’, ‘metformin’, ‘sulfonylurea’, ‘thiazolidinedione’, and ‘type 2 diabetes’. Relevance and frequency of citation of the articles were considered in the selection process.

Oral antidiabetic agents

Sulfonylureas

SUs act by binding to the β-cell sulfonylurea receptor (SUR)- I, inducing immediate release of preformed insulin granules and extended (second-phase) release of granules that are subsequently trafficked to the surface of the β cell7,8. Depending on the functionality of the β cells, insulin release may go on for as long as the drug is active. The main effect of these agents is to reduce fasting hyperglycemic. There are differences in duration of effect in the available SUs, with most being dosed once or twice daily. SUs are metabolized in the liver, with metabolites and routes of elimination differing among the agents. Their high degree of protein binding poses the potential for interaction with other bound drugs, including salicylates, sulfonamides, and warfarin, although these interactions are generally minor and primarily seen with first- generation SUs.

SUs lower A1C by approximately l0 -2%7,9,10. In the United Kingdom Prospective Diabetes Study (UKPDS), ‘intensive’ treatment with either SU or insulin resulted in a 25% reduction in risk of microvascular complications and a 12% reduction in any diabetes endpoint compared with ‘conventional’ treatment (diet) over 10 years in newly diagnosed diabetic patients11; the SU and insulin subgroups had similar outcomes. The smaller-scale STENO 2 study showed that an intensive multifactorial approach centered on SU treatment in a hospital clinic setting reduced risk of both microvascular and macrovascular complications compared with standard treatment in primary care12. The antihyperglycemic effects of SUs have been shown to wane over time. In the ADOPT study, glyburide was associated with a 34% incidence of monotherapy failure after 5 years, compared with 15% for rosiglitazone and 21% for metformin13. This waning of effect with SUs indicates either that their actions exhaust β-cell function or, what is more likely, that decline of β-cell function as part of the diabetic state results in diminished secretagogue activity7,10.

The most common adverse effect of the SUs is hypoglycemia14, which is occasionally life-threatening. Hypoglycemia is more common in patients with adequate glycemic control (i.e., those with AlC levels within or slightly above the nondiabetic range); other risk factors include advanced age, declining renal function, irregular meal schedules, and excessive alcohol consumption10,15. Another common adverse effect is weight gain (e.g., 2-5 kg), which is problematic in a population characterized by overweight people. Other adverse effects of SUs consist of uncommon hypersensitivity reactions. second-generation agents, including glipizide, glyburide, and glimepiride, exhibit a different adverse event profile than the older agents. Among the second-generation agents, weight gain and hypoglycemic occur less frequently in patients treated with glimepiride or glipizide than in those treated with glyburide. SU therapy was associated with increased cardiovascular mortality in the University Group Diabetes Program16, but no increase in risk was observed in the UKPDS11. Still, there remains some concern that SU use should be minimized in patients with overt coronary artery disease10.

Meglitinides

Compared with SUs, the glinides repaglinide and nateglinide induce rapid and short-term insulin secretion by transiently binding to different sites on the pancreatic β cells. For example, in vitro studies with βTC3 insulinoma cells have identified two distinct binding sites for repaglinide and glibenclamide: a high- affinity repaglinide site with a lower affinity for glibenclamide and a high-affinity glibenclamide site with a lower affinity for repaglinide17. The drugs are taken immediately prior to a meal and improve early-phase insulin secretion and reduce postprandial hyperglycemia. Both are metabolized in the liver and excreted via the kidney. Repaglinide appears to be more effective than nateglinide in reducing AlC2. In one head-to-head study of the two agents in 150 patients with type 2 diabetes, mean reduction in AlC after 16 weeks was 1.57% for repaglinide monotherapy and 1.04% for nateglinide monotherapy18. One disadvan\tage of treatment with these rapid-acting secretagogues is the need for three times daily dosing. Hypoglycemia occurs with these agents, but, at least with nateglinide, appears to be less frequent than that seen with some SUs2. Weight gain is also seen less frequently with meglitinides than with SUs9. Repaglinide and nateglinide are metabolized in the liver and excreted via the kidney. Hypersensitivity reactions are also observed, with these generally being transient.

Biguanides

Metformin is the most widely used oral antidiabetic drug, and is recommended for initial treatment of type 2 diabetes along with lifestyle intervention2. It is the only currently available biguanide; another early member of this class (phenformin) was withdrawn from the market in the 1970s due to risk for lactic acidosis. The precise molecular mechanisms by which metformin exerts its effects have yet to be elucidated. Its main effect is to reduce hepatic glucose production in the presence of insulin and reduce fasting glycemia. Metformin is not metabolized and is excreted unchanged in the urine, with clearance occurring predominantly by tubular secretion. There is little plasma protein binding of the drug, further reducing potential for drug interactions.

