2. The American Diabetes Association (ADA) released standards of medical care in diabetes for 2014.
Criteria for diagnosis of diabetes:
DCCT=Diabetes Control and Complications Trial; FPG=fasting plasma glucose; OGTT=oral glucose
tolerance test; PG=plasma glucose
Refer to source document for full recommendations, including level of evidence rating.
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care.
2014;37(suppl 1):S14-S80.
January 2014
This slide was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.

3. The American Diabetes Association (ADA) released standards of medical care in diabetes for 2014.
This slide shows the correlation of A1C with average glucose based on data from the A1C-Derived Average Glucose (ADAG) trial.
Refer to source documents for full recommendations, including level of evidence rating.
Nathan DM, Kuenen J, Borg R, et al. Translating the A1C assay into estimated average glucose
values. Diabetes Care. 2008;31(8):
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care.
2014;37(suppl 1):S14-S80.
January 2014
This slide was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.

4. Natural History of Type 2 Diabetes
Fasting glucose
Type 2 diabetes
Years from
diagnosis 5
–10 –5 10 15
Prediabetes
Onset
Diagnosis
Postprandial glucose
Macrovascular complications
Microvascular complications
Insulin resistance
Insulin secretion
-Cell function
Incretin effect
Figure courtesy of CADRE.
Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25; Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med. 2002;347: ; UKPDS Group. Diabetes. 1995;44: 4 4

6. DCCT: Results Summary
Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329: Diabetes Control and Complications Trial Research Group. Am J Cardiol. 1995;75:

7. DCCT/EDIC: Incidence of Any Cardiovascular Disease Outcome
The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a long-term observational follow-up (mean 17 years) to the Diabetes Control and Complications Trial (DCCT), which studied whether the use of intensive therapy as compared with conventional therapy affected the incidence of cardiovascular disease (CVD) in patients with type 1 diabetes. Ninety-seven percent of the original DCCT cohort joined the EDIC follow-up (N=1,394).
A total of 144 cardiovascular events occurred in 83 patients during mean 17 years of follow-up, 46 among 31 patients assigned to intensive treatment and 98 among 52 patients assigned to conventional treatment.
As compared with conventional treatment, intensive treatment reduced the risk of any CVD outcome by 42% (95% confidence interval, 9% to 63%; P=0.02).
The authors conclude that the large reduction in the risk of cardiovascular events will improve the projected long-term health and economic benefits of intensive therapy for diabetes.
DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:

8. DCCT and EDIC Findings
Intensive treatment reduced the risks of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional treatment
Absolute risks of retinopathy and nephropathy were proportional to the A1C
Intensive treatment was most effective when begun early, before complications were detectable
Risk reductions achieved at a median A1C 7.3% for intensive treatment (vs 9.1% for conventional)
Benefits of 6.5 years of intensive treatment extended well beyond the period of most intensive implementation (“metabolic memory”)
Intensive treatment should be started as soon as is safely possible after the onset of T1DM and maintained thereafter
DCCT/EDIC Research Group. JAMA. 2002;15;287: 8

9. Macrovascular Risk Reduction in T2DM
Individualized glucose control
Hypertension control
Dyslipidemia control
Smoking cessation
Aspirin therapy
Diagnosis and management of:
Autonomic cardiac neuropathy
Kidney disease 9
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 9

10. Glycemic targets
Diabetes Care 2015;38(Suppl. 1):S33–S40 | DOI: /dc15-S009

11. More Stringent HbA1c Targets (6.0 – 6.5%)
Short disease duration
Long life expectancy
No significant CVD
if this can be achieved without significant hypoglycemia or other adverse effects of treatment

12. Less Stringent HbA1c Targets (7.5 – 8.0% or even slightly higher)
History of severe hypoglycemia
Limited life expectancy
Advanced complications
Extensive comorbid conditions
In whom the target is difficult to attain despite intensive self-management education, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin

13. Lifestyle Interventions
At diagnosis, highly motivated patients with HbA1c already near target (<7.5%) could be given the opportunity to engage in lifestyle change for a period of 3–6 months before embarking on pharmacotherapy (usually metformin)

14. Oral Agents and Non-insulin Injectables

15. Metformin Excretion is via the kidney1
Accumulation is associated with a risk of lactic acidosis1
Metformin is contraindicated in patients with eGFR <301
However, some national recommendations allow use at lower eGFR (e.g. NICE)2
2012 KDOQI guidelines state that metformin may be used in patients with an eGFR >453
Agent
Metabolites
Elimination
eGFR (mL/min/1.73m2)
>60
60–30
<30
<15
Metformin4
Unchanged
~100% urine 
*? 
The risk of lactic acidosis associated with metformin is generally considered to be low
 indicated; ? indication variable;  contraindicated; *consider dose reduction, frequent monitoring and relevant health status
eGFR, estimated glomerular filtration rate; NICE, National Institute for Health and Care Excellence; KDOQI, Kidney Disease Outcomes Quality Initiative
1. Bailey CJ, Day C. Br J Diabetes Vasc Dis 2012;12:167–171; 2. National Institute for Health and Clinical Excellence. Clinical guideline 87. Available at: Accessed October 2014; 3. National Kidney Foundation. Am J Kidney Dis 2012;60:850–886; 4. Glucophage Summary of Product Characteristics October 2010.

16. Sulphonylureas Recommendations vary according to drug1
Some SUs have active metabolites that are eliminated by the kidney1
Avoid use or reduce dose in RI, particularly in patients at high risk of hypoglycaemia
Gliclazide2 and tolbutamide3 can be considered in patients with moderate to severe renal impairment
Require appropriate monitoring and dose adjustment if necessary
Attention to hepatic status is important as renal function deteriorates
Agent
Metabolites
Elimination
eGFR (mL/min/1.73m2)
>60
60–30
<30
<15
Glimepiride
Active
~60% urine 
?* 
Glibenclamide
<50% urine
Glipizide
Inactive
~70% urine
Gliclazide
~65% urine ?*
Tolbutamide
~100% urine *
 indicated; ? indication variable;  contraindicated; *consider dose reduction, frequent monitoring and relevant health status
RI, renal impairment, eGFR, estimated glomerular filtration rate; RI, renal impairment; SU, sulphonylurea
1. Bailey CJ, Day C. Br J Diabetes Vasc Dis 2012;12: ; 2. Diamicron Summary of Product Characteristics. March 2003; 3. Tolbutamide Summary of Product Characteristics. April 2004

17. DPP-4 inhibitors
Are generally safe to use with dose reduction in renal impairment, but are associated with modest efficacy
Sitagliptin: Halve dose at eGFR 30–50; quarter at <301
Vildagliptin: Halve dose in moderate-to-severe disease; use with caution in end-stage renal disease/haemodialysis1
Saxagliptin: Halve dose in moderate-to-severe disease; excluded in end-stage renal disease/haemodialysis1
Linagliptin: Not excreted via the kidneys, no dose reduction required1
Agent
Metabolites
Elimination
eGFR (mL/min/1.73m2)
>60
60-30
<30
<15
Sitagliptin2
Unchanged
~90% urine  *
Vildagliptin3
Inactive
~85% urine
Saxagliptin4
Active
~60% urine 
Linagliptin5
Unchangeda
~80% bile
 indicated; ? indication variable;  contraindicated; *consider dose reduction, frequent monitoring and relevant health status
amostly eliminated unchanged in the bile DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate
1. Bailey CJ, Day C. Br J Diabetes Vasc Dis 2012;12:167–171; 2. Januvia Summary of Product Characteristics July 2014; 3. Galvus Summary of Product Characteristics July 2014; 4. Onglyza Summary of Product Characteristics September 2014; 5. Trajenta Summary of Product Characteristics June 2014

