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Dr Boyle is a professor of medicine at the University of New Mexico in Albuquerque, and Dr Freeman is chair and course director in the Division of Endocrinology at the Philadelphia College of Osteopathic Medicine in Philadelphia, Pa.
Address correspondence to Patrick J. Boyle, MD, Professor of Medicine, University of New Mexico, Albuquerque, NM 87131-0001. E-mail: pboyle{at}salud.unm.edu
Approximately two thirds of patients with type 2 diabetes mellitus (T2DM) are unable to reach the hemoglobin A1c target set by the American Diabetes Association (HbA1c <7.0%). Therefore, T2DM continues to be a major public health concern. Incretin mimetics and dipeptidyl peptidase IV inhibitors are medications that have the potential to improve patients' glycemic control, as well as to result in beneficial socioeconomic effects. Research suggests that significant benefits are to be gained from incretin mimetics and dipeptidyl peptidase IV inhibitors, either one used as monotherapy or used together as combination therapy. However, the benefits and risks of these agents need to be evaluated more thoroughly, with emphasis on such adverse effects as edema, hypoglycemia, and weight gain.
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Targets for Management of Type 2 Diabetes Mellitus |
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The National Health and Nutrition Examination Survey (NHANES) analyzed T2DM targets in two patient populations—one with 1215 patients studied from 1988 to 1994 and another with 372 patients studied from 1999 to 2000.1,2 After treatment with insulin, oral antidiabetic drugs, or diet, less than 45% of the combined patient population achieved the HbA1c target of less than 7%. The low-density cholesterol (LDL-C) targets of less than 100 mg/dL in both and women were achieved by about 36% of the patients, while the high-density lipoprotein (HDL-C) targets of 40 mg/dL in men and 55 mg/dL in women were reached by 30% of the patients. Triglyceride concentrations reaching the target of less than 150 mg/dL were achieved by about 65% of the patients. The blood pressure target of 130/80 mm Hg was achieved in about 40% of the population treated with blood pressure–lowering agents.1,2 Therefore, the NHANES study showed that many patients with T2DM have trouble achieving healthcare targets beyond just those associated with glycemic control.
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Pharmacologic Interventions |
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TopTargets for Management of...Pharmacologic InterventionsIncretin Mimetics Compared With...CommentReferences |
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2-agonists, such as clonidine, became available before
ß-blockers and -agonists and -antagonists in the 1970s.
Calcium channel blockers, angiotensin-converting enzyme inhibitors, and
angiotensin-receptor blockers began to appear in the 1980s and 1990s, later
followed by the renin inhibitors.
For T2DM, the development of new drugs remained relatively flat from the
1960s to the 1980s, with sulfonylureas being the main medication available to
patients. Since the 1990s, there has been an exponential rise in research and
development, with the resulting availability of several new agents for T2DM.
In the United States, the introduction of the biguanide compound metformin was
followed by -glucosidase inhibitors, thiazolidinediones, glinide
compounds, incretin mimetics (including glucagon-like peptide 1 [GLP-1]
agonists), amylin analogs, and, most recently, DPP-IV inhibitors.
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Targets for Managing Hyperglycemia
Healthy blood glucose levels are dependent on the dynamic processes of
hepatic production of glucose and skeletal muscle use of glucose. These
dynamic processes include the suppression by insulin of glucose production in
the liver, and the secretion of glucagon by the cells of the pancreas.
Thus, there are three potential targets in the management of hyperglycemia in
patients: excessive hepatic production of glucose, insufficient skeletal
muscle disposal of glucose, and excessive pancreatic production of glucagon.
Treatment strategies designed to improve these processes will result in
improvements in a patient's glycemic status.
Managing Glucose Production and Use
Data from the Diabetes Prevention Program were used by the US Department of
Health and Human Services to recommend that adults exercise for a minimum of
30 minutes per day. Such an exercise program will improve skeletal muscle
mass, the capacity for clearing glucose, and, ultimately, insulin
sensitivity.9-11
Insulin secretagogues (ie, releasers) include sulfonylureas, which directly
stimulate insulin secretion through sulfonylurea receptors on ß cells,
and repaglinide and nateglinide, which work through a somewhat different
mechanism.