Metformin reduces AlC by approximately l-2%9’10. Compared with conventional diet therapy among overweight subjects in the UKPDS, metformin treatment significantly reduced risks for any diabetes endpoint (32%), diabetes-related mortality (42%), all-cause mortality (36%), myocardial infarction (MI) (39%), and all macrovascular endpoints (30%)19. No statistically significant reduction in microvascular endpoints was observed. However, the study was not powered to detect differences in this endpoint, and it seems likely that the almost 30% reduction in microvascular complications seen with metformin treatment is clinically relevant. Initial findings in a UKPDS substudy in which metformin was added to SU treatment indicated increased mortality with the combination, but this increase was no longer apparent on longer-term follow0 – up10,19. The US Diabetes Prevention Program showed that cases of new diabetes in overweight/obese patients with impaired glucose tolerance were reduced by 33% with metformin treatment and by 58% with a program of intensive diet and exercise20. As with SUs, the effects of metformin on hyperglycemia have been found to wane with time in treatment trials21.

Metformin is not associated with hypoglycemia. Treatment results in stable weight or small weight reductions, and it may produce small favorable changes in the lipid profile (e.g., reduced triglycerides, fatty acids, and low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol) in patients with dyslipidemia. The most common adverse effects of metformin are gastrointestinal (GI) complaints such as abdominal pain, nausea, and diarrhea, which may occur initially in as many as half of patients. These can be minimized with food intake, slow dose titration, or dose reduction and slow re-titration. New 24-hour sustained-release preparations of metformin are available that are taken with the evening meal and that may be better tolerated from a GI standpoint. Previous studies have shown that metformin treatment carries a small but definite risk for lactic acidosis that is associated with a high mortality rate2,10,22. A recent analysis suggests that metformin rarely, if ever, causes lactic acidosis when used as labeled19. Nevertheless, patients and physicians should be aware of the symptoms of lactic acidosis, which include malaise, myalgia, respiratory distress, increasing somnolence, and non-specific abdominal distress. Metformin must be used only in patients with renal function sufficient to prevent drug accumulation (e.g., serum creatinine > 120-130 /L) and must be avoided in those at risk for lactic acidosis due to renal impairment or other factors. There should also be heightened awareness of the potential for renal dysfunction (e.g., in the elderly) that is not reflected in elevated serum creatinine levels. Given the risk for acidosis, metformin is contraindicated in patients with cardiac or respiratory insufficiency (e.g., congestive heart failure) or any other condition associated with hypoxia or reduced perfusion, and in those with hepatic dysfunction, alcoholism, or history of metabolic acidosis.

Thiazolidinediones

TZDs are nuclear peroxisome-proliferator-activated receptor (PPAR) γ modulators that act to increase sensitivity of muscle, fat, and liver cells to endogenous and exogenous insulin. The TZDs are rapidly absorbed and are predominantly metabolized in the liver. Rosiglitazone is metabolized primarily by cytochrome P450 2C8 (CYP2C8) to weakly active metabolites that are excreted primarily in urine. Pioglitazone is metabolized in part via CYP3A4, and has more- active metabolites that are excreted in the bile. Although CYP3A4 is a common route of drug metabolism, no significant drug-drug interactions with pioglitazone have been reported thus far.

TZDs reduce Al C by approximately 1-1.5%91423 and may have greater glycemic durability than metformin or SUs. In the ADOPT study, only 15% of patients receiving rosiglitazone monotherapy were classified as treatment failures after 5 years, compared with 21% of metformin patients and 34% of glyburide patients’3. The antihyperglycemic effect is more evident with more preserved β- cell function. These agents have a neutral or beneficial effect on atherogenic lipid profiles, with pioglitazone having a greater beneficial effect in this regard than rosiglitazone. TZDs are not associated with substantial risk of hypoglycemia. The most common adverse effects of these agents are edema and weight gain (e.g., 1- 4 kg) (Table 1). Edema may occur as peripheral edema, but may also be associated with new or worsened heart failure. In European guidelines, use of TZDs is contraindicated in patients with evidence of congestive heart disease or heart failure, and their use in combination with insulin is contraindicated due to heart failure risk. The US guidelines urge a cautious approach to TZD treatment and careful monitoring of patients thought to be at risk for heart failure24. In the recent PROactive trial in 5238 patients with diabetes and macrovascular disease, pioglitazone (n = 2605) was not associated with significant benefit in preventing the primary composite endpoint (allcause mortality, nonfatal MI, stroke, acute coronary syndromes, intervention in coronary or leg arteries, or amputation above the ankle) compared with placebo (n = 2633), although a significant 16% reduction in the secondary endpoint of all-cause mortality, nonfatal MI, or stroke was observed25,26. However, pioglitazone patients had 115 more heart failure events and 221 more cases of edema not associated with heart failure, as well as a 4-kg weight increase and a significantly increased frequency of pneumonia. The first TZD, troglitazone, was removed from the market due to cases of fatal idiopathic hepatotoxicity. Although neither available TZD has been associated with significant hepatotoxicity, a period of liver function monitoring is still recommended and active liver disease remains a contraindication to starting TZD treatment.