18. Other Conventional OADs
Meglitinides are primarily metabolised by the liver1
May be used with caution in renal impairment if hepatic function is sufficient
Pioglitazone may be used in renal impairment but comorbidities must be considered due to the potential for fluid retention and aggravation of congestive heart disease1
Acarbose is mostly degraded in the intestine1
Agent
Metabolites
Elimination
eGFR (mL/min/1.73m2)
>60
60-30
<30
<15
Repaglinide2
Inactive
~90% bile  * ?
Nateglinide3
Inactivea
~80% urine
Pioglitazone4
Active
~55% bile 
Acarbose5
Within gutb
~2% urine
 indicated; ? indication variable;  contraindicated; *consider dose reduction, frequent monitoring and relevant health status
a mostly inactive metabolites; b metabolites formed within the intestine
eGFR, estimated glomerular filtration rate; OAD, oral anti-diabetic drug
1. Bailey CJ, Day C. Br J Diabetes Vasc Dis 2012;12: ; 2. Prandin Summary of Product Characteristics June 2012; 3. Starlix Summary of Product Characteristics July 2014; 4. Actos Summary of Product Characteristics July 2014; 5. Glucobay Summary of Product Characteristics July 2013.

19. Sodium–glucose co-transporter 2 (SGLT2) inhibitors
Provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule
There are two FDA approved agents for use in patients with type 2 diabetes
These agents reduce HbA1c by 0.5–1.0%
Agent
Metabolites
Elimination
eGFR (mL/min/1.73m2)
>60
60-45
<45
<15
Canagliflozin
Inactive
> 90% urine  ? 
Dapagliflozin
> 60 % urine
Empagliflozin
> 50% urine
 indicated; ? indication variable;  contraindicated; *consider dose reduction, frequent monitoring and relevant health status
eGFR, estimated glomerular filtration rate
Clin Pharmacokinet Jan;53(1): doi: /s
N Am J Med Sci Mar; 6(3): 107–113. doi:  /
Diabetes Ther Dec; 4(2): 331–345. doi:  /s

20. Which SU Should Be Used? Among SUs,
based on evidence from observational studies showing lower cardiovascular risks of Gliclazide over other Sus ,
A lower incidence of hypoglycemic events,
Less weight gain.

21. Gliclazide Pharmacokinetics
Well absorption
Peak plasma concentration occurring within 4 -6 hrs
Extensively (94%) bound to plasma proteins
Half-life: Approximately 10–12 hrs
Metabolized in the liver to inactive metabolites:
The metabolites have no significant hypoglycaemic effect.
Metabolites are primarily eliminated via the kidneys (60-70%), or the faeces (10-20%).
<5% of the dose is excreted unchanged in the urine.
Use in pregnancy & lactation:
Category C
There is a dose-dependent relationship between gliclazide and plasma concentrations, no clear correlation with hypoglycaemic activity exists.
Gliclazide 80 mg: Datapharm Communications Ltd ;Summary of product characteristics 2013.
Gliclazide 80 mg: Arrow Pharmaceuticals NZ Limited Fact Sheet 2006.

22. Gliclazide: Posology & Method of Administration
The total daily dose may vary from 40 to 320 mg taken orally.
The dose should be adjusted according to the individual patient’s response, commencing with 40–80 mg daily (½ - 1 tablet) and increasing until adequate control is achieved.
A single dose should not exceed 160 mg (2 tablets).
If > 160 mg/d are required, tablets should be taken twice daily according to the main meals of the day.
Maximum Recommended Dose
Starting Dose
320 mg/day
40-80 mg/day
(1/2-1 of 80 mg tablet)
Summary of product characteristics; Gliclazide 80 mg

23. Gliclazide MR: Dosage and administration
The daily dose of GLICLAZIDE MR may vary from mg (1-4 tablets) once daily.
The recommended starting dose of GLICLAZIDE MR is 1 tablet per day (30 mg), even in elderly patients (> 65 years old).
A single daily dose provides effective blood glucose control.
Dose adjustment should be carried out in steps of 30 mg
Each step should last for at least two weeks.
Administration
It is recommended that the medication be taken at breakfast time. The tablets should be swallowed whole and must not be chewed or crushed.
Previously untreated patients should commence with a dose of 30 mg.
GLICLAZIDE MR can replace gliclazide 80 mg immediate release tablets.
GLICLAZIDE MR can replace an antidiabetic treatment without any transitional period.
PRODUCT MONOGRAPH; Gliclazide Modified Release Tablets 30 mg, AA PHARMA INC., June 25, 2010

24. Drouin P. J Diabetes Complications. 2000; 14(4): 185-91.
Diamicron MR once daily is effective and well tolerated in T2DM: A double-blind, randomized, multinational study
Drouin P. J Diabetes Complications. 2000; 14(4):

25. Jørgensen et al. Cardiovascular Diabetology 2010; 9:54.

26. Zeller et al., J Clin Endocrinol Metab. 2010; 95(11):4993–5002

27. Review of Gliclazide MR effects
Controlling blood glucose, maintaining this control over the long term, and preventing the development of microvascular and macrovascular complications are main challenges in type 2 diabetes management.
Gliclazide MR has an unmatched level of clinical evidence demonstrating powerful glycemic efficacy maintained over the long term, unique ESKD prevention, cardiovascular safety, and an optimal safety profile in terms of hypoglycemia and weight gain.
It is postulated that oxidative stress, which is abnormally high in T2DM, has a negative impact on progression of diabetes by reducing β-cell function, and the development of diabetic nephropathy and cardiovascular disease, particularly by increasing atherosclerosis.
Gliclazide MR, thanks to its unique chemical structure, reduces oxidative stress, increasing the resistance of LDL to oxidation and slowing the progression of atherosclerosis in T2DM.
Ruiz M. Diamicron MR: the secretagogue with clinical benefits beyond insulin secretion. MEDICOGRAPHIA, 2013; 35(1):81-9.

