DPP-4 inhibitors into existing diabetes treatment protocols. Objectives. guidelines for diabetes prevention and. treatment are in place, over 40% of pa …
Focus on Diabetes
Incretin-based Therapies for Diabetes
New treatment options continue to emerge
by Eva Vivian, PharmD, BCPS, CDE, BC-ADM and Natalie Daniels
he prevalence of diabetes has increased over 50 since 19801 Diabetes mellitus now affects over 208 million Americans, with the vast majority having type 2 diabetes mellitus T2DM This increasing prevalence is accompanied by complications associated with diabetes such as heart disease, kidney failure, blindness and other chronic conditions The economic burden of this disease is tremendous, with an estimated 132 billion spent in 2002 in direct medical expenditures and indirect expenditures such as lost productivity1-2 The American Diabetes Association ADA recommends a goal HbA1c of less than 7 for the general population of patients with diabetes and a goal HbA1c of less than 6 in patients who may be
injectable drugs on the market In spite of the numerous therapeutic options available, long-term control of glycemia still remains problematic and treatment failure occurs4 This problem has fueled researchers to look more in depth at the underlying pathophysiology of T2DM One of the outcomes of this research was the discovery of
gut hormones called incretins and their role in glucose homeostasis This review discusses what is currently known about incretins, the clinical application of incretin-based therapies, and the potential role of incretin-based therapies in the management of T2DM
PATHOPHYSIOLOGY
Glucose homeostasis in a healthy individual is maintained by a feedback mechanism involving insulin and glucagon, hormones secreted by the pancreatic and -cells, respecGoal To address the practical issues and concerns of clinitively After a meal, cians considering the incorporation of GLP-1 analogues and -cells of the panDPP-4 inhibitors into existing diabetes treatment protocols creas detect a rise in Objectives 1 Discuss the natural progression of type 2 diaglucose levels and betes focusing on insulin resistance, insulin deficiency, and respond by secretother pathophysiologic changes; 2 Describe the acute and ing insulin Insulin chronic physiologic effects of the incretins GLP-1 and GIP on glucose homeostasis and islet cell health; and 3 Discuss the facilitates the utipotential benefits of incretin-based therapies and where they fit lization of glucose into the existing type 2 diabetes treatment paradigm
in skeletal muscle for energy Insulin also facilitates other at low risk for hypoglycemia3 Although anabolic processes such as glycogenesis, guidelines for diabetes prevention and storage of glucose in the form of glycogen treatment are in place, over 40 of pain the liver, and lipogenesis, the convertients being treated for T2DM remain sion of glucose to fats and triglycerides in uncontrolled3 adipose tissue5 In the presence of fasting Prior to 1995, the only therapeutic and low blood insulin concentrations, gluoptions for the management of type 2 cagon stimulates glycogen breakdown by diabetes were the sulfonylureas and inthe liver glycogenolysis and an increase sulin There are now six classes of oral in free fatty acids into ketone bodies liantidiabetic agents, eight insulins, five polysis to maintain glucose homeostasis premixed insulins, and two non-insulin Therefore, glucagon ensures that glucose10 JPSW July/August 2007
dependent tissues such as the brain have an adequate fuel supply during the fasting state6 During the early stages of T2DM, the ability of insulin to facilitate the diffusion of glucose into the cell is impaired Defects in insulin receptor function, insulin
receptor-signal transduction pathways, glucose transport and phosphorylation, glycogen synthesis and glucose oxidation contribute to muscle insulin resistance7 The pancreas compensates for this deficiency by secreting larger amounts of insulin Patients remain euglycemic until the pancreatic beta-cells are no longer able to compensate for the insulin resistance A decrease in incremental bolus insulin secretion, which controls meal-related glucose excursions often termed as first phase response, occurs in the early stages of diabetes, resulting in postprandial hyperglycemia As the disease progresses with further loss of beta-cell function, low concentrations of insulin are unable to suppress hepatic glucose production and preprandial hyperglycemia results7-8 Until recently, insulin resistance of muscle tissue and impaired hepatic glycogen production were believed to be the primary cause of the excessive postprandial increase in the plasma glucose level
