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Unmet Medical Needs in Diabetes Management
“Current Treatment Limitations”
Professor Lobna El Toony,Head of Internal Medicine Department
Assiut University
Sites of Action of AntidiabeticAgents for T2DM
Increase insulin secretion
GLP-1 analogues, DPP-4 inhibitors, Sulfonylureas, Glinides
Decrease glucagon secretion
DPP-4 inhibitors,GLP-1 analogues
Increase hepatic insulin sensitivity
Metformin, TZDs
Increase satiety
GLP-1 analogues
Decrease renal glucose reabsorption
SGLT2 inhibitors
Increase adipocyte insulin sensitivity
TZDs
Slow gastric emptying or carbohydrate absorption
GLP-1 analogues, Metformin(?),α-Glucosidase inhibitors
Increase muscle insulin sensitivity
TZDs, Metformin
Sites of Action
At insulin initiation, the average patient has
• 5 years with HbA1c >8%
• 10 years with HbA1c >7%
Brown JB, et al. Diabetes Care. 2004;27:1535-1540.
Sulfonylurea or Metformin
Monotherapy
ADA Goal <7%
CombinationTherapy
Diet/Exercise
Me
an H
bA
1c
at L
ast
Vis
it
YearsDiagnosis 2 3 4 5 6 7 8 9 10
9.6%
9.0%8.6%
6%
7%
8%
9%
10% Insulin
Clinical Inertia: Standard Therapeutic
Approaches Lead to Prolonged
Hyperglycemia
Management Challenges
Combination Therapy Provides Superior GlycemicControl Over Continued Monotherapy *
GLY=glyburide; MET=metformin; RSG=rosiglitazone; SU=sulfonylurea; PIO=pioglitazone; EXE=exenatide; TZD=thiazolidinedione; SITA=sitagliptin.
DeFronzo R, et al. N Engl J Med. 1995;333:541-549; Fonseca V, et al. JAMA. 2000;283:1695-1702; Kipnes MS, et al. Am J Med. 2001;111:10-17; DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100; Charbonnel B, et al. Diabetes Care. 2004;27:1647-1653; Rosenstock J, et al. Clin Ther. 2006;28:1556-1568;
Zinman B, et al. Ann Intern Med. 2007;146:477-485.
6.5
7
7.5
8
8.5
9
9.5
10
SU+
PIO
HbA1c %
GLY GLY+
MET
MET+
RSG
MET SU
8.7
8.5
7.1
9.1
8.1
10.0
8.7 8.3
8.0
7.0
7.9
7.2
7.8
7.2
MET MET+
EXE
MET TZD+
EXE
TZD† TZD+
SITA
TZDMET+
SITA
MET
Continued monotherapy Combination therapy
7.4
Management Challenges
*Not head-to-head trials†TZD +/- metformin.
Early vs Late Intervention in T2DM
• ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572;Duckworth W, et al. N Engl J Med. 2009;360:129-139: Holman RR, et al. N Engl J Med. 2008:359;1577-1589.
• Treatment:
• Landmark Clinical
Trials
TrialIntensive Arm
HbA1c Reduction
No. Patients /
Trial DurationDisease Severity
Macrovascular
Benefit
ACCORD
Goal: <6.0%
Endpoint: 6.4%
↓1.4% from BL in 4 months
N=10,251
3.4 yr
CVD or 2 risk
factors
10 yr from T2DM
diagnosis
NoADVANCE
Goal: <6.5%
Endpoint: 6.5%
↓0.6% from BL in 12 months
N=11,140
5.0 yr
Vascular disease or
1 risk factor
8 yr from T2DM
diagnosis
VADT
Goal: ↓1.5% vs standard
Endpoint: 6.9%
↓2.5% from BL in 3 months
N=1791
5.6 yr
12 yr from T2DM
diagnosis
UKPDS 80
Goal: FPG <6.0 mmol/L
(108 mg/dL)
Intervention endpoint: 7.0%
Follow-up: 7.7%
N=4209
17 yr
Newly diagnosed
with T2DMYes
HbA1c Lowering is Nephroprotective
†Median
1. ADVANCE Collaborative Group. N Engl J Med. 2008;358(24):2560–72.2. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–53.
• Good glycaemic control reduces the risk of diabetic nephropathy
Early intervention in renal damage is recommended to prevent long-term complications1
1. Diabetes mellitus: Microalbuminuria management. Northumbria NHS Health Care Trust diabetes protocolhttp://www.gp-training.net/protocol/diabetes/npmicroa.htm (accessed July 2011)
Time
120
80
40
0
Creatinine clearance
Microalbuminuria Overt proteinuria
24 hour urinary protein
16 g
300 mg
30 mg
Once overt proteinuria is present, renal function decline is often inevitable
Early interventionis critical in preventing kidney
complications
At least 67% of all patients with type 2 diabetes have cardiovascular risk factors that also affect the kidneys
Prevalence of risk factors for declining renal function:
Risk factorPrevalence in T2DM
patients
30%3
63%2
67%1
Microalbuminuria**3
1
Poor glycemic control*
2
ArterialHypertension
Dyslipidemia†4 24%** 4,5
1. ADA National Diabetes Fact Sheet 2011. http://www.diabetes.org/diabetes-basics/diabetes-statistics (Accessed June 2011) 2. Saydah SH, et al. JAMA. 2004;291:335–342; 3. Cheung BMY, et al. Am J Med. 2009;122:443–53.
