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