1. Advancing Our Understanding of Glycemic Control: Refocusing on Glucose Regulation in Type 2 Diabetes
Joe L Reese, M.D.
Advancing Our Understanding of Glycemic Control: Refocusing on Glucose Regulation in Type 2 Diabetes

2. Learning Objectives
Describe the multiple factors involved in the pathogenesis of type 2 diabetes and explain their contribution over time.
Explain the role of incretin hormones in maintaining normal glucose homeostasis.
Discuss clinical challenges and guideline recommendations for getting patients to goal.
Describe the efficacy, safety/tolerability profile, and place in therapy for sitagliptin in patients with type 2 diabetes.
Learning Objectives
Welcome to this presentation, entitled Advancing Our Understanding of Glycemic Control: Refocusing on Glucose Regulation in Type 2 Diabetes.
During this slide presentation, we will complete the following 4 learning objectives:
Describe the multiple factors involved in the pathogenesis of type 2 diabetes and explain their contribution over time.
Explain the role of incretin hormones in maintaining normal glucose homeostasis.
Discuss clinical challenges and guideline recommendations for getting patients to goal.
Describe the efficacy, safety/tolerability profile, and place in therapy for sitagliptin in patients with type 2 diabetes.

3. Type 2 Diabetes: Refocusing Priorities
Diabetes: a multifactorial disease
Impairment of insulin secretion coupled with unsuppressed glucagon release
Impairment of insulin action
(ie, insulin resistance)
Pancreatic islet- (alpha- and beta-) cell dysfunction: a central factor in the development of hyperglycemia and progression of type 2 diabetes
Major defect in insulin resistance
already present at onset of diabetes
Type 2 Diabetes: Refocusing Priorities
Type 2 diabetes is a multifactorial disease that affects several feedback mechanisms involving insulin and glucagon, which affect the regulation of glucose homeostasis.1,2
In the normal physiologic state, pancreatic beta cells normally increase insulin secretion to compensate for insulin resistance. However, in patients with type 2 diabetes, impaired beta-cell function is associated with insufficient insulin secretion, leading to the development of hyperglycemia.1
By the time diabetes is diagnosed, beta-cell function has already declined considerably, and it continues to decline over time.1
Pancreatic alpha-cell dysfunction contributes an excessive release of glucagon, leading to hepatic glucose overproduction.1
With impaired insulin secretion, an imbalance between insulin and glucagon can develop.1,2 With decreased insulin secretion, glucose uptake by muscle and adipose tissue is decreased.2 Unsuppressed glucagon levels lead to hepatic glucose overproduction and an increase in blood glucose.1
Purpose
To examine the multifactorial aspects of type 2 diabetes.
Takeaway
Insulin resistance is present when diabetes is diagnosed. Beta-cell dysfunction and alpha-cell dysfunction (ie, elevated hepatic glucose production) are also critical factors in the development of hyperglycemia.
Progressively reduced insulin secretion from beta cells, contributing to
hepatic glucose overproduction
Excess glucagon release from alpha cells, leading to hepatic glucose overproduction
1. Del Prato S et al. Horm Metab Res ;36:775–781.
2. Porte D et al. Clin Invest Med. 1995;18:247–254.
References
1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res ;36:775–781.
2. Porte D Jr, Kahn SE. The key role of islet dysfunction of type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.

4. Manifestations of Beta-Cell Dysfunction in Type 2 Diabetes Mellitus
Abnormal pulsatile insulin response1
Increased proinsulin to insulin ratio1
Beta-Cell Dysfunction
Decreased beta-cell responsiveness to glucose2,3
Decreased insulin production4
Decreased insulin content
Decreased insulin granule density
Manifestations of Beta-Cell Dysfunction in Type 2 Diabetes Mellitus
Type 2 diabetes is characterized by progressive deterioriation in beta-cell function.1 A loss in beta-cell function manifests itself by (1) abnormal pulsatile insulin response,1 (2) decreased beta-cell responsiveness to glucose,2,3 (3) an increased proinsulin to insulin ratio,1 and (4) decreased insulin production.4
The secretion of insulin normally occurs in pulses and oscillating patterns. In type 2 diabetes, the pulsatile nature of insulin release is disrupted.1
In type 2 diabetes, the rate of proinsulin conversion to insulin is decreased, resulting in higher proinsulin levels. The higher proinsulin to insulin ratio is directly proportional to the degree of hyperglycemia and is considered a qualitative marker of beta-cell function.1
Insufficient insulin secretion from beta cells contributes to an inability to maintain normal glycemia in fasting or postprandial states, leading to hyperglycemia. With disease progression, beta-cell function deteriorates and insulin secretion decreases, leading to an increase in fasting glucose and hepatic glucose overproduction.1,2,4
Purpose
To examine beta-cell dysfunction as an underlying factor contributing to the pathophysiology of type 2 diabetes.
Takeaway
Beta-cell dysfunction is characterized by altered insulin response, decreased beta-cell responsiveness to glucose, increased proinsulin to insulin ratio, and decreased insulin production.
1. Buchanan TA. Clin Ther. 2003;25:B32–-B46.
2. Buse JB et al. Williams Textbook of Endocrinology. 2003:1427–1483.
3. Ward WK et al. J Clin Invest. 1984;76:1318–1328.
4. Marchetti P et al. J Clin Endocrinol Metab. 2004;89:5535–5541.
References
1. Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther. 2003;25:B32–B46.
2. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; :1427–1483.
3. Ward WK et al. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984;76:1318–1328.
4. Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab ;89:5535–5541.

5. Over a 10-year Study, Beta-Cell Function Worsened and Insulin Resistance Remained Relatively Constant
Belfast Diet Study
Beta-Cell Function
Insulin Sensitivity 80 60 60 40
HOMA % β
HOMA % S 40 20
Over a 10-Year Study, Beta-Cell Function Worsened and Insulin Resistance Remained Relatively Constant
In the Belfast Diet Study, a cohort of patients aged 40 to 69 years (N=432) with newly diagnosed type 2 diabetes was monitored for 10 years to assess the effect of active dietary management on type 2 diabetes. Drug therapy (insulin, tolbutamide, or metformin) was instituted on the basis of weight and blood glucose according to well-defined and uniform criteria. This trial design provided an opportunity to assess the natural history and progression of type 2 diabetes. Ongoing indexes of beta-cell function and insulin sensitivity were based on assessments of fasting glucose and insulin levels from fasting blood samples taken every 3 months over the first 6 years of the study. Beta-cell function and insulin sensitivity were assessed using homeostasis model assessment (HOMA) analysis of fasting plasma glucose (FPG) and insulin concentrations. Beta-cell function and insulin sensitivity were expressed as percentages of values in a lean, young, nondiabetic reference population.1
Patients continuing on diet therapy alone for the first 10 years after diagnosis experienced a small, continuous increase in FPG, a small, continuous decrease in beta-cell function, and no change in obesity or insulin sensitivity. Failure of diet therapy within the first 10 years was associated with higher rates of glucose increase and beta-cell function decrease. Beta-cell function during the first 6 years of follow-up closely mirrored the increase in FPG. There was no difference in insulin sensitivity in any group at months and no change during the further course of diet therapy.1
The 2 graphs on the slide show data for the 67 patients who required additional pharmacotherapy with either oral antihyperglycemic therapy or insulin during years 5 to 7. These data demonstrate the greater contribution of progressive beta-cell dysfunction versus insulin sensitivity to disease progression.1
Beta-cell function was less than 50% at diagnosis and declined continuously thereafter; however, no change in mean insulin sensitivity was observed.1 20
Purpose
To demonstrate the relationship between between the progression of type 2 diabetes and 2 core pathophysiologies.
Takeaway
The progression of type 2 diabetes is more closely associated with a continuous decline in beta-cell function than with a worsening of insulin resistance. 2 4 6 2 4 6
Years From Diagnosis
N=432
%β=measure of beta-cell function; %S=measure of insulin sensitivity.
Levy J et al. Diabet Med. 1998;15:290–296. Permission requested.
Reference
1. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study Diabet Med. 1998; 15:290–296.