28. Expected HbA1c reduction according to intervention
Expected ↓ in HbA1c (%)
Lifestyle interventions 1 to 2%
Metformin
Sulfonylureas
Insulin
1.5
3.5%
Glinides
1.5%1
Thiazolidinediones
0.5
1.4%
-Glucosidase inhibitors
0.8%
GLP-1 agonist
1.0%
Pramlintide
DPP-IV inhibitors 28 28

29. Long-term Efficacy of Monotherapy: ADOPT
8.0
7.6
7.2
A1C, %
6.8
Rosiglitazone,
Metformin,
Glyburide,
6.4
Kahn et al (A Diabetes Outcome Progression Trial [ADOPT]) evaluated rosiglitazone, metformin, and glyburide as initial treatment for patients recently diagnosed with type 2 diabetes in a double-blind, randomized, controlled trial involving 4360 patients. The patients were treated for a median of 4 years. Within the first 6 months, glycated hemoglobin (A1C) levels decreased in all treatment groups, with the greatest decrease in the glyburide group. However, A1C levels progressively increased over the next 4 years, and at end point, levels were lowest with rosiglitazone followed by metformin and glyburide.
6.0 1 2 3 4 5
Years
A Diabetes Outcome Progression Trial (ADOPT ) 29
Kahn SE, Haffner SM, Heise MA, et al; for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355: 29

30. Weight gain increases with duration of treatment2 8
UKPDS Weight gain up to 8 kg over 12 years 7 6 5
Change in weight (kg) 4
The influence of diabetes treatment on weight was evident in the UKPDS study (UKPDS 34): regardless of treatment, patients gained weight. Patients treated with insulin showed the largest weight increase, with an average gain of 4.0 kg more than conventional therapy at 10 years (UKPDS 33).
The extent of weight gain observed in UKPDS in insulin-treated patients has been confirmed in subsequent studies. For example, in a 6-month study comparing bedtime insulin glargine with NPH insulin once daily (both agents added to existing oral therapy in a treat-to-target protocol), weight gain at the end of the trial period was 3.0 and 2.8 kg, respectively (Riddle et al, 2003).
Generally, weight gain is the consequence of an increase in calorie intake or a decrease in calorie utilisation. It can result from a number of specific factors:
Poor glycaemic control increases metabolic rate and consequently, improving glycaemic control decreases metabolism. If calorie intake is not modified accordingly, then weight will increase.
Improving metabolic control reduces glucosuria (excretion of glucose through the urine), thus fewer calories are lost in this manner.
Normally, insulin suppresses food intake through its effect on CNS appetite control pathways. It has been suggested that this effect of insulin is lost in diabetes patients.
Fear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intake.
Additionally, aside from modifications to calorie intake or utilisation, use of insulin can increase lean body mass through its anabolic nature.
Conventional treatment policy*
“The 411 overweight patients assigned the conventional approach continued to receive dietary advice at 3-monthly clinical visits with the aim of attaining normal bodyweight and FPG to the extent that is feasible in clinical practice. If marked hyperglycaemia developed (defined by the protocol as FPG above 15 mmol/L or symptoms of hyperglycaemia) patients were secondarily randomised to additional non-intensive pharmacological therapy with the other four treatments (metformin, chlorpropamide, glibenclamide, and insulin) in the same proportions as in the primary randomisations, with the aim of avoiding symptoms and maintaining FPG below 15 mmol/L.1 If patients assigned sulphonylurea therapy developed marked hyperglycaemia, metformin was added to their regimen; if marked hyperglycaemia recurred, the allocation was changed to insulin therapy.”
References
UKPDS 34. Lancet 1998;352:854–865
UKPDS 33. Lancet 1998;352:837–853
Riddle et al, Diabetes Care 2003;26:3080–3086 3
Insulin (n=409)
Glibenclamide (n=277)
Metformin (n=342)
Conventional treatment (n=411)* 2 1 3 6 9 12
Years from randomisation 30

31. Treating to target risk of hypoglycaemia3 60 45 50 39 40 35 40 30
Patients (%) achieving HbA1c <7% 30
Many drugs cause hypoglycaemia
Rosiglitazone 10%
Metformin 12%
Glibenclamide 39% 25
Rate (%) 20 20 15 12 10
With nocturnal hypos
With nocturnal hypos 10 10
Total
Total 5
Glargine
NPH
Rosiglitazone
Metformin
Glibenclamide

32. A 52 y/o male comes in with HBA1C 8, FBS 180, 2hrpp 250, Cr. 1
A 52 y/o male comes in with HBA1C 8, FBS 180, 2hrpp 250, Cr. 1.8, Wt : 56 Kg.
What are your recommendations?
Repaglinide
Glutazone
Metformin
Insulin
Combination therapy

33. What are the Incretins ? ( GIP )
Peptides produced by the intestines and
released in response to meals:
1- Glucose-dependent insulinotropic peptide
( GIP )
42 AA , K-cells of proximal duodenum
Brown & Pederson : 1970
Brown , Ross & Watson : 1973

34.  Blood glucose in fasting and postprandial states
Sitagliptin Enhances Active Incretin Levels Through Inhibition of DPP-41–4
Glucose-dependent
Ingestion of food
 Peripheral glucose uptake
Kieffer p878, Figure 2
 Insulin from beta cells
(GLP-1 and GIP)
Ahrén p365, A,B
Pancreas
Release of
active incretins
GLP-1 and GIPa
Drucker p2931, Figure 2
GI tract
 Blood glucose in fasting and postprandial states
Holst p434, A
Beta cells
Alpha cells X
DPP-4 enzyme
Sitagliptin
(DPP-4 inhibitor)
Glucose-dependent
 Glucagon from alpha cells
(GLP-1)
 Hepatic glucose production
Inactive
GLP-1
Inactive
GIP
Sitagliptin Enhances Active Incretin Levels Through Inhibition of DPP-4
This illustration shows the mechanism of action of sitagliptin:
Sitagliptin is a DPP-4 inhibitor believed to slow the inactivation of incretin hormones in patients with type 2 diabetes. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones.
Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4.
The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic adenosine monophosphate.
GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.
By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.
By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.
Purpose To briefly explain the mechanism of action of sitagliptin.
Takeaway By inhibiting dipeptidyl peptidase-4 (DPP-4), sitagliptin slows the inactivation of incretin hormones in patients with type 2 diabetes.
DPP-4=dipeptidyl peptidase 4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal.
1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913.
2. Ahrén B. Curr Diab Rep. 2003;3(5):365–372.
3. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940,
4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430–441.
JAN-WPC a p11,A p12,A
References
Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876–913.
Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3(5):365–372.
Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10):2929–2940.
Holst JJ. Therapy of type 2 diabetes mellitus based on the actions glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18(6): 430–441.
Data on file, MSD.

35. Physiologic actions of GLP-1

36. The Incretin Concept Plasma insulin responses to oral
La Barre : Animal study
A gut extract could elicit blood glucose reductions :
Incretin Hormones
McIntyre et al. :
Elrick et al :
Plasma insulin responses to oral
Glucose is greater than IV glucose

37. GLP-1 Levels Are Decreased in Patients With IGT and T2DM20 a a a a a a a 15
GLP-1, pmol/L 10 a 5
NGT patients
To elucidate the causes of the diminished incretin effect in type 2 diabetes, Toft-Nielsen et al investigated the secretion of the incretin hormones, GLP-1 and GIP, and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-hour mixed meal test in 54 heterogeneous patients with diabetes, 33 matched control patients with normal glucose tolerance, and 15 unmatched patients with impaired glucose tolerance. The GLP-1 response was significantly decreased in patients with type 2 diabetes compared with normal patients and those with impaired glucose tolerance.
IGT patients
T2DM patients 60
120
180
240
Minutes
Nauck et al. : 1986 37
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: 37

38. GLP-1 : pancreatic effects
Insulin synthesis
Glucose dependent
insulin secretion
Somatostatin secretion
GLP-1: functional pancreatic effects
GLP-1 has a direct functional effect on pancreatic cells, influencing secretions from alpha-, beta- and delta- cells. One of its most important effects is to increase insulin secretion. Importantly, however, its insulinotropic action is glucose dependent. Consequently, GLP-1 has the capacity to lower blood glucose while protecting against hypoglycaemia.
GLP-1 also regulates glucagon secretion, partly via an increase in somatostatin secretion, and partly via a direct effect on the alpha-cell. This reduction in glucagon secretion serves to decrease hepatic glucose output.
References
Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438
Ørskov et al. Endocrinology 1988;123:
Hepatic glucose output
Glucagon secretion
-cell
Pancreatic cells:
-cell
-cell