The glitinides cause a similar closure of the potassium channel on the ß cell but not directly through the sulfonylurea receptor. The biguanide compound metformin is the only available medication that suppresses hepatic glucose production by inhibiting hepatic gluconeogenesis and glycogenolysis. The amino glucosidase inhibitors, though not widely used in the United States, have been much used in Europe. These drugs inhibit the hydrolysis of complex starch. When administered to the large intestine, they encourage carbohydrate fermentation by bacteria, resulting in flatus. The thiazolidinediones compounds pioglitazone and rosiglitazone predominantly increase glucose uptake by skeletal muscle. These agents all culminate in the lowering of glucose levels, but from different mechanisms of action.
Incretin Mimetics: Exenatide
The incretin mimetics are medications that mimic the action of incretins,
peptide hormones that originate in the gastrointestinal
tract.3-7
The two major incretins in humans are GLP-1 and glucose-dependent
insulinotropic peptide (GIP). Incretins are released during nutrient
absorption, augmenting insulin secretion.
Incretin mimetics also reduce postprandial glucagon secretion and delay gastric emptying time. As a result, patients using these medications can have improved postprandial glucose excursions and early satiety.3-7 The improved sense of satiety is most likely a separate effect induced by activation of GLP-1 receptors in the brain.5 Exenatide, a synthetic GLP-1 agonist and polypeptide originally isolated from the salivary secretions of the Gila monster, has approximately 53% homology to human GLP-1.12-14 Unlike natural incretins, however, exenatide is resistant to degradation by DPP-IV. Thus, it shows much promise for treating patients with T2DM.
Figure 1 displays results of three 30-week clinical trials that examined the effects of exenatide in patients with T2DM who were also using metformin (N = 336),12 sulfonylurea (N = 377),13 or metformin plus sulfonylurea (N = 733).14 Exenatide was given to patients 15 to 60 minutes before two large meals. Patients using metformin who were also treated with 10 µg of exenatide twice a day had a further reduction of HbA1c of approximately 0.8%, compared with patients using metformin and placebo (P < .001).12 The sulfonylurea-exenatide group13 and the metformin-sulfonylurea-exenatide group14 also had further reductions in their HbA1c levels of about 0.8% compared with their corresponding placebo groups (P < .001). The percentages of patients who completed the study using 10 µg of exenatide and who reached the target HbA1c level of less than 7.0% were the following: approximately 46% in the metformin-exenatide group, 41% in the sulfonylurea-exenatide group, and 34% in the metformin-sulfonylurea-exenatide group (Figure 2).12-14 The lesser reduction in the latter, combined group might be explained by the fact that T2DM was longer standing in those patients, thereby resulting in greater loss of endogenous insulin secretion.
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Blonde et al15 also demonstrated that the body mass index (BMI) of patients with T2DM predicts their degree of weight loss when using exenatide. Patients with the greatest BMI (>40) also had the greatest weight loss during the 82-week course of the study—approximately 8 kg.
Heine et al16 conducted a 26-week randomized controlled trial to compare glargine insulin (one daily dose to maintain fasting glucose levels) with exenatide (10 µg twice a day). Patients with suboptimally controlled T2DM and a mean baseline HbA1c level of 8.2% were randomly assigned to receive either glargine insulin (n = 260) or exenatide (n = 275). At week 26, the average dose of glargine insulin was 25 units per day, a relatively small dose of insulin for most patients with T2DM.
Heine et al16 found that the patients' average HbA1c levels fell to just above 7% in both groups (1.1% drop from the baseline). The body weight of patients using glargine insulin increased an average of 1.8 kg during the study, while that of patients using exenatide decreased an average of 2.3 kg. Thus, the study suggested that glargine insulin and exenatide produce similar benefits in HbA1c levels, but exenatide has the added benefit of weight loss. In addition, measurements of preprandial glycemic and postprandial glycemic excursions indicated a tendency for patients using exenatide to have reduced postprandial glycemic excursions.