6. Alpha-Cell Dysfunction Contributes to Excess Hepatic Glucose Production
Dysregulation of glucagon secretion during fasting
Impaired suppression of glucagon secretion after a meal
Alpha-Cell Dysfunction Contributes to Excess Hepatic Glucose Production
Alpha-cell dysfunction is associated with an inappropriate response to glucose, an increase in glucagon release in the fasting state, and impaired suppression of glucagon secretion after a meal.1 The impaired suppression of glucagon release by alpha cells in response to elevated glucose can result in hepatic glucose overproduction.
This dysregulation of glucagon release contributes to the fasting and postprandial hyperglycemia observed in type 2 diabetes.2,3
Purpose To examine the role of alpha-cell dysfunction in the pathophysiology of type 2 diabetes.
Takeaway In type 2 diabetes, alpha-cell dysfunction is associated with dysregulation of glucagon release, contributing to hyperglycemia in the fasting and fed states.
Fasting and postprandial hyperglycemia in type 2 diabetes
1. Del Prato S et al. Horm Metab Res. 2004;36:775– Clark A et al. Diabetes Res. 1988;9:151–159.
3. Butler PC et al. Diabetes. 1991;40:73–81.
References
1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781.
2. Clark A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 1988;9:151–159.
3. Butler PC, Rizza RA. Contribution to postprandial hyperglycemia and effect on initial splanchnic glucose clearance of hepatic glucose cycling in glucose-intolerant or NIDDM patients. Diabetes. 1991;40:73–81.

7. Fasting and Postprandial Hepatic Glucose Output in Type 2 Diabetes
Meal 20
Subjects Without
Diabetes (n=12) 18 16
Subjects With
Diabetes (n=18) 14
Endogenous Glucose
Production, µmol/min/kg 12 10 8
Fasting and Postprandial Hepatic Glucose Output in Type 2 Diabetes
In this study, 18 subjects with type 2 diabetes were evaluated. Subjects were instructed to arrive a day early, not to exercise on the day before the study, and to follow a balanced diet containing at least 200 g of carbohydrate for the 3 prior days. On the day of admission, subjects were given a balanced dinner and were told to fast overnight. A 12-hour urine collection was made for measurement of glucose and urea nitrogen levels. At 8:30 AM, subjects ingested a standardized liquid meal within 5 minutes and postprandial measurements of endogenous glucose production were performed for 5 hours.1
This figure shows the endogenous glucose production during basal conditions and for 300 minutes after a meal. The defect of suppression of endogenous glucose production in patients with type 2 diabetes was especially apparent during the first 2 hours after the meal was ingested.1
In subjects without type 2 diabetes, ingested glucose suppresses endogenous glucose production. This study shows that, in contrast, subjects with type 2 diabetes have a blunted suppression of endogenous glucose production and reduced clearance of ingested glucose by insulin-insensitive tissues. These in turn contribute to hyperglycemia.1 6
Purpose To examine postprandial glucose (PPG) utilization in type 2 diabetes.
Takeaway Type 2 diabetes is characterized by several abnormalities of the metabolism of postprandial glucose that contribute to hyperglycemia. 4 2
–30 30 60 90
120
150
180
210
240
270
300
Time, min
Kelley D et al. Metabolism. 1994;43:1549–1557. Permission requested.
Reference
1. Kelley D, Mokan M, Veneman T. Impaired postprandial glucose utilization in non-insulin-dependent diabetes mellitus. Metabolism. 1994;43:1549–1557.

8. Glucoregulatory Role of Key Incretin Hormones
GLP-1
GIP
Is released from L cells in ileum and colon1,2
Is released from K cells in duodenum1,2
Stimulates insulin response from beta cells in a glucose-dependent manner1
Stimulates insulin response from beta cells in a glucose-dependent manner1
Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1
Does not affect gastric emptying2
Has no significant effects on satiety or body weight2
Glucoregulatory Role of Key Incretin Hormones
GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are incretin hormones and have key roles in glucose homeostasis.
GLP-1 is released from L cells in the distal gut (ileum and colon), and GIP is released from K cells in the proximal gut (duodenum).1,2
In a glucose-dependent manner, GLP-1 stimulates insulin response from beta cells1 and inhibits glucagon secretion from alpha cells. GLP-1 also inhibits gastric emptying1,2 and reduces food intake and body weight.2
Similar to GLP-1, GIP stimulates insulin response from beta cells in a glucose-dependent manner.1 GIP has no effect on gastric emptying and no significant effects on satiety or body weight.
Inhibits gastric emptying1,2
Purpose
To describe the 2 main incretins, GLP-1 and GIP.
Takeaway
GLP-1 and GIP have key roles in glucose homeostasis. In a glucose-dependent manner, GLP-1 and GIP stimulate insulin secretion, and GLP-1 inhibits glucagon secretion.
Reduces food intake and body weight2
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic peptide.
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
References
1. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.
2. Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

9. The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes
Control Subjects (n=8)
Subjects With Type 2 Diabetes (n=14)
Normal Incretin Effect
Diminished Incretin Effect 80 60 40 20 80 60 40 20
IR Insulin, mU/L
The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes
In 1964, it was demonstrated that the insulin secretory response was greater when glucose was administered orally through the gastrointestinal tract than when glucose was delivered via IV infusion. The term incretin effect was coined to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion.1,2 The incretin effect implies that nutrient 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.1 Studies in humans and animals have shown that the incretin hormones GLP-1 and GIP account for almost all of the incretin effect,3 stimulating insulin release when glucose levels are elevated.4,5
Although the incretin effect is detectable both in healthy subjects and in those with diabetes, it is abnormal in those with diabetes, as demonstrated by the study shown on the slide.6
In this study, patients with type 2 diabetes and weight-matched, metabolically healthy control subjects were given glucose either orally or IV to achieve an isoglycemic load. In those individuals without diabetes (shown on the left), the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect)—that is, the pancreatic beta cells secreted much more insulin when the glucose load was administered through the gastrointestinal tract.
In patients with type 2 diabetes (shown on the right), the same effect was observed but was diminished.
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.7,8
IR Insulin, mU/L
Purpose
To introduce the concept of the incretin effect in healthy individuals and the abnormality in patients with type 2 diabetes.
Takeaway
Gastrointestinal ingestion of glucose stimulates a greater insulin response than that seen from IV glucose infusion. This effect is significantly decreased in patients with type 2 diabetes. The response is largely attributed to the effect of incretins. 60
120
180 60
120
180
Time, min
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
IR=immunoreactive.
Nauck M et al. Diabetologia 1986;29:46–52. Permission requested.
References
1. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75–85.
2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
3. Brubaker PL, Drucker DJ. Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659.
4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544.
5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
6. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia ;29:46–52.
7. Creutzfeldt W. The entero-insular axis in type 2 diabetes—incretins as therapeutic agents. Exp Clin Endocrinol Diabetes ;109(suppl 2):S288 S303.
8. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

10. GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal GLP-1 and GIP release
DPP-4
enzyme
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
GLP-1 and GIP, which are rapidly degraded by the enzyme DPP-4, have short biological half-lives.1–3
After a meal, GLP-1 and GIP are released in the distal gut (ileum and colon) and the proximal gut (duodenum), respectively. Under normal conditions after their release into the circulation, GLP-1 and GIP are rapidly degraded by the DPP-4 enzyme to their inactive forms.1–3
Purpose
To discuss the importance of the DDP-4 enzyme to the biological activity of the incretin hormones GLP-1 and GIP.
Takeaway
The relatively short biological half-lives of GLP-1 and GIP are attributed primarily to their rapid inactivation by the DPP-4 enzyme.
Active GLP-1 and GIPa
Inactive metabolites
Rapid inactivation
aHalf-lives: GLP-1 ~2 minutes; GIP ~5 minutes.
1. Deacon CF et al. Diabetes. 1995;44:1126–1131.
2. Meier JJ et al. Diabetes. 2004;53:654–662.
References
1. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131.
2. Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53:654–662.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.

11. Glucose levels rise Food [Begin speaking]
This animation depicts the role of pancreatic islet cells in maintaining glucose homeostasis.
The gut and the pancreas are physiologically linked through the incretin pathway, which modulates the response of beta and alpha cells to oral food intake.1–3 Normally during fasting, alpha cells secrete glucagon, which stimulates hepatic glucose production and release, thus preventing hypoglycemia.1–4
[Click for animation to start] When food enters the digestive system, glucose is subsequently absorbed from the gut, resulting in an increase in plasma glucose levels.
[Click for animation to continue] Increased circulating levels of glucose trigger beta-cells to release insulin (which promotes glucose uptake) and also signal the alpha cells to suppress glucagon release and thus decrease hepatic glucose production (HGP).
The role that incretins play in maintaining glucose homeostasis after a meal, is depicted on the next animation.
[Click for animation to continue] Again, after a meal, glucose absorption results in an increase in circulating plasma glucose levels. As a physiologic response to elevated glucose levels, gut-derived incretin hormones (GLP-1 from the L cells in the ileum and colon and GIP from the K cells in the duodenum) are released into circulation.5,6 Within minutes, the DPP-4 enzyme degrades both incretins.
In healthy individuals, GLP-1 and GIP reach the pancreas, where they bind to receptors on the surface of pancreatic islet cells (beta and alpha cells), triggering both insulin secretion and suppression of glucagon release, thus achieving glucose homeoostasis.
In patients with type 2 diabetes, alterations in the incretin pathway have been observed that contribute to abnormalities in glucose homeostasis. Postprandial GLP-1 levels are decreased7,8 and insulin response to GIP diminished.9,10
Given the important role that incretins play in maintaining glucose homeostasis, for patients with type 2 diabetes, prolonging the concentrations of active incretins is expected to help improve glucose control.
[Click to resume animation] Here we see the effects of a DPP-4 enzyme inhibitor, increasing the half life of GLP-1 and GIP, which can then trigger glucose-dependent insulin secretion from beta cells and suppression of glucagon release from alpha cells.
[Animation ends]
These actions result in increased glucose uptake by the muscles and tissues and decreased glucose output by the liver, with an overall reduction in circulating glucose levels and a lowering in plasma glucose levels.
[Click advance to next slide]
References
1. Triplitt C, Wright A, Chiquette E. Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus. Pharmacotherapy. 2006;26:360–374.
2. Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and regulation: beyond insulin and glucagon. Diabetes Spectrum. 2004;17:183–190.
3. Muller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med. 1970;283:109–115.
4. Unger RH. Alpha- and beta-cell interrelationships in health and disease. Metabolism. 1974;23:581–593.
5. Meier JJ, Nauck MA. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
6. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.
7. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717–3723.
8. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide-1 in type 2 diabetic patients. Diabetes. 2001;50:609–613.
9. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.
10.Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

12. 
Insulin secretion 
Glucagon suppression

14. Food
Glucose levels rise

15. Blood Vessel
GLP-1
GIP

16. GLP-1
GIP
DPP-4

17. GLP-1
GIP
DPP-4
DPP-4 Inhibitor

18. GLP-1
GIP
DPP-4 Inhibitor

20. 
Insulin 
Glucagon

21. ADA and AACE/ACE Guidelines: Treatment Goals for A1C, FPG, and PPG
Parameter
Normal1,2 Level
ADA3 Goal
AACE/ACE2 Goal
FPG, mg/dL
<100
90–130
<110
PPG, mg/dL
<140
<180
A1C, %
4–6
<7a
≤6.5
ADA and AACE Guidelines: Treatment Goals for A1C, FPG, and PPG
The table presents guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE).1–3
ADA and AACE recommend slightly different treatment goals for FPG, PPG, and A1C for patients with type 2 diabetes.1,2 Both organizations emphasize the importance of good glycemic control.
The ADA suggests that the goal of treatment in the management of diabetes should be an A1C value less than 7%.1,2 The AACE has recommended an A1C goal of ≤6.5%.1,3
The ADA target of FPG levels between 90 and 130 mg/dL is based on the estimate of the range of average glucose values that would be associated with low risk of hypoglycemia and A1C <7%. The AACE target of <110 mg/dL is an effort to achieve normal levels of glycemia.1
The ADA recommends reducing average PPG values (peak posprandial glucose level <180 mg/dL),2 whereas the AACE recommends targeting 2-hour postchallenge PPG values of <140 mg/dL.1
Purpose
To provide a reminder of current guidelines for type 2 diabetes.
Takeaway
All 3 parameters (A1C, FPG, and PPG) are important in attaining glycemic control.
aThe goal for an individual patient is to achieve an A1C as close to normal (<6%) as possible without significant hypoglycemia.
FPG=fasting plasma glucose; PPG=postprandial glucose; ADA=American Diabetes Association; AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology.
1. Adapted from Buse J et al. In: Williams Textbook of Endocrinology. 10th ed Permission requested.
2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68.
3. ADA. Diabetes Care. 2007;30:S4–S41.
References
1. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
2. ADA. Standards of Medical Care in Diabetes–2007. Diabetes Care. 2007;30:S4–S41.
3. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus. Endocrine Practice. 2007;13(suppl 1):3–68.

22. Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles
This study evaluated the relative contributions of FPG and PPG to overall hyperglycemia in 290 non–insulin-, non–acarbose-using patients with type 2 diabetes. The analysis suggested that both FPG and PPG contribute to overall hyperglycemia.1
The relative contribution of PPG levels decreased progressively from the lowest to the highest quintile of A1C.1 In contrast, the relative contribution of FPG showed a gradual increase with increasing levels of A1C.1
Thus, targeting both FPG and PPG may be required to optimize blood glucose levels.1
Purpose
To demonstrate that both FPG and PPG contribute to elevated A1C in patients with type 2 diabetes.
Takeaway
The relative contribution of FPG and PPG may vary by level of A1C, and both FPG and PPG may have to be addressed to get the patient to goal.
n = 58
n = 58
n = 58
n = 58
n = 58
A1C
Monnier L et al. Diabetes Care. 2003;26:881–885. Permission requested.
Reference
1. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26:881–885.