Table 1. Side effects of select oral antidiabetic agents

α-Glucosidase inhibitors

AGIs inhibit intestinal oc-glucosidase enzymes, reducing the rate of polysaccharide digestion in the proximal small intestine and thus reducing postprandial hyperglycemia. These agents, which include acarbose, miglitol, and voglibose, are taken three times daily and need to be taken with meals that contain digestible carbohydrates. AGIs reduce AlC by 0.5-1.0%, with their effects generally being additive to other antidiabetic agents9,10,14. In the STOP-NIDDM trial, acarbose reduced risk of progression to overt diabetes by 25% in subjects with impaired glucose tolerance compared with placebo27; the acarbose group had fewer cases of new-onset hypertension and major cardiovascular events. The risk for hypoglycmie with AGIs is small (Table 1); however, hypoglycemia that occurs when they are used in combination with other agents must be treated by administering glucose itself rather than complex carbohydrates. The agents do not cause weight gain. The delay of carbohydrate absorption to the more distal intestine results in increased delivery of carbohydrate to the colon, which is accompanied by significant GI symptoms, including flatulence, abdominal discomfort, and diarrhea. Such side-effects have resulted in discontinuation of AGIs in 25-45% of patients in clinical trials2. Elevated liver enzyme levels can occur at higher doses of acarbose, and regular monitoring is recommended in patients receiving maximum dosing.

DPP-4 inhibitors

The oral DPP-4 inhibitors in the most advanced phases of clinical development are vildagliptin and sitagliptin, the latter of which was recently approved for use. These agents act primarily by inhibiting rapid degradation of the gut incretin hormone GLP-I, resulting in higher levels of biologically active GLP-I. GLP-I enhances insulin secretion from β cells and reduces hepatic glucose production by inhibiting glucagon release from α cells3,28,31. GLP-1 also stimulates proliferation and inhibits apoptosis of β cells in rodents and promotes differentiation of these cells from human precursor cells32-35. These findings suggest that DPP-4 inhibition might favorably impact the progressive loss of β-cell function characteristic of type 2 diabetes. In preclinical studies, DPP-4 inhibition increased circulating levels of intact GLP-1 and improved glucose tolerance in many animal models of insulin resistance. Further, longterm DPP-4 inhibitor treatment with vildagliptin was shown to both increase and preserve β- cell number through apparent stimulation of islet neogenesis andβ-cell regeneration or enhanced insulin biosynthesis in the rat34, with histological examination of the pancreas showing increased numbers of islets and β cells.

Initial short-term studies of the mechanisms of effect of DPP-4 inhibitors at therapeutic doses in patients with type 2 diabetes showed increased active GLP-1 concentrations, reduced glycemia, improved insulin sensitivity, improved β-cell function and insulin secretion, and reduced postprandial and 24-hour glucagon levels6,30,3541. Several studies have confirmed improved β- cell function with DPP-4 inhibitor treatment. In a 4-week study in patients with type 2 diabetes, vildagliptin was shown to improve β-cell function by improving insulin secretory tone, with insulin secretion improving at any given glucose level compared with placebo37. In a 52-week meal-test study, insulin secretion (suprabasal C-peptide area under the curve divided by glucose area under the curve during standardized meal) was increased at 12 weeks in patients who had vildagliptin added to metformin compared with metformin alone, with this increase sustained over 52 weeks42. Insulin sensitivity during the meal and insulin secretion related to insulin sensitivity (adaptation index) both increased significantly with vildagliptin, and the change in the adaptation index was significantly correlated with change in AlC (between-group difference of-1.1% in the vildagliptin/metformin group at 52 weeks). Similarly, two 24-week placebo-controlled studies of sitagliptin showed significant improvement in β-cell function assessed by homeostasis model assessment of β-cell function (HOMA-B)43,44, a technique that allows quantitative measurement of the contributions of deficient β-cell function to fasting hyperglycemia45.