4. Mooradian A, Nat Clin Pract Endocrinol Metab. 2009:5;150–15; 5. Kannel WB. Am Heart J. 1985;110;1100–7.
Risk range is likely to be significantly higher than 67% due to overlap of risk factors in individuals*Defined as not reaching the target HbA1c of 7.0%2. **Defined as defined as a urinary albumin-to-creatinine ratio ≥ 30 ug/mg† defined as hypertriglyceridemia in male subjects
There is a close relationship between cardiac and renal pathophysiology in type 2 diabetes
Concomitant cardiorenal dysfunction in type 2 diabetes1
Acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of
the other
1. Ronco C, et al. J Am Col Cardiol. 2008;52(19):1527–1539; 2. AACE. Endocr Pract. 2007;13 Suppl 1:1-683;3. Wajchenberg BL. Endocr Rev. 2007; 28(2):187-218; 4. Afghahi H et al. Nephrol Dial Transplant. 2011;26(4):1236-43;
5. Radbill B et al. Mayo Clin Proc. 2008;83(12):1373-1381; 6. UKPDS Group. BMJ. 2000;321:405-412.
Type 2 diabetesSmokingObesity
HypertensionDyslipidemia
Genetic risk factorsAcquired
risk factors
Heart DiseaseIncreased ischaemic risk
Left ventricular hypertrophy
CKD Stage 1-2Glomerular/Interstitial
damage
Cardiorenal Risk factors
The Unmet Medical Need:
Trade-offs with Current Oral Anti-Diabetes Drugs for Type 2 Diabetes
1. AACE. Available at: http://www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf
2. Ryden L. et al. Eur Heart J. 2007;28:88–136.
aRole uncertainSU = sufhonylureaTZD = thiazolidinedioneGI = gastrointestinal
1. Rodbard HW, et al. Endocr Pract. 2009;15:540-559. 2. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. 3. Onglyza (saxagliptin) [prescribing
information]. Princeton, NJ; Bristol-Meyers Squibb 2009. 4. Victoza (liraglutide) [prescribing information]. Princeton, NJ: Novo Nordisk; 2010. 5. Byetta (exenatide) Injection
[prescribing information]. San Diego, CA; Amylin Pharmaceuticals, Inc; 2009.
CKD Is a Serious Consideration When Choosing an Antidiabetic Agent1-5
MetforminDPP-4
inhibitor*GLP-1
agonistSU Glinide TZD AGI Insulin
Risk or Indication with CKD
Severe risk of lactic acidosis. Contra-indicated when SCr ≥1.4 women, ≥1.5 in men
Reduce dose
Renal monitoring
*Currently marketed DPP-4 excl. Linagliptin
Potential for altered renal function
Use with caution; do not use exenatide/liraglutidein severe RI or ESRD
Increased risk of hypo-glycemia
Dose adjust-ment
Renal monitoring
Increased risk of hypo-glycemia with nateglinide
Risk of fluid retention
Contra-indication in severe RI
Increased risk of hypo-glycemia
Change in pharmaco-dynamics of insulin
Dose adjustment
As CKD Progresses, Diabetes Treatment Choice Becomes More and More Limited
Degree of renal issues
DPP-4 inhibitors2 Other OAD Injectables
Sitagliptin Vildagliptin Saxagliptin Metformin TZD SUGLP-1
mimeticsInsulin
CKD 1–2
US 100% 100% 100% 100% 100% 100% 100%
EU 100% 100% 100% 100% 100% 100% 100% 100%
CKD 3 moderate renal impairment
US 50% 50% 100% 100% 100% Caution 100%
EU Not rec. Not rec. Not rec. Contra ind. 100% 100% Not rec. Monitor
CKD 4 severe renal impairment
US 25% 50% Contra ind. 100% Contra ind.3 Caution Monitor
EU Not rec. Not rec. Not rec. Contra ind. 100% Contra ind. 3 Not rec. Monitor
CKD 5 end-stage renal disease
US 25% 50% Contra ind. 100% Contra ind. 3 Not rec. Monitor
EU Not rec. Not rec. Not rec. Contra ind. 100% Contra ind. 3 Not rec. Monitor
1. Off-label usage not shown. According to expert interviews, substantial off-label usage of metformin despite contraindication for CKD 3-5 and SUs despite contraindication for CKD 5. Dose adjustment for DPP-4s partially neglected for CKD 42. Vildagliptin not approved in US; Alogliptin excluded, as not yet approved in any region3. Contraindicated for long-acting SUs e.g. Glimepiride “Not rec." = not recommended; "contra ind." = contraindicatedSource: US prescribing information; EMEA summary of product characteristics; expert interviews.
Recommended dose depending on degree of renal issues1, in percent of daily dose´for patients without renal issues
Unmet Needs of T2DM Therapies
An ideal antidiabetic agent would• Delay or prevent β-cell decline and failure
• Address multiple pathophysiologic defects
• Help control weight
• Carry few adverse effects
Management Challenges