23. Published Conceptual Approach
Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal
Published Conceptual Approach
OAD +
multiple daily
insulin injections
Diet and exercise
OAD
monotherapy
OAD up-titration
OAD
combination
OAD +
basal insulin 10
A1C, % 9 8
Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy
The yellow line depicts a conceptual view of a conventional stepwise treatment approach. Hypothetically, patients treated with this approach would have a considerable glycemic burden (time spent above A1C goals). The orange line depicts a conceptual view of an aggressive A1C goal-oriented approach that would initiate changes in therapy earlier (within several months of goals not met). Hypothetically, patients treated with this approach might be able to achieve A1C results such as those depicted by the straight orange line. This approach also calls for earlier use of combination therapy in appropriate patients.1
Mean A1C of patients
Purpose
To show conceptually that early, aggressive intervention may reduce the glycemic burden of type 2 diabetes.
Takeaway
A treat-to-goal therapeutic approach with aggressive treatment and a low threshold for action (A1C >7%) may reduce the glycemic burden of type 2 diabetes. 7 6
Duration of Diabetes
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. Permission requested.
Reference
1. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B, on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345–1355.

24. Case Study: Mona Female, 60 years old, obese
Serum creatinine: 1.4 mg/dL
A1C: 7.1%
Antihypertensive therapy
History of inflammatory bowel disease
Recent myocardial infarction
Treatment-naive for diabetes
Case Study: Mona
Mona is a 60-year-old obese woman with a serum creatinine level of 1.4 mg/dL and an A1C of 7.1%. She is treatment-naive for diabetes. Her medical history includes hypertension and inflammatory bowel disease, and she had a heart attack 2 years ago.
We will return to consider potential oral antihyperglycemic treatment options for this patient later in this presentation.
Purpose
To discuss current treatment options for patients with type 2 diabetes.

25. Case Study: Archie Male, 54 years old, obese
Serum creatinine: 0.9 mg/dL
A1C: 8.0%
Has been receiving metformin 1,000 mg twice a day for past 6 months
Case Study: Archie
Archie is a 54-year-old obese man with a serum creatinine level of 0.9 mg/dL and an A1C of 8.0%. Archie has been receiving metformin 1,000 mg twice daily for the past 6 months.
We will return to consider potential oral antihyperglycemic treatment options for this patient later in this presentation.
Purpose
To discuss current treatment options for patients with type 2 diabetes.

26. Case Study: Nancy Female, 55 years old, obese
Serum creatinine: 1.0 mg/dL
A1C: 8.5%
Mild edema
Antihypertensive therapy
Treatment-naive for diabetes
Case Study: Nancy
Nancy is a 55-year-old obese woman with a serum creatinine level of 1.0 mg/dL and an A1C of 8.5%. She is treatment-naive for diabetes. Her medical history includes hypertension and mild edema.
We will return to consider potential oral antihyperglycemic treatment options for this patient later in this presentation.
Purpose
To discuss current treatment options for patients with type 2 diabetes.

27. Major Targets of Oral Drug Classes
Pancreatic Islet Cells
Sulfonylureas
Meglitinides
DPP-4 inhibitors
Liver
Muscle and Fat
Biguanides
TZDs
TZDs
Biguanides
↓Glucose level
DPP-4 inhibitors
Major Targets of Oral Drug Classes
Available therapeutic agents for the treatment of type 2 diabetes have different mechanisms of action to control hyperglycemia.1,2
Sulfonylureas act on the beta cell, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1,2 Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the beta cells.They are used to control postprandial hyperglycemia.1 Thiazolidinediones (TZDs) are selective peroxisome proliferator-activated receptor gamma (PPARγ) agonists that act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1 Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action prevents glucose entry into the systemic circulation.1 Biguanides (metformin) are believed to act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle.1,2
DPP-4 inhibitors are another class of agents for the treatment type 2 diabetes that inhibit the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones produced in the gut. GLP-1 and GIP regulate the production and secretion of insulin through a glucose-dependent mechanism that targets insulin release and hepatic glucose production.3
Purpose
To provide an overview of the general mechanisms of action of oral antihyperglycemic drug classes and their effects on the pancreas and the liver.
Takeaway
Available drug classes have different mechanisms of action.
Gut
alpha-Glucosidase inhibitors
DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinediones.
1. DeFronzo RA. Ann Intern Med. 1999;131:281–303.
2. Buse JB et al. In: Williams Textbook of Endocrinology. 2003:1427–1483.
References
1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.
2. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
3. Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53:654–662.

28. JANUVIA™ (sitagliptin) Tablets
JANUVIA™ (sitagliptin) Tablets: Clinical Overview
We will now discuss the clinical overview of JANUVIA.
Clinical Overview

29. JANUVIA™ (sitagliptin)
Indication
JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Important limitations of use
JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
JANUVIA has not been studied in combination with insulin.
JANUVIA has been studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, and glimepiride plus metformin.
JANUVIA™ (sitagliptin)
Indications
Januvia is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Important limitations of use
JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
JANUVIA has not been studied in combination with insulin.
JANUVIA has been studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, and glimepiride plus metformin.

30. Dosage and Administration
Usual Dosing for JANUVIA™ (sitagliptin)a
The recommended dose of JANUVIA is 100 mg once a day
Patients With Renal Insufficiencya,b
50 mg once a day
25 mg once a day
Moderate
Severe and ESRD
CrCl 30 to <50 mL/min
(~Serum Cr levels [mg/dL]
Men: >1.7–≤3.0; Women: >1.5–≤2.5)
CrCl <30 mL/min
Men: >3.0; Women: >2.5; or on dialysis)
Dosage and Administration This slide shows the recommended dosage and administration of JANUVIA™ (sitagliptin) in patients with type 2 diabetes.
The recommended dose of JANUVIA is 100 mg once daily.
JANUVIA can be taken with or without food.
For patients with mild renal insufficiency (CrCl 50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.
For patients with moderate renal insufficiency (CrCl 30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women), the dosage of JANUVIA is 50 mg once a day.
For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dosage of JANUVIA is 25 mg once a day. JANUVIA may be administered without regard to the timing of hemodialysis.
Because there is a need for dosage adjustment based on renal function, assessment of renal function is recommended before JANUVIA is initiated and periodically thereafter.
Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula.
Assessment of renal function is recommended before initiation of JANUVIA and periodically thereafter.
aJANUVIA can be taken with or without food. bPatients with mild renal insufficiency—100 mg once a day.
ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis; CrCl=creatinine clearance.

31. Contraindications/Warnings and Precautions
History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema
Warnings and Precautions
Use in patients with renal insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Assessment of renal function is recommended prior to initiating JANUVIA™ (sitagliptin) and periodically thereafter.
Use with medications known to cause hypoglycemia: As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when JANUVIA was used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.
Contraindications/Warnings and Precautions
Contraindications
History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema
Warnings and Precautions
Use in patients with renal insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Assessment of renal function is recommended prior to initiating JANUVIA™ (sitagliptin) and periodically thereafter.
Use with medications known to cause hypoglycemia: As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when JANUVIA was used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

32. Contraindications/Warnings and Precautions (cont)
Hypersensitivity reactions:
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA™ (sitagliptin). Reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.
Contraindications/Warnings and Precautions (cont)
Warnings and Precautions (cont)
Hypersensitivity reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA™ (sitagliptin). Reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes. .