The differences in adverse effects between glargine insulin and exenatide are striking. Heine et al16 found that nausea occurred in about 9% of patients using glargine insulin, while it occurred in 57% of patients using exenatide. Vomiting occurred in about 4% of patients using glargine insulin and 17% of patients using exenatide (P < .001). The hypoglycemia rate in both groups was comparable, with 6.3 events per patient-year in the glargine group and 7.3 events per patient-year in the group using exenatide. However, the occurrence of nocturnal hypoglycemia was slightly higher in the group using glargine.
Incretin Mimetics: Liraglutide
Liraglutide is a long-lasting incretin mimetic that is currently under
investigation.17,18
It is a receptor agonist like exenatide; it is an analog of GLP-1 that is
DPP-IV resistant. In a 12-week controlled trial by Madsbad et
al,17 193 patients
with T2DM were evenly randomly assigned to receive one of five dosages of
liraglutide (0.045 mg once a day to 0.75 mg once a day), the sulfonylurea
glimepiride, or placebo. Both liraglutide and glimepiride produced comparable
reductions in HbA1c and fasting glucose levels. However,
glimepiride use led to increases in body weight, while liraglutide led to
decreases in weight. The reduction in HbA1c level by liraglutide
was dosedependent, with the lowest dosage failing to lead to a decrease in
HbA1c level.
Dipeptidyl Peptidase IV Inhibitors
Glucagon-like peptide 1 is synthesized in the villi of the epithelium of
the small intestine. Immediately after synthesis, GLP-1 can be acted on by
DPP-IV. The DPP-IV inactivation process causes greater than 50% inactivation
of GLP-1 within 1 to 2 minutes—before the GLP-1 reaches general
circulation.19-23
Dipeptidyl peptidase IV inhibitors are drugs that block the action of this
degradation pathway. By blocking this action, DPP-IV inhibitors can lead to an
increase in endogenous GLP-1 concentration, benefiting patients with T2DM.
Several DPP-IV inhibitors are under
development.24-31
Table 1 presents the results of an 18-week trial by Raz et al24 in which 521 patients with T2DM were randomly assigned to receive monotherapy with one of two different dosages of the DPP-IV inhibitor sitagliptin (100 mg once a day or 200 mg once a day) or placebo. At week 18, the placebo-subtracted HbA1c reductions in patients taking sitagliptin were 0.6% in the group assigned to 100 mg once a day and 0.48% in the group assigned to 200 mg once a day (P<.001). Approximately 33% of the patients with T2DM achieved the HbA1c target of less than 7%. Patients with higher baseline HbA1c levels had greater HbA1c reductions with sitagliptin. If the patients' baseline HbA1c levels were less than 8%, the reductions of HbA1c were 0.44% in the group assigned to 100 mg once a day and 0.33% in the group assigned to 200 mg once a day. If the baseline HbA1c levels were greater than 9%, the reductions of HbA1c were 1.2% in the group assigned to 100 mg once a day and 1.04% in the group assigned to 200 mg once a day).
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Postprandial glucose levels in patients with T2DM taking sitagliptin for 18 weeks were reduced approximately 40 mg/dL in the group using 100 mg once a day and 50 mg/dL in the group using 200 mg once a day.24 The 2-hour postprandial glucose reduction in patients taking sitagliptin reached statistical significance compared with placebo (P < .001). This result was most likely caused by a reduction in postprandial hyperglucagonemia.
Research into using sitagliptin is influenced by current concepts regarding ß cells. The ß cells of the pancreas are believed to have a lifespan of approximately 7 years. Precursors to ß cells are stem cells. If these precursor cells fail to differentiate into new ß cells, T2DM may develop in patients at an age of approximately 30 years.24 Table 1 shows a reduction in the proinsulin-insulin ratio—a marker of insulin secretion and ß-cell function—in patients who received either dosage of sitagliptin for 18 weeks.24 In addition, the results of the homeostasis model assessment (HOMA) also indicated an increase in ß-cell function with both dosages of sitagliptin (Table 1).