In 18- to 24-week treatment trials, sitagliptin monotherapy at 100 or 200 mg q.d. reduced A1C by 0.5-0.9%,with reductions of 1.0- 1.5% in patients with baseline A1C ≥ 9%43,46. In 6-month trials, vildagliptin monotherapy at 50 mg b.i.d. reduced A1C by 0.5% (0.7% in patients diagnosed with diabetes ≥ 3 months prior to enrollment) to 1.1 %47,48 with a reduction of 1.0% observed in a year-long comparison with metformin49. Pooled analysis of 1301 drug- nave patients with the same study entry criteria shows that vildagliptin 50 mg b.i.d. reduced A1C by 1.1% overall, by 1.3% in those with baseline AlC > 8% (n = 838), and by 1.7% in those with levels > 9% (n = 440)39,50.

In 6-month combination trials, the addition of sitagliptin 100 mg q.d. to metformin or pioglitazone reduced AlC by 0.65-0.7%44,51; in a 1-year trial, the addition of sitagliptin 100 mg/day to metformin produced a 0.7% reduction52. In 6-month trials, the addition of vildagliptin 50 mg q.d. or b.i.d. to ongoing metformin produced reductions in A1C of 0.7% and 1.1%, respectively53, and an initial combination of vildagliptin 100 mg/day with pioglitazone 30 mg/day produced a 1.9% reduction overall and a 2.8% reduction in those patients with baseline A1C levels of ≥ 9% or greater54. The addition of vildagliptin 50 mg b.i.d. to insulin therapy reduced A1C by 0.5% overall, and by 0.7% in patients 65 years of age or older55.

Studies of vildagliptin have shown a significant benefit in improving postprandial triglyceride-rich lipoprotein metabolism56, and significant improvement in atherogenic lipid profile compared with rosiglitazone48, as well as modest improvement in blood pressure57.

The DPP-4 inhibitors are not associated with weight gain or any substantial risk for hypoglycemia. In controlled trials, the safety and tolerability of vildagliptin and sitagliptin have been comparable to placebo, including rates of hypoglycemia39. In comparative trials, hypoglycemia in vildagliptin patients was mild and infrequent, with similar rates being observed in comparison with rosiglitazone (one event in each group over 6 months)48 and metformin (<1% over 1 year)49. Frequency and severity of hypoglycemia were reduced when vildagliptin was added to insulin therapy compared with insulin alone55. Body weight has generally been unchanged or exhibited small decreases with DPP-4 inhibitor treatment35,43,48,53. The addition of vildagliptin to ongoing metformin therapy resulted in a significant decrease in GI side- effects compared with metformin alone53.

Vildagliptin is metabolized via hydrolysis and both changed and unchanged drug are eliminated in the urine, and no dose adjustment is required on the basis of age, body mass index, or degree of renal impairment58,59. Sitagliptin is largely not metabolized and is excreted mostly unchanged in urine. Dose adjustment is required for patients with moderate or severe renal impairment60.

GLP-1 receptor agonists

While they need to be administered parenterally, the GLP-I receptor agonists warrant mention here because they also represent the approach of enhancing GLP-I activity and are likely to find a place in the antidiabetic armamentarium. Exenatide is a synthetic form of a naturally occurring 39-amino-acid peptide exendin-4 that resists degradation by DPP-4 and exhibits glucoregulatory activities similar to GLP0 -128,29,40,61. It is approved as a twice-daily subcutaneous (SC) injection before meals in patients who are taking metformin and/ or SU and who have not achieved adequate glycmie control. Exenatide combined with ongoing metformin and/or an SU reduced A1C by approximately 1.0% over 6 months and produced significant dose-dependent weight loss at the approved 5-g and 10-g b.i.d. doses, ranging from 0.9 kg when added to metformin plus SU to 2.5 kg when added to metformin62-64. Interim analysis of 82-week results in a relatively small patient group from a placebo- controlled trial showed maintained reduction in AlC (-1.3%), continued weight loss (-5.3kg), and significant improvements in lipid measures65. Compared with insulin glargine in patients with inadequate glycemic control on metformin plus SU, exenatide produced an identical reduction in A1C of 1.1% after 26 weeks66, and was associated with a 2.3-kg weight loss versus a weight gain of 1.8 kg in insulin glargine patients. Exenatide patients had a higher frequency of GI side-effects, such as nausea and vomiting, and an increased dropout rate. Although severe hypoglycemia has been rare, it has occurred in 14-36% of patients also receiving SU or metformin/ SU65, and dose reduction for SU is recommended when the agents are combined67.