33. Adverse Reactions
The most common adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA™ (sitagliptin) as monotherapy or in combination therapy and more commonly than in patients treated with placebo are:
Upper respiratory tract infection
Nasopharyngitis
Headache.
Hypoglycemia was also reported regardless of investigation assessment of causality more commonly in patients treated with the combination of JANUVIA and sulfonylurea, with or without metformin, than in patients given the combination of placebo and sulfonylurea, with or without metformin.
Additional adverse reactions identified during postapproval use (reported voluntarily from a population of uncertain size) including:
Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome.
Adverse Reactions
The most common adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA™ (sitagliptin) as monotherapy or in combination therapy and more commonly than in patients treated with placebo are:
Upper respiratory tract infection
Nasopharyngitis
Headache
Hypoglycemia was also reported more commonly in patients treated with the combination of JANUVIA and sulfonylurea, with or without metformin, than in patients given the combination of placebo and sulfonylurea, with or without metformin.
Additional adverse reactions identified during postapproval use (reported voluntarily from a population of uncertain size):
Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome.

34. Initial Combination With Sitagliptin Plus Metformin Study: Design
Week 24
Patients Not Using OHA or Monotherapy or Low-Dose OHA Combination
Placebo
Eligible if A1C 7.5%–11%
Sitagliptin 100 mg qd
Metformin 500 mg bid
Metformin 1,000 mg bid
Single-Blind Placebo
Run-in Period
Screening Period
Diet and Exercise Run-In Period R
Initial Combination Therapy With Sitagliptin Plus Metformin Study: Design
This was a multinational, randomized, double-blind, placebo-controlled study.
At screening:
Patients with an A1C of 7.5% to 11% and not on an oral antihyperglycemic agent (OHA) for ≥8 weeks were eligible to directly enter a 2-week, single-blind, placebo run-in period.
Patients with an A1C of >11% and not on an OHA entered a diet and exercise run-in period of up to 6 weeks.
Patients on an OHA with an A1C of 7% to 10.5% had the agent(s) discontinued and entered a washout period of 6 to 10 weeks (8–12 weeks for those on thiazolidinediones).1
After the run-in period, patients with an A1C of 7.5% to 11% entered a 2-week, single-blind, placebo run-in period. All patients with adequate compliance during the placebo run-in period were randomly assigned to one of six treatment regimens for 24 weeks. Patients who met nonglycemic eligibility criteria but who had an A1C >11% or a fasting glucose value >280 mg/dL after the run-in period were not eligible for randomization; these patients could participate in an open-label substudy and were treated with sitagliptin 50 mg/metformin 1,000 mg twice daily for 24 weeks.1
Sitagliptin 50 mg/
Metformin 500 mg bid
Purpose
To provide an overview of a initial combination study of sitagliptin with metformin.
Takeaway
Sitagliptin was evaluated as initial combination therapy in a large, randomized, double-blind, placebo-controlled study.
If on OHA: discontinue therapy
Sitagliptin 50 mg/
Metformin 1,000 mg bid
Week –2
Day 1
OHA=oral antihyperglycemic; bid=twice a day. Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
Reference
1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.

35. Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results
Placebo
Metformin 1,000 mg bid
Sitagliptin 100 mg qd
Sitagliptin 50 mg bid + metformin 500 mg bid
Metformin 500 mg bid
Sitagliptin 50 mg bid + metformin 1,000 mg bid
–0.5
LSM A1C Change
From Baseline, %
–1.0
Initial Combination Therapy With Sitagliptin Plus Metformin: A1C Results
This slide demonstrates that after initial therapy with sitagliptin plus metformin, the A1C change from baseline was greater than that achieved when either agent was used alone.
Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options should be left to the discretion of the health care provider.
–1.5
Purpose
To demonstrate the A1C lowering efficacy of sitagliptin when used in initial combination with metformin.
Takeaway
Initial combination therapy of sitagliptin with metformin provides significantly greater decrease in A1C from baseline than achieved when either agent is used alone.
–2.0 6 12 18 24
Week
qd=once a day; bid=twice a day.

36. 24-Week Placebo-Adjusted Results LSM A1C Change From Baseline, %
Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results
24-Week Placebo-Adjusted Results
Mean A1C = 8.8%
0.5
Open label
117
–2.9a
0.0 n=
175
178
177
183
178
–0.5
Sitagliptin 100 mg qd
–0.8
–1.0
–1.0
Metformin 500 mg bid
–1.3
LSM A1C Change From Baseline, %
–1.5
Metformin 1,000 mg bid
–1.6
Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results
This slide demonstrates that after initial therapy with sitagliptin plus metformin, the A1C change from baseline was greater than that achieved when either agent was used alone.1
Mean reductions from baseline A1C were generally greater for patients with higher baseline A1C values.1
Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options should be left to the discretion of the health care provider.
–2.0
Sitagliptin 50 mg + metformin 500 mg bid
–2.1
Purpose
To demonstrate the A1C lowering efficacy of sitagliptin when used in initial combination with metformin.
Takeaway Initial combination therapy of sitagliptin with metformin provides significantly greater decrease in A1C from baseline than achieved when either agent is used alone.
–2.5
Sitagliptin 50 mg + metformin 1,000 mg bid
–3.0
–3.5
aLSM change from baseline without adjustment for placebo.
qd=once a day; bid=twice a day.
Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
Reference
1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.

37. Initial Combination Therapy With Sitagliptin Plus Metformin Study: FPG and PPG Results
24-Week Placebo-Adjusted Results
Sitagliptin 100 mg qd
Metformin 500 mg bid
Metformin 1,000 mg bid
Sitagliptin 50 mg + metformin 500 mg bid
Sitagliptin 50 mg + metformin 1,000 mg bid
FPG
Mean baseline level: 197–205 mg/dL
2-h PPG
Mean baseline level: 283–293 mg/dL
n=178
n=179
n=179
n=183
n=180
n=136
n=141
n=138
n=147
n=152
–25
–25
–23a
–50
LSM FPG Change, mg/dLb
–33a
LSM PPG Change, mg/dLb
–35a
–52a
–54a
Initial Combination Therapy With Sitagliptin Plus Metformin Study: FPG and PPG Results
This was a 24-week, randomized, double-blind, placebo-controlled study evaluating the efficacy of sitagliptin when administered as initial combination with metformin for patients whose diabetes was inadequately controlled on diet and exercise.1
This slide shows the results of glycemic parameters at 24 weeks for combination therapy with sitagliptin and metformin as initial therapy. Sitagliptin and metformin provided significant improvements in FPG and 2-hour PPG compared with metformin monotherapy:
FPG: –20 mg/dL to –35 mg/dL, P<0.001 relative to placebo
PPG: –39 mg/dL, P<0.001 vs placebo1
–75
–50
–78a
Purpose
To demonstrate the mean FPG and 2-hour PPG reductions at 24 weeks in the initial combination therapy with sitagliptin and metformin study.
Takeaway
Sitagliptin combined with metformin provided significant improvements in mean FPG and 2-hour PPG vs metformin monotherapy in patients whose diabetes was inadequately controlled on diet and exercise.
–53a
–100
–93a
–75
–70a
–125
–117a
aLSM adjusted for baseline value.
bDifference from placebo.
Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
Reference
1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.