39. Exenatide Infusion Restores First-Phase Insulin Response in T2DM
Healthy Patients, Placebo
T2DM Patients, Placebo
T2DM Patients, Exenatide
Insulin Secretion,
pmol•kg-1•min-1
This phase II, randomized, single-blind, single-center crossover study (N=25) was designed to determine whether exenatide could restore a more normal pattern of insulin secretion in patients with type 2 diabetes. After receiving an IV insulin infusion to achieve plasma glucose levels <5.6 mmol/L, patients received placebo or exenatide followed by a glucose challenge. Exenatide-treated type 2 diabetes patients had an insulin secretory pattern similar to healthy volunteers in both first (0- 10 min) and second ( min) phases after glucose challenge compared with saline-treated patients with type 2 diabetes. Without exenatide treatment, patients with type 2 diabetes had diminished first-phase insulin secretion compared to healthy control subjects. In patients who received continuous insulin infusion followed by either exenatide or saline, an increase in insulin secretion was not observed until after glucose challenge was initiated.
Time, min 39
Fehse F, Trautmann M, Holst JJ, et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab ;90: 39

40. DPP-4 Inhibitors Alogliptin Vildagliptin (Galvus )
Sitagliptin (Januvia )
Saxagliptin ( Onglysa )
Alogliptin

41. Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval.
Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients. ADA meeting, Chicago, June 2007.
They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin.
They look to be at least weight neutral

42. Conclusions: There was a reduction in all-cause mortality for patients treated with metformin combined with DPP-4i versus metformin plus
SU, and a similar trend for MACE.
9/18/20189/18/2018

43. What are the Recommendations?

44. Diabetes Care 2015;38:140–149 | DOI: 10.2337/dc14-2441

46. What are the Recommendations?

47. Initial Drug Therapy Metformin
If not contraindicated and if tolerated, is the preferred initial pharmacological agent for type 2 diabetes. A
Diabetes Care 2015;38(Suppl. 1):S42 | DOI: /dc15-S009

48. Initial Drug Therapy Patients with a high baseline HbA1c (≥ 9.0%)
Low probability of achieving a near normal target with monotherapy
It is justified to start directly with a combination of two noninsulin agents or with insulin itself in this circumstance
Diabetes Care 2015;38:145 | DOI: /dc

49. Initial Drug Therapy
If BS> 300–350 mg/dL or HbA1c≥ 10.0 –12.0% consider combination injectable therapy
especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen.
Diabetes Care 2015;38:145 | DOI: /dc

50. Comparative Effectiveness Meta-analyses
Each new class of noninsulin agents added to initial therapy lowers A1C around 0.9 – 1.1%
Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2- drug combinations. Ann Intern Med 2011;154:602–613.

51. Oral Anti-hyperglycemic agents for use in T2DM
† A1C percentage/relative reduction expected when agent from this class is added to metformin therapy
S.A. Imran et al. Canadian Diabetes Association. Can J Diabetes 2013; 37: S62

52. Oral Anti-hyperglycemic agents for use in T2DM
† A1C percentage/relative reduction expected when agent from this class is added to metformin therapy
S.A. Imran et al. Canadian Diabetes Association. Can J Diabetes 2013; 37: S63

53. Oral Anti-hyperglycemic agents for use in T2DM
† A1C percentage/relative reduction expected when agent from this class is added to metformin therapy
S.A. Imran et al. Canadian Diabetes Association. Can J Diabetes 2013; 37: S63

54. Antihyperglycemic Agents and Renal Function
Not recommended / contraindicated
Safe
Caution and/or dose reduction
Repaglinide
Metformin 30 60
Saxagliptin
Linagliptin
Glyburide 50
Thiazolidinediones
GFR (mL/min):
< 15
15-29
30-59
60-89
≥ 90
CKD Stage: 5 4 3 2 1
Gliclazide/Glimepiride 15
Liraglutide
Exenatide
Acarbose 25
Sitagliptin
2.5 mg
50 mg
25 mg
Adapted from: Product Monographs as of March 1, 2013; CDA Guidelines 2008; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10.
guidelines.diabetes.ca | BANTING ( ) | diabetes.ca . Copyright © 2013 Canadian Diabetes Association

55. Effects of GLP-1 on Insulin and Glucagon Shown to Be Glucose Dependent in Type 2 Diabetes
15.0
With hyperglycemia
GLP-1 stimulated insulin and suppressed glucagon.
When glucose levels approached normal,
insulin levels declined
and glucagon was no longer suppressed.
Placebo
GLP-1 infusion
12.5 *
Glucose (mmol/L)
10.0 *
7.5
5.0
Infusion
250
Insulin (pmol/L)
200
This slide shows results from a study that characterized changes in glucose, insulin, and glucagon levels in response to a pharmacologic dose of GLP-1. Ten patients with type 2 diabetes mellitus, all of whom had been treated with diet and sulfonylureas (some additionally received metformin or acarbose), due to unsatisfactory metabolic control (mean HbA1c 11.6±1.7%), received an intravenous infusion of GLP-1 or placebo over 240 minutes (infusion rate 1.2 pmol/kg/min) after an overnight fast. During infusion, blood was drawn at 30-minute intervals to permit assay of glucose, insulin, C-peptide, and glucagon concentrations. The patients were studied on two occasions (once with GLP-1 and once with placebo). All antidiabetic medication was continued until the morning before the studies. A regular meal and drug schedule was allowed for one day between the experiments. On study days, all medication was withheld until the end of the experiment.1
Infusion of GLP-1 over 240 minutes lowered plasma glucose to normal basal levels (4.9±0.3 mmol/L) in all patients, with significant mean reductions observed at all time points from 60 minutes onward (p<0.05 vs. placebo). During GLP-1 infusion, plasma insulin increased and glucagon decreased. However, as plasma glucose values approached normal basal levels, insulin and glucagon returned to baseline or near-baseline values, thus indicating that the glucose-dependent nature of the effects of GLP-1 is retained even in poorly controlled type 2 diabetes.1
150
100 50 20
Glucagon (pmol/L) 15 10 5 60
120
180
240
Time (minutes)
N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule was allowed for one day between the experiments with GLP-1 and placebo.
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741–744.
Reference
Nauck MA, Kleine N, Ørskov C et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993;36:741–744.

