pores and cores of new anti diabetic therapy

Cores and Pores new anti-diabetic therapy

DR .OSAMA ELMARAGHIM.B.CH.B , MS, Internal Medicine, ALEX.

Diabetes Diploma Leicester , UK.NAEEM DIABETIC CLINIC

JAHRA-KUWAIT19 nov.2016

Lovely AlexandriaAzur hotel

World diabetes day14 nov.2016

Diabetes is a global disease!Estimated global prevalence of diabetes

International Diabetes Federation. IDF Diabetes Atlas. Seventh Edition. 2015

2000 2015 2040151 million 415 million 642 million

Diabetes: A global emergency

Insulin resistance and -cell dysfunction are core defects of type 2 diabetes

Insulinresistance

Genetic susceptibility,obesity, Western lifestyle

Type 2 diabetes

IR -celldysfunction

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

peripheralglucose uptake hepatic

glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

incretineffect

HYPERGLYCEMIA

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological Abnormalities in T2DM

_

_

+renal glucose excretion

1 Gastrointestinal2 Thiazolidinedione

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40

Current Therapies Do Not Address the Multiple Defects in Type 2 Diabetes

Sulfonylureas and glinides

insulin

Impaired insulinaction

incretin defect

Glucoseinflux from GI1 tract

α-Glucosidaseinhibitors

TZDs2

Metforamin

Increase renalGlucos

excresion

Plasma glucose and disease progression

Acuteβ-cell

dysfunction

unmet need unmet need




Sulfonylureas

Glinides and insulin

incretin defect


TZDs2

Metforamin



Glucagon-Like Peptide–1 (GLP-1) Increases-Cell Response and Decreases -Cell Workload

Larsson H et al. Acta Physiol Scand .1997;160:413-422 | Drucker DJ. Diabetes. 1998;47:159-169.

Stomach: Helps regulate

gastric emptying

-Cell workload

-Cell response

-Cells: Enhance glucose-dependent insulin

secretion

GLP-1 secreted upon the ingestion of food

-Cells: Postprandial

glucagon secretion

Promotes satiety and reduces appetite

Liver: Glucagon reduces

hepatic glucose output

DPP-4Enzymes

Strategies for GLP-1 Enhancement

Pipe line of incretin based therapy

GLP-1 analogs

• FDA approved:• exenatide BID and qwk (byatta

and bydorium)• liraglutide (victoza) qd• Lixisenatide(lyxomia)twice daily• Dulaglutide (trulicity) qwk• Semaglutide qwk (waiting for

FDA approval)• Subcutaneous injection

DPP-4 inhibitors

• FDA approved: • Sitagliptin (januvia)• Saxagliptin(onglyza)• Linagliptin (trajenda)• Vildagliptin (galvus) (approved

outside United States)• Oral administration

Drucker DJ, et al. Lancet. 2006;368:1696-1705. Gallwitz B. Pediatr Nephrol. 2010;25:1207-1217. ClinicalTrials.gov. 2013. Accessed 12/11/13 at: http://www.clinicaltrials.gov.

DPP4i drugs

1-Reduce Hba1c% 2- Low hypoglycemic risk 3- Weight neutral or reduced weight.4- Targets all hormonal abnormalities of diabetes

pathophysiology.5-Saved B cell function

Nauck et al. Diabetes Obes Metab. 2007;9:194–205

Saxagliptin had a neutral effect on ischemic events, including MI, stroke, and CV death, but the rate of hospitalization for heart failure increased compared to patients receiving placebo (3.5% vs 2.8%; HR 1.27).

Alogliptin had a neutral effect on the primary endpoint of major adverse coronary events (MACE) and its use was associated with a numerically higher but not statistically significant increased risk for hHF Lancet. 2015;385(9982):2067-2076.

Sitagliptin had a neutral effect on the primary endpoint of major adverse coronary events (MACE) and there was no increase in heart failure rates

DPP4i Adverse Reactions - Adverse reactions and discontinuation rates were similar to placebo (both as monotherapy and as combination therapy)- Symptoms of upper respiratory tract infection, nasopharyngitis, and headache.- Hyperensetvity ,Skin eruption and itching . - Pancreatitis

Ferreira et al Diabetes, Metabolism and the Heart 2011, volume 20

GLP1-Available as injection twice, once daily and once weekly- Reduce Hba1c- No hypoglycemia- Reduce wight- Reduce systolic BP

bydorium)

The ELIXA study It found that lixisenatide had a neutral effect on the primary outcome of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. Furthermore, there was no increase in hospitalization for heart failure.

LEADER study Liraglutide did better than just being safe; it improved outcomes. There was a statistically significant reduction of 12% in the major adverse cardiovascular events (MACE) outcome. There was a 22% very significant risk reduction in CV mortality. There was not an increase in pancreatitis in patients who were on liraglutide. But there was, as expected, an increase in gastrointestinal side effects.

Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.

Medullary thyroid carcinoma (MTC),

Glucagon-like peptide receptor (GLP-1R) agonists have been associated with the development of thyroid C-cell tumors after lifetime exposure in rodentsIn humans, C-cell cancer, or medullary thyroid cancer (MTC), is rare FDA warning that tumors of the thyroid gland (thyroid C-cell tumors) have been observed in rodent studies with GLP1 but that it is unknown whether GLP1 causes thyroid C-cell tumors, or medullary thyroid cancer (MTC), in humans. GLP1 should not be used in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 .

http://press.endocrine.org/doi/10.1210/en.2011-1864#sthash.Waqh1kx3.dpuf




Sulfonylureas

Glinides and insulin


TZDs2

Metforamin

Increase renalGlucos

excresion



Empagliflozin significantly reduced the incidence of new or worsening nephropathy by 39% in the population of type 2 diabetes patients studied, who were at high cardiovascular risk .Again, this was primarily driven by a reduction in new-onset macroalbuminuria of 38% with empagliflozin compared with placebo.

EMPA-REG OUTCOME: Effect of empagliflozin on Nephropathy

pores and cores of new anti diabetic therapy

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