THE INCRETIN EFFECT
Beta cell secretory response is greater after food ingestion or when glucose is administered orally through the gastrointestinal tract than after intravenous IV glucose infusion Figure 1 This difference, termed
incretin effect, was used to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion The incretin effect implies that food ingestion causes the gut to release substances that enhance insulin secretion beyond the release caused by the
rise in glucose secondary to absorption of digested nutrients Studies in humans and animals have shown that the incretin hormones glucagon-like peptide-1 GLP1 and glucose-dependent insulinotropic peptide GIP account for almost all of the incretin effect, stimulating insulin release when glucose levels are elevated Studies have shown that the incretin effect accounts for approximately 60 of the total postprandial insulin response Although the incretin effect is detectable in both healthy subjects and in those with diabetes, it is abnormal in those with diabetes The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone
PHYSIOLOGY OF INCRETIN HORMONES
beneficial effects on -cell mass and survival in humans18-20 The incretin effect is responsible
for over 50 of the insulin secreted after a meal in a non-diabetic person However, this effect is diminished in patients with type 2 diabetes due to impaired response
Figure 1
to GIP and depressed levels of GLP Patients with T2DM have normal or slightly depressed postprandial GIP levels, but impaired insulin secretory response to GIP In contrast, postprandial levels of GLP-1 are decreased following a meal in patients with T2DM, but the insulin
After food is ingested, GIP is released from K cells in the proximal gut duodenum and GLP-1 is released from L cells in the distal gut ileum and colon Under normal circumstances, dipeptidyl-peptidase 4 DPP-4 rapidly degrades these incretins to their inactive forms after their release into the circulation As a result, the plasma half life of GIP and GLP is less than five minutes GLP-1 and GIP stimulate insulin response in pancreatic beta-cells GLP-1 but not GIP also suppresses glucagon production in pancreatic alpha-cells when the glucose level is elevated The subsequent increase in glucose uptake in muscles and reduced glucose output from the liver help maintain glucose homeostasis Figure 2 Thus, the incretins GLP-1 and GIP are important
glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner11-12 Most patients with type 2 diabetes have lost over 40 of their -cell function at the time of diagnosis This progressive decline in -cell function results in further loss of insulin secretory capacity13-14 GIP and GLP have been shown to stimulate pancreatic islet -cell neogenesis, proliferation, and survival in animal models15-17 Inhibition of DPP-4, leading to increased levels of GLP-1 and GIP, might produce
With kind permisson of Springer Science and Business Media Nauck J et al Reduced incretin effect in Type 2 non-insulin-dependent diabetes J Diabetologia 1986;29:50 fig 4
Figure 2
Reprinted with permission from J Med Chem Copyright 2004 American Chemical Society
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DOSING AND ADMINISTRATION CONSIDERATIONS FOR INCRETIN THERAPIES
Exenatide GLP-1 Analogue
Status: FDA approved April 2005 Route of administration and effective dose: Subcutaneous SC 5 mcg twice a day administered before morning and evening meals May increase to 10 mcg twice a day do not give after meals Adverse effects: Hypoglycemia when
combined with sulfonylureas Nausea common; vomiting, diarrhea, dizziness, headache, jitteriness Special considerations: Exenatide may slow the rate and extent of absorption of other drugs due to its gastric emptying effect, especially contraceptives and antibiotics Therefore other drugs should be taken one hour before exenatide dose
Liraglutide GLP-1 Analogue
Status: Phase III study commenced February 2006 Route of administration and effective dose: SC: 06-075 mg once daily Adverse effects: Hypoglycemia uncommon; nausea common
Vildagliptin DPP-4 inhibitor
Status: Pending FDA approval 2007 Route of administration and effective dose: Oral: 100 mg once daily Adverse Effects: Hypoglycemia when used in combination with sulfonylurea, nausea, vomiting
Sitagliptin DPP-4 inhibitor