56. Beta-Cell Dysfunction Hepatic Glucose Overproduction (HGO)
Sitagliptin and Metformin Target the Core Metabolic Defects of Type 2 Diabetes
Beta-Cell Dysfunction
Insulin Resistance
Aschner p.2635, A p.2637, A
Sitagliptin improves beta-cell function and increases insulin synthesis and release.1
Abbasi p.1303, Table 1 p.1302, Fig 1, A
Metformin has insulin- sensitizing properties.3–5
(Liver > Muscle, fat)
Kirpichnikov p.26, A p.27, Fig 1 (caption) p.29, A
JAN-WPC a p.11, A
Zhou p.1171, Fig 4a,b p.1171, A p.1172, A
Sitagliptin reduces HGO through suppression of glucagon from alpha cells.2
Sitagliptin and Metformin Target the Core Metabolic Defects of Type 2 Diabetes
The combination of sitagliptin and metformin improves glycemic control via complementary mechanisms of action. Sitagliptin improves beta-cell function1 and increases insulin synthesis and release. Sitagliptin indirectly reduces hepatic glucose overproduction through suppression of glucagon from alpha cells.2
Metformin decreases hepatic glucose overproduction by directly targeting the liver to decrease gluconeogenesis and glycogenolysis.4 Metformin also increases insulin sensitivity.4,5
In combination, these agents help to improve glycemic control as a result of their complementary MOAs. Sitagliptin targets islet-cell dysfunction, metformin addresses insulin resistance, and both sitagliptin and metformin target hepatic glucose overproduction but in different, complementary ways.1,4
Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.4
Purpose To describe how metformin and sitagliptin act differently but in a complementary manner.
Takeaway Sitagliptin plus metformin targets the 3 core defects of type 2 diabetes with additive efficacy for glycemic parameters.
Hepatic Glucose Overproduction (HGO)
Aschner p.2635, A p.2637, A
JAN-WPC a p.11, A
Abbasi p.1303, Table 1 p.1302, Fig 1, A
1. Aschner P et al. Diabetes Care. 2006;29(12):2632–2637.
2. Data on file.
3. Abbasi F et al. Diabetes Care. 1998;21(8):1301–1305.
4. Kirpichnikov D et al. Ann Intern Med. 2002;137(1):25–33.
5. Zhou G et al. J Clin Invest. 2001;108(8):1167–1174.
Kirpichnikov p.26, A p.27, Fig 1 (caption) p.29, A
Zhou p.1171, Fig 4a,b p.1171, A p.1172, A
References
Aschner P, Kipnes MS, Lunceford JK, 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(12):2632–2637.
Data on file.
Abbasi F, Carantoni M, Chen YD, Reaven GM. Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care. 1998;21(8):1301–1305.
Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med. 2002;137(1):25–33.
Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174.

57. Mechanisms of Action of Major Oral Monotherapies Are Unable to Address the 3 Core Defects in Type 2 Diabetes
Oral Monotherapies
SUs
Meglitinides
TZDs
Metformin
α-Glucosidase Inhibitors
DPP-4 Inhibitors
Improves insulin secretion 
Improves insulin resistance
Lowers hepatic glucose production
Mechanisms of Action of Major Oral Monotherapies Are Unable to Address the 3 Core Defects in Type 2 Diabetes
Given the multiple pathophysiologic abnormalities in type 2 diabetes, combination therapy with 2 or 3 drugs with distinct mechanisms of action is a logical approach to managing the disease.1
As can be seen from the table above, a combination of metformin with a DPP-4 inhibitor may help target 3 contributing pathophysiologies of type 2 diabetes1-4
Using smaller doses of 2 drugs in combination may also result in fewer adverse events than titrating a single drug to maximal doses1,3
A combination of metformin and a DPP-4 inhibitor may not compromise weight gain or hypoglycaemic risk to help get to glucose control,2,3 and would not cause oedema, anaemia, or congestive heart failure
Combination therapy may provide4
More glycaemic control than individual monotherapies
More comprehensive action of key pathophysiologies of type 2 diabetes than monotherapy
An appropriately chosen combination therapy may help more patients get to their HbA1c goal without increasing adverse events1,3
Purpose:
Examine the limitations of oral monotherapies in addressing all 3 pathophysiologies of type 2 diabetes.
Take-away:
No single drug class addresses all 3 pathophysiologies of type 2 diabetes, and some are associated with adverse event treatment limitations.
Mechanisms of Action
SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.
Inzucchi SE. JAMA 2002;287:360–372; Gallwitz B. Minerva Endocrinol. 2006;31:133–147; Nathan DM et al. Diabetologia. 2006;49:1711–1721.
References
1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA. 2002;287:360–372.
2. Gallwitz B. Therapies for the treatment of type 2 diabetes mellitus based on incretin action. Minerva Endocrinol. 2006;31:133–147.
3. Bell DS. The case for combination therapy as first-line treatment for the type 2 diabetic patient. Treat Endocrinol. 2006;5:131–137.
4. Nathan DM, Buse JB, Davidson MB, et al; Professional Practice Committee, American Diabetes Association; European Association for the Study of Diabetes. Management of hyperglycaemia 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. Diabetologia. 2006;49:1711–1721. 16

58. Sitagliptin 50 mg bid + metformin 1000 bida (n=626)
Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin Monotherapy: Study Design
079A CSR
p.64, Fig 2.4.1
Sitagliptin 50 mg bid + metformin 1000 bida (n=626)
Reasner 2009 Fig. 1, C
Reasner 2009 F
T2DM, aged 18–78 yrs, Off OHA ≥4 months, HbA1c ≥7.5%
079A CSR
p.4, A
079A CSR
p.3, B p.5, A R
Metformin 1000 mg bida (n=624)
Reasner 2009 B
079A CSR
p.3, B
Reasner 2009 Fig. 1, C
079A CSR
p.3, B
Screening
period
Phase A
Phase B
Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin Monotherapy: Study Design
This was a multicenter, randomized, double-blind, active-comparator study in patients (aged 18 to 78 years) with type 2 diabetes who had an HbA1c ≥7.5% and who had inadequate glycemic control on diet and exercise alone. Patients could not have been treated with any oral antihyperglycemic agent in the previous 4 months.1,2
The duration of the study was 45 weeks, consisting of a 1-week screening period and a 44-week double-blind, active treatment period. The active treatment period consisted of a 18-week treatment period (phase A) and a 26-week treatment period (phase B).1,2
After the screening period, patients who met all enrollment criteria were randomly assigned in a 1:1 ratio to sitagliptin/metformin FDC (n=626) or metformin monotherapy (n=624).1,2
Patients remained on double-blind active treatment during both phase A and phase B.2 Treatment with sitagliptin/metformin FDC was initiated at a dose of 50 mg twice-daily (bid) and 500 mg bid, and metformin was up-titrated over 4 weeks to 1000 mg bid. Similarly, treatment with metformin monotherapy started with 500 mg bid and was up-titrated over 4 weeks to 1000 mg bid. Patients who could not tolerate the maximum dose of sitagliptin/metformin FDC or metformin monotherapy were allowed to down-titrate to a minimum dose of sitagliptin 50 mg bid plus metformin 500 mg bid or metformin 500 mg bid, respectively.1,2
Patients who did not tolerate sitagliptin 50 mg bid plus metformin 500 mg bid or who did not tolerate metformin 500 mg bid were discontinued.1,2
Primary efficacy analyses were assessed at the end of week 18 (phase A) for the full-analysis-set population, which consisted of all randomly assigned patients who received at least 1 dose of study medication, had a baseline measurement, and had at least 1 postrandomization measurement. Missing data were imputed using the last-observation-carried-forward method.1,2
1 week
Purpose To provide an overview of the study design.
Takeaway This study assessed the efficacy and safety of sitagliptin/metformin FDC (JANUMET) as initial fixed-dose combination therapy vs metformin monotherapy in patients with type 2 diabetes.
18 weeks
26 weeks
Reasner 2009
F and G
Day 1
Randomization
Screening
Week 18
Week 44
079A CSR
p.3, B p.5, A
aMetformin was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks. Patients who were unable to tolerate the maximum dose of sitagliptin/metformin FDC or metformin were allowed to be down-titrated to a minimum dose of sitagliptin/metformin FDC 50/500 mg bid or metformin 500 mg bid. bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus. 1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, Data on file, MSD.
Reasner 2009
B, G
079A CSR
p.3, B
Reasner2009
Fig 1, G
079A CSR
p.3, B p.4, A
079A CSR
p.65, A
Reanser 2009
C, H
079A CSR
p.3, B p.4, B
Reasner 2009 H
079A CSR
p.4, B
079A CSR
p.3, C p.6, A
Reasner 2009
B, D, I, M
References
1. Reasner C, Olnasky L, Seck TL, et al. Initial therapy with the fixed-dose combination (FDC) of sitagliptin and metformin (JANUMET™) in patients with type 2 diabetes mellitus provides superior glycemic control and hemoglobin A1C goal attainment with lower rates of abdominal pain and diarrhea versus metformin alone. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.

59. Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin Monotherapy: HbA1c Results Over 18 Weeks
Reasner 2009 D
FAS Population 10
079A CSR
p.12, Figure 2-1
Reasner 2009
Fig 2
079A CSR
p.12, Figure 2-1 9
HbA1c LS Mean (±SE) Change From Baseline, %
Reasner 2009
Table 2
079A CSR
p.11, Table 2-5 8
LS means difference –0.6; P<0.001
Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin Monotherapy: HbA1c Change From Baseline Over 18 Weeks
This graph shows the change in HbA1c over the 18-week treatment period. The mean baseline HbA1c was 9.9% for the sitagliptin/metformin FDC group and 9.8% for the metformin monotherapy group.1,2
At week 18, the least-squares mean reduction with sitagliptin/metformin FDC initial combination therapy (–2.4%) was significantly greater than that of metformin monotherapy (–1.8%; P<0.001). The between-groups difference at week 18 was –0.6% (95% confidence interval [CI]: –0.8, –0.4).1,2
Purpose To show the HbA1c-lowering efficacy of sitagliptin/metformin FDC therapy vs that of metformin monotherapy over 18 weeks of treatment in patients naive to drug therapy.
Takeaway Initial combination therapy with sitagliptin/metformin FDC resulted in significant reductions in HbA1c at week 18 compared with metformin monotherapy. 7 6 12 18
Week
Sitagliptin/metformin FDC (n=560) Mean baseline HbA1c=9.9%
Metformin (n=566) Mean baseline HbA1c=9.8%
Reasner 2009
Table 2
FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error. 1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, Data on file, MSD.
079A CSR
p.11, Table 2-5
Reasner 2009
Table 2
079A CSR
p.11, Table 2-5
References
1. Reasner C, Olnasky L, Seck TL, et al. Initial therapy with the fixed-dose combination (FDC) of sitagliptin and metformin (JANUMET™) in patients with type 2 diabetes mellitus provides superior glycemic control and hemoglobin A1C goal attainment with lower rates of abdominal pain and diarrhea versus metformin alone. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.

60. HbA1c LS Mean Change from Baseline, %
Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin Monotherapy: Change from Baseline in HbA1c by Baseline HbA1c at Week 18
Note: This slide must be preceded by the presentation of the primary end point: analysis of “by mean baseline HbA1c” (slides 6 and 7)
FAS (Week 18)
079A CSR p.15,
Table 2-8 (B)
(including n-values)
Baseline HbA1c,% < ≥8 and < ≥9 and < ≥10 and < ≥11
Mean HbA1c,%
Reasner Fig. 4 n= 87
101
124
109 99 95 99
111
150
148
–0.5
079A CSR p.15,
Table 2-8 (B)
(p-values)
–1.0
–0.8
–1.1
–1.1
–1.5
HbA1c LS Mean Change from Baseline, %
P=0.158
–1.6
–1.7
–2.0
–2.0
–2.1
Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin Monotherapy: Change from Baseline in HbA1c by Baseline HbA1c at Week 18
This graph shows the effect of treatment on HbA1c according to baseline HbA1c levels.
As baseline HbA1c levels increased, the least-squares (LS) mean HbA1c reduction from baseline increased for both treatment groups. The sitagliptin/metformin FDC group experienced greater numeric LS mean reductions for all HbA1c subgroups. The between-group differences were significant for the ≥8% to <9% HbA1c subgroup (P=0.009), as well as for the ≥10% to <11% and ≥11% subgroups (P<0.001 for both subgroups).1,2
P=0.009
–2.5
P=0.111
–2.7
–3.0
–2.9
Purpose To show the change from baseline in HbA1c levels by HbA1c values at baseline.
Takeaway The changes from baseline in HbA1c were increased for patients with higher baseline HbA1cvalues for both treatment groups.
–3.5
P<0.001
Sitagliptin/metformin FDC
–3.6
–4.0
Metformin
P<0.001
FAS=full analysis set; FDC=fixed-dose combination. 1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, Data on file, MSD.
079A CSR p.15, Table 2-8, (B)
Reasner Fig. 4
References
1. Reasner C, Olnasky L, Seck TL, et al. Initial therapy with the fixed-dose combination (FDC) of sitagliptin and metformin (JANUMET™) in patients with type 2 diabetes mellitus provides superior glycemic control and hemoglobin A1C goal attainment with lower rates of abdominal pain and diarrhea versus metformin alone. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.

61. Sitagliptin Side effects
Rare: Acute pancreatitis was in 0.1 per 100 patient-years.
Nasopharyngitis 1-10 percent.
Hypersensitivity..Rarely angioedema, Steven Johnson.
Hepatic enzyme elevation.
Worsening renal function.
HTN.
Headache

62. 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
Nauck p.195, A p.196, A
Continue/start
metformin
monotherapy
Week -2: Eligible if A1C
6.5% to 10%
Mean baseline HbA1c: 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 who had inadequate glycemic control on metformin monotherapy.1
The goal of the study was to compare the efficacy and safety of sitagliptin with those of glipizide when added to the treatment regimen of patients with type 2 diabetes who had inadequate glycemic control on metformin monotherapy.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.
Single-blind
placebo
Purpose To provide an overview of a noninferiority study of sitagliptin compared with glipizide.
Takeaway Sitagliptin was evaluated in comparison with glipizide in patients with type 2 diabetes who had inadequate glycemic control.
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 p.195, A,B p.196, A
bid=twice a day; qd=once a day.
Nauck MA et al. Diabetes Obes Metab. 2007;9(2):194–205.
Reference
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(2):194–205.