Liraglutide is an acylated GLP-1 mimetic with a half-life long enough to permit once-daily SC dosing. In a recent placebo- controlled study, liraglutide 0.65, 1.25, and 1.9 mg once daily significantly reduced AlC over 14 weeks, with a reduction of 1.7% observed at the highest dose68,69. Body weight was reduced in a dose- dependent manner, with a reduction of 3.0 kg from baseline and 1.2 kg versus placebo observed at the highest dose. GI adverse effects of nausea and vomiting were common but decreased over time. Liraglutide treatment was also associated with positive effects on cardiovascular biomarkers and blood pressure.

Conclusion

Oral antidiabetic agents differ with regard to AlClowering efficacy, mechanism of action, safety, and tolerability. Selection from among these medications should be guided by these characteristics as they interact with individual patient clinical and metabolic characteristics and needs in the context of achieving and maintaining glycemic control. The recent ADA/ EASD consensus statement urges that AlC of 7% or above be considered a call to action, that glycemia be reduced to and maintained as close to normal as possible, and that, to this end, medications be rapidly added or regimens changed when glycmie goals are not met or maintained. It is recommended that initial therapy consists of lifestyle intervention and metformin and that another agent be added within 2-3 months if goal glycemia is not achieved. Of course, metformin is recommended as initial therapy only in the absence of specific contraindications, and special considerations for individual patients may dictate varying approaches to initial treatment. For example, in the setting of severely uncontrolled diabetes with catabolism, insulin therapy in combination with lifestyle intervention would be the treatment of choice.

The oral DPP-4 inhibitors are likely to initially find a variety of roles in combined regimens based on their AlC-lowering efficacy, weight neutrality, and lack of risk for hypoglycemia. The first role for DPP-4 inhibitors in current treatment algorithms may be as combination therapy with metformin or a TZD in those patients who fail to reach glycemic goals with metformin monotherapy and lifestyle intervention. Benefits in combination with metformin are suggested by the complementary mechanisms of action and AlC- lowering efficacy in year-long trials, and possibly by the reduction in GI adverse events with the DPP-4 inhibitor/metformin combination. Moreover, because the DPP-4 inhibitors are associated with a neutral impact on weight (vs. weight gain for SUs and TZDs), lower risk of hypoglycemia than SUs, less edema than TZDs, and a reduction in GI events when combined with metformin (vs. an increase in GI events with exenatide), they may be more appropriate than SUs, TZDs, or exenatide for use in initial combination therapy with metformin. Combinations of DPP-4 inhibitors with SUs and TZDs have also shown good AlC-lowering efficacy and favorable safety profiles. Triple combination with metformin, a TZD, and a DPP-4 inhibitor might be considered as a means of rapidly achieving and maintaining glycemic goals. The DPP-4 inhibitors and GLP-I mimetics also offer the potential for reversing or delaying loss of β-cell function in diabetes. Should the presence of this activity be borne out in further clinical studies and experience, a major role for these agents in treating early diabetes or in preventing disease would b\e likely. However, some caution is warranted when discussing the use of DPP-4 inhibitors in diabetes treatment regimens. Durability of glycemic control beyond 52 weeks has not been established and, as with all investigational or newly approved antidiabetic agents, a smaller body of safety/tolerability data is available compared with more established agents such as metformin or SUs. Moreover, it should be noted that the effects of DPP-4 inhibitors on β-cell function in humans remain speculative.

Acknowledgments

Declaration of interest: Development of this review article was supported by an unrestricted educational grant from Novartis Pharma AG. Editorial assistance in its preparation was provided by BioScience Communications, New York, NY.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3822_3, Accepted for publication: 02 January 2007

Published Online: 16 March 2007

doi: 10.1185/030079907X178766

Claresa Levetan

Department of Endocrinology, Lankenau Hospital, Wynnewood, PA, USA

Address for correspondence: Claresa Levetan, MO, Department of Endocrinology, Lankenau

Hospital, 222 Lankenau MOB South, 100 E. Lancaster Avenue, Wynnewood, PA 19096, USA.

Tel.: +1 610-649-1922; Fax: +1 610-649-2121; email: levetan@juno.com

Copyright Librapharm Apr 2007

(c) 2007 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.