38. Initial Combination Therapy With Sitagliptin Plus Metformin Study: Percentage of Patients Achieving <7% A1C at 24 Weeks
Sitagliptin 50 mg + metformin 1,000 mg bid
Metformin 1,000 mg bid
Sitagliptin 100 mg qd
Sitagliptin 50 mg + metformin 500 mg bid
Metformin 500 mg bid
Placebo 70
66a 60 50
44a
43a 38
To Goal, % 40 30
Initial Combination Therapy With Sitagliptin Plus Metformin Study: Percentage of Patients Achieving <7% A1C at 24 Weeks
This slide shows that significantly more patients receiving combination therapy achieved A1C goals than did those receiving monotherapy (P<0.01).1 20
22a 23 20 20
Purpose
To demonstrate the percentage of patients achieving A1C goals in initial combination therapy study.
Takeaway
Significantly more patients receiving initial combination therapy achieved A1C goals (<6.5% or < 7%) than did those receiving monotherapy. 10 9 9 10 2
165
175
178
177
183
178
165
175
178
177
183
178
A1C <6.5%
A1C <7%
aP<0.01 vs monotherapy.
Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
Reference
1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.

39. Initial Combination Therapy With Sitagliptin Plus Metformin Study: Change in Body Weight and Incidence of Hypoglycemia
Sitagliptin 50 mg + metformin 1,000 mg bid
Metformin 1,000 mg bid
Sitagliptin 100 mg qd
Sitagliptin 50 mg + metformin 500 mg bid
Metformin 500 mg bid
Placebo 1
LSM Change From Baseline, kg
Rates of Hypoglycemia in Combination With Sitagliptin
Placebo
Sita 100
MF bid
MF 1,000 bid
Sita 50 +
MF 500
bid
Hypoglycemia n/N (%)
1/176 (0.6)
1/179 (0.6)
1/182 (0.5)
2/182 (1.1)
2/190 (1.1)
4/182 (2.2)
167
175
179
175
184
178
Initial Combination Therapy With Sitagliptin Plus Metformin Study: Changes in Body Weight and Incidence of Hypoglycemia
After 24 weeks of therapy, significant reductions in body weight relative to baseline (–0.6 to –1.3 kg; P<0.05) were observed in all groups except those administered sitagliptin monotherapy, for whom no change in baseline (0.0 kg) was observed.1
The incidence of hypoglycemia was low and similar across treatment groups.1 –1
Purpose
To demonstrate the effect of initial combination therapy with sitagliptin and metformin on weight gain and hypoglycemia at 24 weeks.
Takeaway
Initial combination therapy of sitagliptin and metformin had no effect on weight gain and was associated with a low incidence of hypoglycemia. –2
Sita=sitagliptin; MF=metformin.
Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
Reference
1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.

40. Sitagliptin Monotherapy Studies: Design
discontinued
Eligible if A1C
7% to 10%
Eligible patients:
On therapy or not on therapy ≥8 weeks
Randomization
Screening
Diet/exercise run-in
Double-blind treatment
7 weeks
Washout
2 weeks
Single-blind
placebo
18 weeks1 or 24 weeks2
2 randomized, double-blind, placebo-controlled studies in patients with type 2 diabetes
18- and 24-week treatment periods (placebo or sitagliptin 100 mg or 200 mg once daily)1,2
Sitagliptin Monotherapy Studies: Design
Two randomized, placebo-controlled, double-blind studies were conducted to evaluate the efficacy and safety of monotherapy with sitagliptin in patients with type 2 diabetes and inadequate glycemic control.
In 2 multinational studies, one lasting 18 weeks (N=521) and one lasting 24 weeks (N=741), patients received either placebo or sitagliptin 100 mg or 200 mg once daily. Overall, the 200-mg daily dose did not provide greater glycemic efficacy than the 100-mg daily dose. For this reason, this presentation only will focus only on the 100-mg dose.
Patients 18 to 75 years who had inadequate glycemic control (defined as A1C 7%–10%) on diet and exercise were eligible for enrollment.
Additional inclusion criteria included no antihyperglycemic agent for ≥8 weeks; on a single antihyperglycemic agent; or on a low-dose, dual, oral combination therapy.
In both the 18-week and 24-week monotherapy studies, patients taking an antihyperglycemic agent stopped taking it and underwent a diet, exercise, and drug washout period of about 7 weeks.
Patients with inadequate glycemic control after the washout period were randomized to treatments after completing a 2-week, single-blind, placebo run-in period. Patients not taking antihyperglycemic agents (off therapy for at least weeks) with inadequate glycemic control were also randomized after completing the 2-week, single-blind, placebo run-in period.
Primary end points of each study were change in A1C levels from baseline compared with placebo and safety and tolerability.
Purpose
To provide an overview of two phase 3 monotherapy studies for sitagliptin.
Takeaway
The efficacy of sitagliptin was evaluated in 18-week and 24-week placebo-controlled studies in patients with mild to moderate hyperglycemia who were either previously treated or not on therapy ≥8 weeks.
1. Raz I et al. Diabetologia. 2006;49:2564–2571.
2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
References
1. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H; for Sitagliptin 023 Study 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.
2. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE; for the Sitagliptin Study 021 Group. 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.

41. Sitagliptin Monotherapy Studies: A1C Reductions
Placebo-Adjusted Results
Inclusion criteria A1C: 7%–10%
Mean baseline A1C: 8.0%
P < 0.001a
Prespecified pooled analysis at 18 weekse
Baseline A1C, %
Overall < ≥8–< ≥9
0.0
0.0
–0.2
–0.2
–0.4
n=411d
–0.4
–0.6
n=769d
n=239d
–0.6
Mean Change in A1C, %c
n=193
–0.8
–0.7
–0.7
–0.6
Mean Change in A1C, %
–0.6b
–1.0
n=229
–0.8
Sitagliptin Monotherapy Studies: A1C Reductions
Monotherapy with sitagliptin significantly reduced A1C compared with placebo.1,2
In the 18-week study, the average baseline A1C in the group treated with sitagliptin 100 mg was 8%. At week 18, patients receiving sitagliptin 100 mg achieved significant (P<0.001) placebo-subtracted A1C reductions (–0.6%) compared with those receiving placebo.1
In the 24-week study, the average baseline A1C in the group treated with sitagliptin 100 mg was 8%. At week 24, patients receiving sitagliptin 100 mg achieved significant (P<0.001) placebo-subtracted A1C reductions (–0.8%) compared with those receiving placebo.2
For both studies, the A1C-lowering effects of sitagliptin 100 mg were consistent across demographic, anthropometric, and disease characteristics subgroups.1,2
As is typical of agents used to treat type 2 diabetes, the mean response to sitagliptin appeared to be related to the degree of A1C elevation at baseline.
In a pooled analysis of these monotherapy studies at week 18, the overall patient population demonstrated a 0.7% decrease in mean placebo-subtracted A1C.
Additionally, in a prespecified subgroup analysis, the study showed that when patients were grouped by baseline A1C into those with mildly elevated A1C levels (<8%, n=411), moderately elevated A1C levels (≥8%–<9%, n=239), and highest elevated A1C levels (≥9%, n=119), mean placebo-subtracted reductions in A1C after 18 weeks were –0.6%, –0.7%, and –1.4%, respectively (P<0.001 overall and for treatment by subgroup interactions).
–1.2
–0.8b
n=119d
Purpose
To demonstrate the A1C reductions in the 2 trials of sitagliptin monotherapy and in a prespecified subgroup analysis by baseline A1C.
Takeaway
Monotherapy with sitagliptin significantly reduced A1C compared with placebo, and the magnitude of the mean response appeared to be related to the degree of A1C elevation at baseline.
–1.4
–1.0
24-week monotherapy study2
(95% CI: –1.0, –0.6)
18-week monotherapy study1 (95% CI: –0.8, –0.4)
–1.4
–1.6
–1.8
aCompared with placebo. bLeast squares mean (LSM) adjusted for prior antihyperglycemic therapy status and baseline value. cDifference from placebo. dCombined number of patients on sitagliptin or placebo. eP<0.001 overall and for treatment-by-subgroup interactions.
CI, confidence interval.
1. Raz I et al. Diabetologia. 2006;49:2564–2571.
2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
Study 021 and 023
References
1. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H; for Sitagliptin 023 Study 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.
2. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE; for the Sitagliptin Study 021 Group. 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.