63. Achieved primary hypothesis of noninferiority to sulfonylurea
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy
Nauck p.201, Figure 2A p.197, A
p.196, A
Per-protocol Population LSM change from baseline at 52 weeks (for both groups): –0.7%
8.2
8.0
Sulfonylureaa + metformin (n=411)
7.8
Sitagliptinb + metformin (n=382)
7.6
Achieved primary hypothesis of noninferiority to sulfonylurea
7.4
HbA1c, % ±SE
7.2
7.0
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy
Sitagliptin 100 mg once daily with metformin was similar (noninferior) to a sulfonylurea (glipizide) with metformin in lowering HbA1c, for the per-protocol population, which was the primary efficacy end point of the study.1
At week 52, the least squares mean (LSM) change from baseline in HbA1c was –0.7% in both groups in the per-protocol population.1
The graph shows the reduction in HbA1c obtained with sitagliptin 100 mg once daily with metformin over the study period of 52 weeks.1
An estimate of durability from 24 to 52 weeks (coefficient of durability, [COD]) showed a lower COD for sitagliptin with metformin (0.008%/week) than for sulfonylurea (glipizide) with metformin (0.011%/week), indicating that durability was better for sitagliptin 100 mg once daily with metformin than for sulfonylurea with metformin (COD difference between treatments was –0.003%).1
6.8
6.6
Purpose To provide efficacy results of sitagliptin compared with the sulfonylurea glipizide in patients who had inadequate glycemic control on metformin monotherapy.
Takeaway Sitagliptin was shown to have efficacy comparable to that of a sulfonylurea when added to patients who had inadequate glycemic control on metformin monotherapy.
6.4
6.2 6 12 18 24 30 38 46 52
Weeks
Nauck p.197, A
p.198, A
p.198, C
p.201, Figure 2A
Adapted from Nauck MA, Meininger G, Sheng D, et al, 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;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
aSpecifically glipizide ≤20 mg/day;
bSitagliptin 100 mg/day with metformin (≥1500 mg/day). LSM=least squares mean.
SE=standard error.
Reference
Nauck MA, Meininger G, Sheng D, et al, 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;9:194–205.

64. All-patients-as-treated Population
Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycemia
All-patients-as-treated Population
 between groups at Week 52 = –2.5 kg
Least squares mean change from baseline
Body Weight, kg ± SE
Sulfonylureaa + metformin (n=416)
Sitagliptinb + metformin (n=389) −3 −2 −1 1 2 3
Weeks 12 24 38 52
P<0.001
Hypoglycemia
P<0.001
32% 5% 10 20 30 40 50
Week 52
Patients With ≥1 Episode Over 52 Weeks, %
Sulfonylureaa + metformin (n=584)
Sitagliptinb + metformin (n=588)
Nauck p.200, A/B
p.202, B (Figure 4)
p.202, C (Table 3)
p.196, A
Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycemia
The graph on the left shows the change in body weight observed during the study period of 52 weeks with sitagliptin 100 mg once daily with metformin and sulfonylurea (specifically glipizide) with metformin.1
Sitagliptin 100 mg once daily with metformin resulted in a significant decrease in body weight that was maintained through week 52 of the study (–1.5 kg), whereas sulfonylurea (specifically glipizide) with metformin resulted in a significant increase in body weight compared with baseline values (1.1 kg).1
The difference in body weight between the sitagliptin 100 mg once daily with metformin and the sulfonylurea (specifically glipizide) with metformin treatment groups was significant (–2.5 kg, P<0.001).1
The graph on the right shows that sitagliptin 100 mg once daily with metformin resulted in a significantly lower incidence of hypoglycemic episodes than sulfonylurea (specifically glipizide) with metformin (5% vs 32%, respectively).1 The difference in hypoglycemia between the sitagliptin 100 mg once daily with metformin and sulfonylurea (specifically glipizide) with metformin treatment groups was significant (P<0.001).1
There was no meaningful differences between the groups with regard to the incidence of overall clinical adverse events or clinical adverse experiences that were assessed as serious or leading to discontinuation. Two serious adverse events were reported in the glipizide group and none in the sitagliptin group. The overall incidence of GI adverse events was similar for the treatment groups (20.4% for sitagliptin cohort, 19.3% for glipizide cohort).1
Purpose To review some key prespecified adverse events of interest from the head-to-head study vs glipizide on a background of metformin.
Takeaway Patients treated with sitagliptin experienced significant weight loss compared with patients treated with glipizide. There was also a significantly lower percentage of patients who developed hypoglycemia in the sitagliptin-treated group compared with the glipizide-treated group.
aSpecifically glipizide ≤20 mg/day; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day); Least squares mean between-group difference at week 52 (95% CI): change in body weight at Week 52 = –2.5 kg [–3.1, –2.0] (P<.001); Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<.001).
Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
Adapted from Nauck MA, Meininger G, Sheng D, et al, 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;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
Nauck p.200, A/B
p. 202, B (Figure 4)
p.199, B-D
Reference
Nauck MA, Meininger G, Sheng D, et al; 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;9:194–205.

65. Sitagliptin or Glipizide as Add-on Combination With Metformin Post Hoc Analysis
Patients Achieving Composite EP of The composite endpoint of A1C reduction (>0.5%), no body weight gain and no hypoglycemia Over 52 Weeks
Presented
ADA 2010
Adapted from Thomas L. Seck et al. poster presented American Diabetes Association 70th Scientific Sessions. Orlando, USA. June 25–29, 2010.

66. Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Study Design1
Arechavaleta 2010
p.161, D, E
Sitagliptin 100 mg qd
Patients ≥18 years of age with T2DM on stable dose of metformin (≥1500 mg/day) for ≥12 weeks and HbA1c 6.5%– 9.0% R
Glimepiride (started at 1 mg qd and up-titrated until week 18 as needed up to maximum dose of 6 mg qd)
Continue stable dose of metformin
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Study Design
This was a multinational, double-blind, randomized, parallel-group study, which included screening period of up to 2 weeks, a 2-week placebo run-in period, and a 30-week, double-blind treatment period.1
Patients who met all enrollment criteria entered a 2-week, single-blind placebo run-in period. Patients who continued to meet the study enrollment criteria were randomized to treatment with sitagliptin 100 mg once daily or glimepiride in a 1:1 ratio, for a 30-week, double-blind treatment period.1
Patients in the glimepiride-treatment group were started on a dose of 1 mg per day, and uptitrated—based on self-blood glucose monitoring results and to avoid excessive hypoglycemia—to a maximum dose no higher than 6 mg per day. After the initial 18 weeks of the double-blind treatment period, uptitration of glimepiride was not allowed, and downtitration was allowed only to avoid or control recurrent hypoglycemia.1
The mean dose of glimepiride achieved in this study was 2.1 mg/day, which is similar to the mean daily dose of glimepiride used in clinical practice of about 2.3 mg.
Screening Period
Purpose To present the design of the study.
Takeaway This study was a 30-week, multinational, double-blind, randomized, parallel-group study in which patients were randomized to sitagliptin 100 mg once daily or glimepiride on background of metformin therapy.
Single-blind Placebo Run-in
Double-blind Treatment Period
Week –4
Week –2
Day 1
Week 30
Arechavaleta 2010
p.161, D
qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Arechavaleta 2010
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Arechavaleta 2010
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Arechavaleta 2010 p.166, C
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