Status: FDA approved October 2006 Route of administration and effective dose: Oral: 100 mg once daily; 50 mg once daily CrCl 30 to 50 mL/min; 25 mg once daily CrCl 30 mL/min Adverse effects: Hypoglycemia rare except when used in combination with sulfonylurea; nausea, diarrhea Special considerations: Lower doses of sitagliptin are recommended in moderate and serve renal insufficiency
secretory response to GLP-1
is preserved Vilsboll and colleagues compared the effects of GIP and GLP-1 in patients with T2DM20 Insulin concentrations, reflected by an increase in circulating C-peptide levels, increased significantly in patients who received GLP-1 infusion, whereas C-peptide levels in patients receiving GIP were similar to the placebo arm Exogenous administration of GIP does not increase insulin secretion, but restoration of GLP-1 has some clinical benefit It is this reason that GLP-1 has been the focus of clinical research20
THE GLP-1 ANALOGUES
GLP-1 mimetics: exenatide, liraglutide Analogues of GLP-1 or incretin mimetics, serve as agonists at the GLP-1 receptor site thus mimicking the action of GLP-1 The two most extensively studied drugs in this class are exenatide and liraglutide
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Exenatide is a synthetic form of the 39 amino acid peptide exendin-4 Exenatide is highly resistant to the proteolytic effects of DPP-4, has a prolonged half life and a higher in vivo potency than endogenous GLP-1 Exenatide is FDA-approved as a twicedaily SC injection before meals in patients who are receiving metformin, a sulfonylurea SU, or both, and who have not achieved their targets
for glycemic control In six-month phase III trials in patients with type 2 diabetes, the addition of exenatide to metformin and/or SU therapy reduced HbA1c by approximately 10 The improvement in glycemic control was accompanied by a significant amount of weight loss, ranging from 09 kg when exenatide was added to metformin/SU to 25 kg when it was added to metformin21-23 In the continuation of a trial in a small group of overweight patients receiv-
ing metformin, exenatide was associated with a sustained reduction in HbA1c and continued weight loss 53 kg over 82 weeks24 In a comparison of exenatide with a prolonged-duration insulin analog insulin glargine, both treatments reduced HbA1c levels by 11 Additionally, exenatide therapy was associated with a 23 kg weight loss compared with a weight gain of 18 kg with insulin glargine25 Although severe hypoglycemia has been infrequently reported during exenatide therapy, hypoglycemia was reported in 1436 of patients receiving exenatide plus SU or metformin plus SU; accordingly, a reduction in SU dose is recommended when these agents are combined26 In addition to the need for twicedaily SC injection, the use of exenatide may be limited by a
high frequency of GI symptoms, principally nausea and vomiting As exenatide reduces the rate of gastric emptying, it could reduce absorption of other drugs Patients should be advised to take other medications one hour prior to exenatide administration A long-acting exenatide formulation is in development and may be effective when injected only once-weekly In all likelihood, such a formulation would markedly improve patient acceptance Another GLP-1 analogue-agonist currently under investigation by the FDA is liraglutide Liraglutide is an acylated GLP-1 mimetic that has a prolonged halflife 12-13 hours for administration as a once-daily SC injection In a 14-week study in obese patients, once-daily liraglutide reduced HbA1c concentrations at doses of 065, 125, and 19 mg 17 reduction in HbA1c with the 19-mg dose Improved blood glucose levels were associated with dose-dependent reductions in body weight a reduction of 30 kg was observed with the highest dose of liraglutide compared with a 12 kg reduction with placebo27 GI symptoms were common, but appeared to decrease with longer durations of therapy
THE DPP-4 INHIBITORS
DPP-4 inhibitors: sitagliptin, vildagliptin Sitagliptin was the
first drug in this class to be approved for use in the United States It is indicated for patients with T2DM as monotherapy or as add-on
therapy to metformin or thiazolidinedones TZDs in patients who have inadequate glycemic control using these or other agents Another agent in this class, vildagliptin, is expected to be approved in 2007 Both of these DPP-4 inhibitors increase levels of endogenous GLP-1, suppress glucagon secretion, reduce fasting and postprandial glucose levels and reduce HbA1c as monotherapy or as an addition to other oral drugs metformin, SU, and TZDs In addition, neither sitagliptin nor vildagliptin causes weight gain or poses a substantial risk of hypoglycemia Both agents are also devoid of side effects such as peripheral edema or prominent GI disturbances28-34 In clinical trials, HbA1c reductions have ranged from 0511 in monotherapy when these agents have been administered orally at therapeutic doses once or twice daily Greater reductions have been observed in patients with higher baseline HbA1c concentrations35 A pooled analysis of 1301 drug-naïve patients receiving vildagliptin 100 mg/day showed a reduction in HbA1c of 11 overall, 13 in patients with a