42. LSM Change From Baseline, %
Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results From Patients not on Antihyperglycemic Therapy at Study Entry
Placebo
Sitagliptin 100 mg qd
Metformin 500 mg bid
Metformin 1,000 mg bid
Sitagliptin 50 mg + metformin 500 mg bid
Sitagliptin 50 mg + metformin 1,000 mg bid
–0.2
n=83
–1.1
n=88
–1.1
n=90
n=87
–1.6
n=100
–1.9
n=86
–0.2
–0.4
–0.6
LSM Change From Baseline, %
–0.8
–1.0
–1.2
Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results From Patients not on Antihyperglycemic Therapy at Study Entry
Initial therapy with the combination of sitagliptin and metformin provided significant improvements in A1C in patients not on an antihyperglycemic agent at study entry.
Considerations regarding initial treatment and subsequent management of type 2 diabetes should be left to the discretion of the health care provider.
–1.4
–1.2
Purpose
To demonstrate the A1C reductions in patients not on antihyperglycemic therapy at study entry.
Takeaway
Initial therapy with the combination of sitagliptin and metformin provided significant improvements in A1C in patients not on an antihyperglycemic therapy at study entry.
–1.6
–1.8
–2.0
LSM=least squares mean change.
Data available on request from Merck & Co., Inc.
Study 036
Reference
1. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA

43. Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Design
Patients with type 2 diabetes (on any monotherapy or dual combination with metformin)
Noninferiority design
Continue/start
metformin
monotherapy
Week -2:
Eligible if A1C
6.5% to 10%
Mean baseline A1C: 7.65%
Glipizide: 5 mg qd increased to 10 mg bid (held if premeal fingerstick glucose < 6.1 mmol/L or hypoglycemia)
Day 1
Randomization
Week 52
Screening
Period
Metformin monotherapy run-in period
Double-blind treatment period:
glipizide or sitagliptin 100 mg qd
Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Design
This was a multicenter, double-blind, randomized study to evaluate the safety and efficacy of the addition of sitagliptin compared with sulfonylurea therapy in patients with type 2 diabetes with inadequate glycemic control on metformin monotherapy.1
The goal of the study was to compare the efficacy and safety of sitagliptin vs glipizide when added to the treatment regimen of patients with type 2 diabetes who had inadequate glycemic control on metformin.1
Baseline glycemic and disease characteristics were balanced between groups.1
Note: At any time during the study, glipizide could be down-titrated to prevent recurrent hypoglycemic events.
Purpose
To provide an overview of a noninferiority study of sitagliptin compared with glipizide.
Takeaway
Sitagliptin was evaluated relative to glipizide in patients inadequately controlled on metformin monotherapy.
Single-blind
placebo
Metformin (stable dose >1,500 mg/day)
Glipizide dosing
Mean titrated dose 10 mg/day
Per protocol, glipizide was kept constant except for down-titration if needed to prevent hypoglycemia
Nauck MA, et al. Diabetes Obes Metab. 2007;9:194–205.
Reference
1. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:

44. Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Glycemic Parameters (Intent-to-Treat)a
Glycemic Parameters at Final Visit (Week 52)
Sitagliptin 100 mg
Glipizide
A1C (%)
N=576
N=559
Baseline (mean)
7.7
7.6
Change from baseline (adjusted meanb)
–0.5
–0.6
FPG (mg/dL)
N=583
N=568
166
164 –8
Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Glycemic Parameters (Intent-to-Treat)
Sitagliptin 100 mg once a day with metformin was similar (noninferior) to sulfonylurea (glipizide) with metformin in lowering A1C, the primary efficacy end point of the study. At week 52, the least squares mean (LSM) change from baseline in A1C was –0.5% and –0.6% for the sitagliptin and the glipizide groups, respectively, in the intent-to-treat population.
A conclusion in favor of the noninferiority of sitagliptin to glipizide may be limited to patients with A1C comparable to those included in the study (>70% of patients had baseline A1C <8% and >90% had A1C <9%)
Purpose
To assess the efficacy and safety of sitagliptin compared with glipizide in patients whose type 2 diabetes inadequately controlled on metformin monotherapy.
Takeaway
Sitagliptin was noninferior to (similar to) glipizide when administered to patients whose type 2 diabetes was inadequately controlled on metformin monotherapy.
aThe intent-to-treat analysis used the patients' last observation in the study before discontinuation.
bLeast squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.

45. LSM A1C Change From Baseline, %
Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: A1C Results (Per-Protocol Population)
0.0
Glipizide
Sitagliptin 100 mg
–0.3
–0.6
LSM A1C Change From Baseline, %
–0.9
Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Glycemic Parameters (Per-Protocol Population)
In the per-protocol population, sitagliptin 100 mg once a day with metformin was similar (noninferior) to sulfonylurea (glipizide) with metformin in lowering A1C, the primary efficacy end point of the study. At week 52, the least squares mean (LSM) change from baseline in A1C was –0.7% for both groups.
A conclusion in favor of the noninferiority of JANUVIA to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%)
–1.2
Purpose
To asses the efficacy and safety of sitagliptin compared with glipizide in patients whose type 2 diabetes inadequately controlled on metformin monotherapy.
Takeaway
Sitagliptin was noninferior to (similar to) glipizide when administered to patients whose type 2 diabetes was inadequately controlled on metformin monotherapy.
–1.5 6 12 18 24 30 38 46 52
Week
LSM=least squares mean.

46. Incidence of Hypoglycemia at 52 Weeks LSM Change From Baseline, kg
Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Weight Change and Incidence of Hypoglycemia
Glipizide
Sitagliptin 100 mg
Body Weight at 52 Weeks
Incidence of Hypoglycemia at 52 Weeks
P<0.001
n=411
LSM Change From Baseline, kg
Incidence, %
Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Weight Change and Incidence of Hypoglycemia
The graph on the left shows that sitagliptin 100 mg once a day with metformin induced a significant decrease in body weight at week 52 of the study (–1.5 kg), whereas glipizide with metformin induced a significant increase in body weight compared with baseline values (1.1 kg). The difference in body weight between sitagliptin 100 mg once a day with metformin and the glipizide with metformin treatment groups was significant (–2.5 kg, P<0.001).
The graph on the right shows that sitagliptin 100 mg once a day with metformin was associated with a significantly lower incidence of hypoglycemic episodes than glipizide with metformin (5% vs 32%, respectively). The difference in hypoglycemia between the treatment group receiving sitagliptin 100 mg once a day with metformin and the treatment group receiving glipizide with metformin was significant (27%, P<0.001).
Purpose
To review some key safety and tolerability findings from the noninferiority study vs glipizide on a background of metformin.
Takeaway
Patients treated with sitagliptin experienced significant weight loss compared with patients treated with glipizide and a significantly lower rate of hypoglycemia compared with patients treated with glipizide.
n=382
n=584
n=588
P<0.001
LSM=least squares mean.
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
Reference
1. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:

47. Sitagliptin Add-on to Glimepiride With or Without Metformin Study: DesignZ T
Patients with type 2 diabetes mellitus aged 18–75 years
Placebo (n=219)
Sitagliptin 100 mg once daily (n=222)
Stratum 1 Glimepiride (≥4 mg/day) (n=212)
Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Design
This was a multinational, randomized, double-blind, parallel-group study with a single-blind placebo run-in period followed by a double-blind placebo-controlled treatment period. At the screening visit, patients assigned to receive glimepiride alone (stratum 1) or glimepiride plus metformin (stratum 2) based on their oral antihyperglycemic regimen at the screening visit and their baseline A1C.
Patients with A1C ≥7.5% to ≤10.5% who were already taking a stable dose of glimepiride (≥4–8 mg/day) alone or in combination with metformin (≥1,500–3,000 mg/day) for at least 10 weeks entered a 2-week, single-blind placebo run-in period.
The following patient types discontinued their prior regimen and were switched to treatment with glimepiride with or without metformin
Not on oral antihyperglycemic therapy with A1C ≥9%,
Taking other oral antihyperglycemic monotherapy with A1C ≥7.5%,
Taking other oral antihyperglycemic therapy in dual or triple therapy with A1C ≥6.5% to ≤10.5%1
Patients entered a dose titration period of up to 4 weeks and then a dose stabilization run-in period of up to 10 weeks. If A1C was ≥7.5% to ≤10.5% after the run-in period, patients entered a 2-week, single-blind placebo run-in period. Patients with adequate compliance (≥75%) during this placebo run-in period underwent baseline evaluations and were assigned randomly to the addition of either sitagliptin 100 mg once daily or placebo to ongoing stable doses of glimepiride, alone or in combination with metformin.1
Screening
Period
Stratum 2 Glimepiride + Metformin ≥1500 mg/day) (n=229)
Purpose
To provide an overview of a study evaluating sitagliptin as add-on therapy to a sulfonylurea.
Takeaway
Sitagliptin was evaluated in a large, randomized, double-blind, parallel-group study as add-on therapy to a sulfonylurea.
Single-blind
Placebo
Double-Blind
Week 0
Week 24
Continue/start
regimen of glimepiride
± metformin
Week –2 eligible if
A1C 7.5%–10.5%
Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
Reference
1. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745.

48. 24-Week Placebo-Adjusted Results
Sitagliptin Add-on to Glimepiride With or Without Metformin Study: A1C Results
24-Week Placebo-Adjusted Results
0.0
–0.1
–0.2
–0.3
–0.4
LSM A1C Change
from Baseline, %
–0.5
–0.6
–0.6a
Sitagliptin Add-on to Glimepiride With or Without Metformin Study: A1C Results
This slide demonstrates that, at 24 weeks of therapy, when sitagliptin was added-on to glimepiride alone or to glimiperide plus metformin, sitagliptin provided significant improvements in A1C.
In patients treated with sitagliptin and glimepiride (stratum 1), sitagliptin led to a 0.6% placebo-subtracted reduction in A1C. In patients treated with sitagliptin plus glimepiride plus metformin (stratum 2), sitagliptin led to a placebo-subtracted A1C reduction of 0.9%. In the entire cohort, sitagliptin plus glimepiride with or without metformin, there was a placebo-subtracted A1C reduction of 0.7%.
–0.7
–0.7a
Purpose
To demonstrate mean placebo-adjusted A1C reductions from baseline for sitagliptin at 24 weeks in the entire cohort and the subset (stratum) of patients taking glimepiride alone and of those taking glimepiride in combination with metformin.
Takeaway
When used in combination with glimepiride or glimepiride plus metformin, sitagliptin provided significant improvements in A1C.
–0.8
–0.9
–0.9a
–1.0
Entire cohort (Sitagliptin + glimepiride ± metformin)
Stratum 1 (sitagliptin + glimepiride)
LSM=least squares mean.
aP<0.001 vs placebo. Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
Stratum 2 (sitagliptin + glimepiride + metformin)
Reference
1. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745.

49. LSM Change From Baseline, kg
Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Change in Body Weight
Change in Body Weight at 24 Weeksa
Sitagliptin + glimepiride ± metformin
Placebo + glimepiride ± metformin
LSM Change From Baseline, kg
Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Change in Body Weight at Week 24
The addition of sitagliptin 100 mg to ongoing therapy with glimepiride, alone or in combination with metformin, was generally well tolerated.
This slide shows the effect of sitagliptin on body weight after 24 weeks. When sitagliptin was used in combination with glimepiride with or without metformin, an increase in body weight (1.1 kg) was noted compared with placebo.
Purpose
To demonstrate the effect of sitagliptin on body weight compared with active placebo.
Takeaway
In this study, weight gain was observed in patients receiving sitagliptin plus glimepiride with or without metformin in comparison with patients receiving placebo in combination with glimepiride with or without metformin.
P=0.016
LSM=least squares mean.
aDifference in LSM change from baseline 1.1 kg. Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
Reference
1. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745.

50. Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Incidence of Hypoglycemia
Treatment Group N
Overall
n (%)
Sitagliptin + Glimepiride ± Metformin
222
27 (12.2)
Placebo + Glimepiride ± Metformin
219
4 (1.8)
Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Incidence of Hypoglycemia
The addition of sitagliptin 100 mg to ongoing therapy with glimepiride and metformin was generally well tolerated.
This slide shows the total number of hypoglycemic episodes.
Purpose
To discuss the prevalence of hypoglycemic events in patients receiving sitagliptin in combination with glimepiride and metformin.
Takeaway
As is generally observed when other antihyperglycemic agents are used in combination with a sulfonylurea, the incidence of hypoglycemia (compared with placebo) was increased when sitagliptin was added to glimepiride (27 episodes vs 4).
As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when sitagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased over that of placebo.
Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
Reference
1. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745.

51. Treatment Paradigm Challenge
Case Studies Group Discussion

52. Case Study: Mona (cont)
Female, 60 years old, obese
Serum creatinine: 1.4 mg/dL
A1C: 7.1%
Treatment-naive for diabetes
Antihypertensive therapy
History of inflammatory bowel disease
Recent myocardial infarction
Case Study: Mona (cont)
What treatment options would you consider? ?
Treatment option(s):

53. Case Study: Archie (cont)
Male, 54 years old, obese
Serum creatinine: 0.9 mg/dL
A1C: 8.0%
Has been receiving metformin ,000 mg twice a day for past 6 months
Case Study: Archie (cont)
What treatment options would you consider? ?
Treatment option(s):

54. Case Study: Nancy (cont)
Female, 55 years old, obese
Serum creatinine: 1.0 mg/dL
A1C: 8.5%
Treatment-naive for diabetes
Mild edema
Antihypertensive therapy
Case Study: Nancy (cont)
What treatment options would you consider? ?
Treatment option(s):

55. Before prescribing JANUVIA™ (sitagliptin), please read the Prescribing Information available with this presentation.
Merck & Co., Inc., does not recommend the use of any product in any manner different than as described in the Prescribing Information.
Before prescribing JANUVIA™ (sitagliptin), please read the Prescribing Information, available with this presentation.
Merck & Co., Inc., does not recommend the use of any product in any manner different than as described in the Prescribing Information.
JANUVIA is a trademark of Merck & Co., Inc
Copyright © 2007 Merck & Co., Inc. All rights reserved (1)-10/07-JAN
Printed in USA. Minimum 10% Recycled Paper
Januvia.com 55
JANUVIA is a trademark of Merck & Co., Inc
Copyright © 2007 Merck & Co., Inc. All rights reserved (1)-10/07-JAN
Printed in USA. Minimum 10% Recycled Paper
Januvia.com