Therefore, the 18-week study by Raz et al24 demonstrated significant benefits of sitagliptin in improving ß-cell function; HbA1c levels; postprandial glucose excursions; postprandial insulin levels; and the proinsulin-insulin ratio.
Charbonnel et al25 reported on 701 patients who were randomly assigned to receive either sitagliptin (100 mg once a day) or placebo in addition to their ongoing regimen of metformin. This 24-week add-on study showed that patients taking sitagliptin had an additional HbA1c decline of 0.65%, an additional fasting plasma glucose decline of about 25 mg/dL, and an additional 2-hour postprandial glucose reduction of about 50 mg/dL, compared with placebo (P < .001) (Table 2). The patients using sitagliptin also had reductions in their proinsulin-insulin ratio; increases in their C-peptide, fasting insulin, and postprandial insulin; and increases in their (ß)-cell function as indicated by the HOMA (Table 2).25
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In a 24-week trial reported by Rosenstock at al26, 30 mg to 45 mg of sitagliptin added to a regimen of pioglitazone led to a reduction in HbA1c of <0.7% in patients with inadequately controlled T2DM, compared with placebo. Approximately 45% of the patients using sitagliptin sustained an HbA1c level of less than 7% through the duration of study.
A second DPP-IV inhibitor that has been investigated is vildagliptin. A 12-week monotherapy study by Pratley et al27 compared patients with T2DM receiving 25 mg of vildagliptin twice a day (n = 70) with those receiving placebo (n = 28). The group receiving vildagliptin had a reduction in HbA1c of approximately 0.6% compared with the group receiving placebo (P < .001). The fasting glucose levels of the group using vildagliptin were also improved over those in the group using placebo.
According to Schweizer et al,28 drugnaïve patients with T2DM who received 1 year of treatment with 50 mg of vildagliptin twice a day (n = 526) and patients receiving metformin had a significant sustained decrease in HbA1c of about 1%, compared with patients receiving metformin (n = 254). The group using vildagliptin had a 1.0%-reduction in HbA1c compared with baseline (P< .001), and the group receiving metformin had a 1.4% decrease from baseline (P< .001).28
Rosenstock et al29 compared dosages of 50 mg of vildagliptin twice a day (n = 459) with 8 mg of rosiglitazone once a day (n = 238) in a 24-week trial of patients with T2DM. Both vildagliptin and rosiglitazone resulted in comparable reductions in HbA1c of more than 1% from baseline. Patients using rosiglitazone, however, had an average increase in body weight of 1.5 kg at the end of the study, while patients using vildagliptin had an average decrease in weight of 0.3 kg. Rosenstock et al29 noted that the loss in body weight with vildagliptin was not statistically significant. According to them, the gliptins will most likely remain weight-neutral medications with glucose-lowering properties, providing a probable advantage over existing thiazolidinedones.
Treatment of patients with T2DM with a vildagliptin-metformin combination (50 mg of vildagliptin once daily, 1500 mg-3000 mg of metformin once daily) was compared with a placebo-metformin combination in a 12-week open-label feasibility study and 40-week extension by Ahren et al.30 During the first 12 weeks, the group treated with the vildagliptin-metformin combination (n = 56) showed a reduction in HbA1c levels. This reduction continued throughout the extension. By contrast, the group using the placebo-metformin combination (n = 51) showed a sustained increase in HbA1c levels after week 4. This study provided an opportunity to assess and compare the durability of vildagliptin and metformin in patients. At the end of 1 year of treatment, the patients using vildagliptin with metformin had a decline of approximately 1.1% in their HbA1c levels compared with the patients using placebo with metformin (P < .001). The reduction in HbA1c compared with baseline was 0.6% in the group treated with the vildagliptin-metformin combination.