baseline HbA1c 80, and 17 in subjects with a baseline HbA1c 9035 Modeling studies have indicated that these agents improve -cell function36-37 In a 52-week meal-test study with vildagliptin, improved -cell function was seen at 12 weeks in patients who had vildagliptin added to metformin compared with metformin alone; this improvement was maintained over 52 weeks36 Postmeal insulin sensitivity was also improved in patients receiving the DPP-4 inhibitor compared with metformin alone, suggesting that DPP-4 inhibition may not only improve -cell function, but also reduce insulin resistance The overall frequency of hypoglycemia with the currently approved 100-mg dose of sitagliptin was 12 compared with 09 with placebo in controlled trials33 Hypoglycemia in vildagliptin-treated patients has been mild and infrequent, with rates similar to those encountered with rosiglitazone one event in each group over six months28or metformin 1 of patients over one year33 The DPP-4 inhibitors stimulate insulin secretion in a dose-dependent manner, thus minimizing hypoglycemia and resultant weight g 
ain
As already mentioned, the DPP-4 inhibitors generally appear to be weight neutral,28,35 although some
reduction in body weight has been observed in comparative studies For example, vildagliptin produced a 03 kg reduction in weight compared with a 16 kg increase with rosiglitazone35 Among obese patients, vildagliptin was associated with a 11 kg decrease and rosiglitazone with a 17 kg increase
ROLE OF GLP-1 ANALOGUES AND DPP-4 INHIBITORS
apy Exenatide and sitagliptin have not been evaluated in combination with insulin, but may be rational choices, pending study results Use of exenatide or a DPP-4 inhibitor in combination with other oral antidiabetic agents may offer benefits by helping to address unmet needs in T2DM pathophysiology
CONCLUSION
The ADA and the European Association for the Study of Diabetes38 recommend early intervention with metformin in combination with lifestyle changes medical nutrition therapy and physical activity with close monitoring to ensure that the HbA1c does not rise above 7 in any patient Combination therapy with a sulfonylurea, thiazolidinedione or insulin as a means of achieving and maintaining recommended levels of glycemic control ie, HbA1c 7 for most patients is necessary to prevent lifetime risk of serious complications associated with prolonged
hyperglycemia Overall, the findings with the GLP1 analogues are promising in terms of their potential utility in overweight or obese patients with T2DM The GLP-1 analogues have shown clinical efficacy in reducing glucagon secretion and postprandial hyperglycemia in patients with type 2 diabetes They offer benefits such as increased satiety and weight loss when used in combination with existing oral therapies If experience in clinical practice substantiates the benefits suggested in the clinical trial data, these agents should provide an exciting new option for obese patients with type 2 diabetes Although the DPP-4 inhibitors do not appear to produce the consistently significant reduction in body weight observed with GLP-1 mimetics, their weight neutrality, together with the absence of a need for injection, absence of significant adverse GI effects and low risk for hypoglycemia are attractive features for obese and non-obese patients alike A trial of exenatide or sitagliptin before initiating insulin therapy may be useful in patients who fail to obtain glycemic control with antidiabetic combination ther-
Additional studies will identify the role of GLP-1 analogues and DPP-4
inhibitors in the management of type 2 diabetes mellitus While they do not lower blood glucose levels to a greater extent than sulfonylureas, metformin, or thiazolidinedones, they offer some advantages, including a low risk of hypoglycemia and possible beta-cell neogenesis
Eva Vivian is a clinical associate professor at the UW School of Pharmacy Natalie Daniels is a fourth-year PharmD student at the UW School of Pharmacy