67. Per-Protocol Population Prespecified noninferiority margin = 0.40%
HbA1c-Lowering Efficacy of Sitagliptin at Week 30 Was Noninferior to That of Glimepiride in Patients Inadequately Controlled on Metformin1
Per-Protocol Population
Arechavaleta 2010
p.164, Table 2 p.164, Fig. 2
8.0
Sitagliptin 100 mg + metformin (n=443)
7.8
Glimepiridea + metformin (n=436)
7.6
7.4
7.2
–0.47
 (95% CI) 0.07% (–0.03, 0.16)
LS Mean (±SE) HbA1c, %
7.0
Arechavaleta 2010
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6.8
–0.54
HbA1c-Lowering Efficacy of Sitagliptin at Week 30 Was Noninferior to That of Glimepiride in Patients Inadequately Controlled on Metformin
This slide shows HbA1c values over time by treatment group using the per-protocol population.
Sitagliptin was noninferior to glimepiride in reducing HbA1c at week 30 (ie, the upper limit of the 95% confidence interval for the least squares mean between-group difference was 0.16%, less than the prespecified noninferiority margin of 0.40%).1
6.6
Prespecified noninferiority margin = 0.40%
6.4
Purpose To present data showing change from baseline in HbA1c over time in patients treated with the addition of sitagliptin or glimepiride.
Takeaway
HbA1c-lowering efficacy of sitagliptin at Week 30 was noninferior to that of glimepiride in patients inadequately controlled on metformin alone.
6.2
6.0 6 12 18 24 30
Week
LS=least squares; SE=standard error.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Arechavaleta 2010
p.162, C p.164, Table 2
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

68. Per-Protocol Population
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Proportion of Patients at HbA1c Goal at Week 301
Per-Protocol Population
Arechavaleta 2010
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 (95% CI) –7.5% (–13.8, –1.1)
Arechavaleta 2010
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Sitagliptin 100 mg + metformin (n=443)
Glimepiridea + metformin (n=436)
 (95% CI) –6.7% (–12.3, –1.1)
Arechavaleta 2010
p.162, D
Patients at HbA1c Goal, %
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Proportion of Patients at HbA1c at Week 30
This slide shows the results for the analysis of the percentage of patients at HbA1c goal (<6.5% or <7.0%) at week 30 (secondary end point) using the per-protocol population.
A smaller proportion of sitagliptin-treated patients vs glimepiride-treated patients had an HbA1c <6.5% at week 30 (between-group difference: –6.7%, 95% confidence interval [CI] excluded 0).1
A smaller proportion of sitagliptin-treated patients vs glimepiride-treated patients had an HbA1c <7.0% at week 30 (between-group difference: –7.5%, 95% CI excluded 0). Note that the majority of patients in both groups had an HbA1c <7.0% at week 30.1
Purpose To present data showing the proportion of sitagliptin- and glimepiride-treated patients with HbA1c of <6.5% or <7.0% at week 30.
Takeaway
Fewer sitagliptin-treated patients were below the HbA1C target of <6.5% or <7.0% at week 30 compared with glimepiride-treated patients.
CI=confidence interval.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Arechavaleta 2010
p.163, B
Arechavaleta 2010
p.163, A p.165, A
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

69. Patients With ≥1 Hypoglycemic Episode, %
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Clinical Assessment of Hypoglycemia Over 30 Weeks1
APaT Population
Arechavaleta 2010
p.165, Table 4
 (95% CI) –15.0% (–19.3, –10.9) (P<0.001)
Sitagliptin 100 mg + metformin (n=516)
Arechavaleta 2010
p.162, D
Patients With ≥1 Hypoglycemic Episode, %
Glimepiridea + metformin (n=518)
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Clinical Assessment of Hypoglycemia Over 30 Weeks
This slide presents the cumulative incidence of hypoglycemia by treatment group in the all patients as treated population. Adverse experiences of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required.1
Despite similar glycemic control, after 30 weeks, significantly more glimepiride-treated than sitagliptin-treated patients experienced at least 1 episode of hypoglycemia (22% vs 7%; P<0.001).1
In addition, a total 8 hypoglycemic episodes requiring nonmedical assistance occurred in 8 patients in the glimepiride group, compared with 1 such episode experienced by a patient in the sitagliptin group. Furthermore, 3 patients in the glimepiride group had a total of 6 hypoglycemic episodes requiring medical assistance or that were accompanied by neurologic symptoms, compared with 1 such episode in a patient receiving sitagliptin.
Patients in the glimepiride group were also more likely to experience multiple episodes of hypoglycemia compared with the sitagliptin group. Thus, 23 (4.4%) patients experienced ≥6 hypoglycemic episodes in the glimepiride group compared with 2 (0.4%) patients in the sitagliptin group.
Purpose To present the clinical assessment of hypoglycemia in sitagliptin and glimepiride recipients.
Takeaway
Hypoglycemia was more common in the glimepiride treatment group vs the sitagliptin treatment group, despite similar glycemic control after 30 weeks.
Arechavaleta 2010
p.161, F
APaT=all patients as treated; CI=confidence interval.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Arechavaleta 2010
p.164, A p.165, Table 4
Arechavaleta 2010
p.164,D
Arechavaleta 2010
p.164, D p.165, Table 4
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

70. LS Mean Change (±SE) in Body Weight From Baseline, kg
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Body Weight Change from Baseline1
APaT Population
Arechavaleta 2010
p.166, Fig. 4
Sitagliptin 100 mg + metformin 6 12 18 24 30 –1 1 2
Glimepiridea + metformin
Arechavaleta 2010
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1.2 kgb
LS Mean Change (±SE) in Body Weight From Baseline, kg
Arechavaleta 2010
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 = –2.0 kg (P<0.001)
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Body Weight Change from Baseline
This slide shows the change from baseline in body weight over 30 weeks by study group in the APaT population.
Noticeable differences in body weight change from baseline were apparent between groups. At 30 weeks, glimepiride-treated patients gained weight whereas sitagliptin-treated patients experienced a small weight loss, resulting in a significant between-group difference of 2.0 kg (P<0.001).1
Purpose To present the effect of sitagliptin and glimepiride on body weight at week 30 for the all patients as treated (APaT) population.
Takeaway
Glimepiride-treated patients gained weight vs sitagliptin-treated patients, resulting in a significant between-group difference of 2.0 kg at Week 30.
–0.8 kgb
Week
APaT=all patients as treated; LS=least squares; SE=standard error.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. bLS mean body weight change at 30 weeks.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Arechavaleta 2010
p.165, C p.166, Fig. 4
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

71. CASE - 1 :
A 48-year-old woman, presents with polyuria and polydipsia during the past 3 months. She is overweight and complains of feeling tired all the time.
FBS = 245 mg/dl
HDL = 30 mg/dL
LDL = 170 mg/dL.
A1c = 9.4%.
which of the following is the most appropriate intervention that should be initiated as the first step in treating new-onset type 2 diabetes mellitus (T2DM)?
1- Basal insulin
2- Lifestyle and metformin
3- Lifestyle and metformin and sulfonylurea
4- Lifestyle and metformin and basal insulin

72. CASE :
A 35-y old woman with T2DM has been on the maximum tolerated dose of Metformin since 8 months ago. Over the past 7 months, her postdinner blood glucose level rose to 200 mg/dL, and her A1c level is now at 7.7%.
She has been compliant with her medications and has continued to follow a diet that has resulted in the loss of almost 6 kg since diagnosis. She states that she wants to lose more weight because it has helped her self-esteem. Which of the following is the next most appropriate intervention for her to help achieve glycemic control?
1- Add a glucagon-like peptide (GLP)-1 receptor agonist
2- Add a sulfonylurea
3- Add a thiazolidinedione (TZD)
4- Add a dipeptidyl peptidase (DPP)-4 inhibitor
5- Add basal insulin