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Incretin Mimetics Compared With Dipeptidyl Peptidase IV Inhibitors |
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Comment |
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Footnotes |
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Presented in part by Dr Boyle at the 111th Annual American Osteopathic Association Convention and Scientific Seminar in Las Vegas, Nev, on October 16, 2006.
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References |
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2. Fan T, Koro CE, Fedder DO, Bowlin SJ. Ethnic disparities and trends in glycemic control among adults with type 2 diabetes in the U.S. from 1988 to 2002. Diabetes Care. 2006;29:1924-1925. Available at: http://care.diabetesjournals.org/cgi/content/full/29/8/1924. Accessed March 19, 2007.
3. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, et
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4. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940. Available at: http://care.diabetesjournals.org/cgi/reprint/26/10/2929. Accessed January 8, 2007.
5. Drucker DJ. Incretin-based therapies: a clinical need filled by
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6. Visboll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus [review]. Diabetologia. 2004;47:357-366. Epub 2004 Nov 24. Available at: http://www.springerlink.com/content/0qk4t7u90jgakth9/fulltext.html. Accessed January 9, 2007.
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12. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100. Available at: http://care.diabetesjournals.org/cgi/reprint/28/5/1092. Accessed February 28, 2007.
13. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-2635. Available at: http://care.diabetesjournals.org/cgi/content/full/27/11/2628. Accessed February 28, 2007.
14. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091. Available at: http://care.diabetesjournals.org/cgi/reprint/28/5/1083. Accessed February 28, 2007.
15. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab.2006; 8:436 -447.[Medline]
16. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; for the GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559-569. Available at: http://www.annals.org/cgi/reprint/143/8/559.pdf. Accessed February 28, 2007.
17. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR; for the NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27:1335-1342. Available at: http://care.diabetesjournals.org/cgi/content/full/27/6/1335. Accessed March 19, 2007.
18. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J; for the NN2211-1499 Study Group. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes. 2006;114:417 -423.[Medline]
19. Hansen L, Deacon C, Orskov C, Holst JJ. Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology. 1999;140:5356-5363. Available at: http://endo.endojournals.org/cgi/content/full/140/11/5356. Accessed March 19, 2007.
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23. Ahren B., Hughes TE. Inhibition of dipeptidyl peptidase-4 augments insulin secretin in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice. Endocrinology. 2005:146:2055-2059. Available at: http://endo.endojournals.org/cgi/reprint/146/4/2055. Accessed January 9, 2007.
24. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H; for the Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia.2006; 49:2564 -2571. Epub Sep 26, 2006.[Medline]
25. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin
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26. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Study Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-bline, placebo-controlled, parallel study group. Clin Ther.2006; 28:1556 -1568..[Medline]
27. Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D. Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes. Horm Metab Res.2006; 38:423 -428.[Medline]
28. Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1-year in drug-naïve patients with type 2 diabetes. Diabet Med. May 17, 2007 [Epub ahead of print].
29. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison
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30. Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2874-2880. Available at: http://care.diabetesjournals.org/cgi/reprint/27/12/2874. Accessed February 28, 2007.
31. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin to improve glycaemic control in type 2 diabetes. Diabetologia.2007; 50:1148 -1155. Epub Mar 27, 2007.[Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
P <.001 versus placebo. Abbreviations: BID, twice a day;
HbA1c, hemoglobin A1c. (Reprinted with permission of
the National Diabetes Education Initiative [NDEI]. Sources: DeFronzo RA,
Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide
(exendin-4) on glycemic control and weight over 30 weeks in metformin-treated
patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100; Buse
JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; for the Exenatide-113
Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control
over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.
Diabetes Care. 2004;27:2628-2635; Kendall DM, Riddle MC, Rosenstock J,
Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on
glycemic control over 30 weeks in patients with type 2 diabetes treated with
metformin and a sulfonylurea. Diabetes Care.
2005;28:1083-1091.)