REFERENCES 1 Trends in the prevalence and incidence of self-reported diabetes mellitus-United States, 1980-1994 Morb Mortal Wky Rep 1997; 46:1014-1018 2 Hogan P, Dall T, Nikolow P Economic costs of diabetes in the US in 2002 Diabetes Care 2003; 26:917-932 3 American Diabetes Association Standards of medical care in diabetes-2007 Diabetes Care 2007; 30suppl 1:S4-41 4 Saaddine JB, Cadwell B, Gregg EW, et al Improvements in diabetes processes of care and intermediate outcomes: United States, 1988-2002 Ann Intern Med 2006;144:465-474 5 Reaven GM The role of insulin resistance in human disease Diabetes 1998; 37:15951607 6 Ward WK, Beard JC, Porte D Clinical aspects of islet B cell function in non-insulin dependent diabetes mellitus Diabetes Metab Rev 1986; 2:297313 7
Leahy JL Natural history of B-cell dysfunction in NIDDM Diabetes Care 1991; 13:9921010 8 Luz L, DeFronzo RA Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans Am J Physiol 1989; 257:E241E246 9 Nauck MA, Homberger E, Siegel EG, et al Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses J Clin Endocrinol Metab 1986; 63:492-498
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10 Gallwitz B Glucagon-like peptide-1 based therapies for the treatment of type 2 diabetes mellitus Treat Endocrinol 2005; 4:361-370 11 Druck DJ The biology of incretin hormones Cell Metab 2006; 3:153-165 12 Gallwitz B Glucagon-like peptide-1 based therapies for the treatment of type 2 diabetes mellitus Treat Endocrinol 2005; 4:361-370 13 Ramio-Halsted BA, Edelman SV The natural history of type 2 diabetes Implications for clinical practice Prim Care 1999; 26:771-789 14 Kahn SE The relative contributions of insulin
resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes Diabetologia 2003; 46:3-19 15 Gomis R, Novials A, Coves MJ, et al Suppression by insulin treatment of glucose induced inhibition of insulin release in noninsulin dependent diabetics Diabetes Res Clin Pract 1989; 6:191-198 16 Nauck MA, Bartels E, Orskow C, et al Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon like peptide-1-7-36 amide infused at near physiological insulinotropic hormone and glucose concentrations J Clin Endocrinol Metab 1993; 76:912-917 17 Nauck M, Schmidt WE, Ebert R, et al Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8 J Clin Endocrinol Metab 1989; 69:654-662 18 Mari A, Sallas WM, He YL, et al Vildagliptin, a dipeptidyl peptidase IV inhibitor, improves model assessed beta cell function in patients with type 2 diabetes J Clin Endocrinol Metab 2005; 90:4888-4894 19 Ahren B, Pacini G, Foley JE, Schweizer A Improved meal related beta cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in
metformin-treated patients with type 2 diabetes over 1 year Diabetes Care 2005; 28:1936-1940 20 Vilsboll, Krarup T, Madsbad S, Holst JJ Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients Diabetologia 2002; 45:1111-1119
21 Buse JB, Henry RR, Han J, et al; for the Exenatide-113 Clinical Study Group Effects of exenatide exendin-4 on glycemic control and weight over 30 weeks in sulfonylurea-treated patients with type 2 diabetes Diabetes Care 2004; 27:26282635 22 DeFronzo RA, Ratner RE, Han J, et al 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 23 Kendall DM, Riddle MS, Rosenstock J, 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 24 Ratner RE, Maggs D, Nielsen LL, et al Long term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus Diabetes Obes Metab 2006; 4:419-428 25 Heine RJ, Van Gaal LF,
Johns D, et al; 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 26 Byetta [package insert] San Diego, CA; Amylin Pharmaceuticals, Inc, 2006 27 Vilsboll T, Zdravkovic M, Le-Thi T, et al Liraglutide significantly improves glycemic control, and lowers body weight without risk of either major or minor hypoglycemic episodes in subject with type 2 diabetes [abstract] Diabetes 2006; 55suppl 1:A462, Abstract A27A28, Abstract 115-OR 28 Aschner P, Kipnes M, Lunceford J, et al Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes Diabetes Care 2006; 29:2632-2637 29 Dejager S, Razac S, Foley JE, Schweizer A Vildagliptin in drug-naïve patients with type 2 diabetes: a 24-week, doubleblind, randomized, placebo-controlled, multiple-dose study Horm Metab Res In press 30 Dejager S, Lebeaut A, Couturier A, Schweizer A Sustained reduction in HbA1c during one-year treatment with vildagliptin in patients with type 2 diabetes T2DM [abstract]
Diabetes 2006; 55suppl 1:A29, Abstract 120-OR 31 Bosi E, Camisasca RP,
