Pores and cores of new anti diabetic therapy
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Transcript of 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
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
Glinides and insulin
incretin defect
α-Glucosidaseinhibitors
TZDs2
Metforamin
Plasma glucose and disease progression
unmet need unmet need
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
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
Glinides and insulin
α-Glucosidaseinhibitors
TZDs2
Metforamin
Increase renalGlucos
excresion
Plasma glucose and disease progression
unmet need unmet need
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