Collober C, et al Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin Diabetes Care Epub 2007 Feb 2 32 Charbonnel B, Karasik A, Liu J, et al Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone Diabetes Care 2006; 29:2638-2643 33 Rosenstock J, Baron MA, Dejager S, et al Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial Diabetes Care 2007; 30:217-223 34 Rosenstock J, Brazg R, Andryuk PJ, et al 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-blind, placebocontrolled, parallel-group study Clinical Therapeutics 2006; 28:1556-1568 35 Barnett A DPP-4 inhibitors and their potential role in the management of type 2 diabetes Int J Clin Pract 2006; 60:1454-1470 36 Ahrén B, Pacini G, Foley J, Schweizer A Improved mealrelated beta-cell function and insulin sensitivity by
the dipetidyl peptidase IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year Diabetes Care 2005; 28:1936-1940 37 Mari A, Sallas M, He YL, et al Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes J Clin Endocrinol Metab 2005; 90:4888-4894 38 Nathan DM, Buse JB, Davidson MB, et al Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care 2006; 29:1963-1972
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SELF ASSESSMENT QUESTIONS
Incretin-based Therapies for Diabetes
COMPLETE ARTICLE AND CE EXAM AVAILABLE ONLINE WWWPSWIORG
1 The incretin effect is defined as: a The difference in insulin response to oral and intravenous glucose loads b The difference in blood glucose levels with different glucose loads c The amount of insulin produced as a result of incretin release d None of the above 2
The incretin GLP-1 has been shown to promote the following in animal and human research: a Increased glucose-dependent insulin secretion b Increased satiety and decreased food intake c Decreased glucagon secretion d Delayed gastric emptying e All of the above 3 The incretin GIP has been shown to promote the following in animal and human research: a Increased glucose-dependent insulin secretion b Decreased glucagon secretion c Increased glucose uptake in muscle cells d Facilitates glycogenesis in the liver 4 Individuals with type 2 diabetes mellitus are often characterized by: a Elevated glucagon levels b Increased insulin resistance c Insulin deficiency d GLP-1 deficiency e All of the above are correct 5 Which of the following is NOT an important hormone in maintaining glucose homeostasis? a Insulin d Glucagon b GIP e All of the above are correct c Norepinephrine 6 Which of the following statements about GLP-1 is TRUE? a GLP-1 levels are normal in patients with type 2 diabetes b GLP-1 action is defective in patients with type 2 diabetes c GLP-1 is secreted by the K cells in the upper gut d GLP-1 actions regulate insulin in a glucose-dependent manner 7 A 40-year-old woman with a
past medical history of type 2 diabetes fails to obtain an HbA1c of less than 7 despite adherence to treatment which consists of metformin 1000 mg once a twice a day and glipizide 10 mg twice a day
Which of the following is the most appropriate choice for this patient? a Start exenatide 5 mcg twice a day and continue metformin 1000 mg twice a day and glipizide 10 mg twice a day b Start exenatide 10 mcg twice a day and continue metformin 1000 mg twice a day and glipizide 10 mg twice a day c Start exenatide 5 mcg twice a day, continue metformin 1000 mg twice a day and decrease glipizide dose to 5 mg twice a day d Start exenatide 5 mcg twice a day and continue metformin 1000 mg twice a day and discontinue glipizide 10 mg twice a day e Start exenatide 10 mcg twice a day and discontinue metformin 1000 mg twice a day and glipizide 10 mg twice a day 8 A 29-year-old woman with type 2 diabetes is currently receiving exenatide 10 mcg twice a day before meals and metformin 1000 mg twice a day Her doctor prescribes an oral contraceptive during her visit How would you counsel this patient? a Take the oral contraceptive at the same time each day along with the exenatide and metformin b Take the
oral contraceptive one hour before giving the exenatide injection c Do not take oral contraceptive while taking exenatide 9 The addition of sitagliptin may be beneficial in which of the following scenarios: a A 45-year-old male recently diagnosed with type 2 diabetes uncontrolled on diet management b A 28-year-old male with uncontrolled type 1 diabetes currently on insulin therapy and experiencing significant weight gain c A 16-year-old female recently diagnosed with type 1 diabetes uncontrolled on insulin therapy 10 Which of the following agents was associated with a sustained reduction in HbA1c and weight loss 53 kg over 82 weeks in a clinical trial? a Exenatide c Vildagliptin b Sitagliptin d All of the above
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