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Presented by Ben SherrillDoctor of Pharmacy CandidateUGA College of Pharmacy
Class of 2012
The Lancet Vol. 378July 9, 2011Pages 182195
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DMII is a complex disease state
Multifaceted endocrine and metabolic disorder
Environmental and genetic factors play roles indisease progression and severity
Ex: Obesity; Genes PPARG, CAPN10, etc.
Variable levels of insulin resistance and -celldysfunction
Many other hormones play roles in insulinresistance, insulin secretion, and hyperglycemia
Provide potential new targets for therapy
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Current therapies have drawbacks Improvements in glycemia are not sustained
Side effects
GI upset Weight gain Hypoglycemia Peripheral edema Cardiovascular effects
New treatments are needed Sustained glycemic control Reversal of decline in -cell function
Improve insulin action
Avoidance of negative side effects
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The image to the rightdepicts the varioussystems, locations, andmechanisms within thebody that are being
targeted in current,new, and futuremedications for thetreatment of Type IIDiabetes (DMII).
There are currently 8classes of non-insulinmedications used forDMII, each offering adifferent mechanism orapproach for treatingthe disease. In thefuture, the number ofclasses available will
potentially double,possibly even triple, asnew researchcontinues.
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Pancreatic contribution to serum glucose
-cells
Secrete glucagon Suppresses hepatic glycogen synthesis
Stimulates gluconeogenisis and glycogenolysis
Excess will prevent normal suppression of hepaticglucose output, leading to hyperglycemia
-cells Secrete insulin, C-peptide, and amylin
Bowels L cells secrete incretins
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Renal contribution to serum glucose
Sodium-glucose-cotransporter-1 and -2
(SGLT1 & SGLT2) Reabsorb glucose
Renal gluconeogensis contributes 20-25% oftotal glucose production
Hepatic contribution Glycogen synthesis and metabolism
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Rationale:
High insulin response to glucose that is
administered orally is brought about byincretins
Glucagon-like peptide 1 (GLP-1) & glucose-dependant insulinotropic peptide (GIP)
Reduced GLP-1 concentrations in DM II Potency still remains, making it a potential
target
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GLP-1 effects: Potentiates glucose-dependant insulin secretion
and glucagon suppression
Slows gastric emptying Reduces food intake
In animal studies, it increased mass anddecreased apoptosis of -cells
Other potential effects: Promote accumulation of glycogen in liver
Increase glucose uptake
Lower concentrations of triglycerides
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GLP-1 Rapidly inactivated by
dipeptidyl peptidase 4 (DPP-4)
Short circulating t1/2 (
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GLP-1 Mimetics
Advantages Weight loss
Low risk ofhypoglycemia
Possible effect on -cell survival anddecline
Disadvantages Unknown long-term
safety Unconfirmed
association withpancreatitis andmedullary cellcarcinoma
GI side effects(exenatide once-weekly)
Avoid in renal failure
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New GLP-1 mimetics in the pipeline:
Shortacting
Lixisenatide Sustained-release
Exenatide once-weekly, taspoglutide,albiglutide, CJC-1134-PC
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Other new/potential incretin-basedtherapies Oral S4P and Boc5
Activate GLP-1R
Chemical (non-peptide) GLP-1R agonist
Orally active GIP agonists
Linagliptin and alogliptin
New oral DPP-4 inhibitors Linagliptinlow risk of hypoglycemia, no renal
adjustment
Alogliptingood GI tolerability
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Glucokinase Activators(GAs) Once it enters the -cell,
glucose isphosphorylated by
glucokinase Affects the rate of glucosemetabolism and ATPproduction
Effects in animal andhuman DM II models: Increased insulin
concentrations
Reduced glucoseconcentrations
Additional reduction ofglucose by effects onhepatic glucosemetabolism
Glucokinase activation isassociated withincreased triglycerides
and risk of hypoglycemia Drugs being studied:
Piragliptin
Compound 14
R1511
AZD1656
AZD6370
Compund 6
ID1101
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Excess glucagon management Incretin based treatments
Reduce secretion in a glucose-dependant manner
(only in association with hyperglycemia) Dont compromise hypoglycemia counter-
regulation
Blocking of glucagon receptor or signalingpathway after binding with the hormone
Models show significant reduction in basalglycemia and improved glucose tolerance
Might reduce bodys ability to counteracthypoglycemia
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Dual-Acting Peptide for Diabetes (DAPD) GLP-1R agonist that also binds to the glucagon
receptor without activating it
In animal tests: Extended duration, increased insulin secretion,
improved glucose tolerance, reduced glucoseconcentrations
However, it increased glucagon concentration
Oxyntomodulin Agonist at GLP-1R and Glucagon receptor
Induced weight loss, reduced food intake, andincreased energy expenditure in rats
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These are mostly theorized drugs for now
Attempt to activate insulin receptor or post-
receptor signaling intermediaries Many belong to other regulatory pathways,
including cell death, making theseapproaches difficult
Other potential mechanisms: Attempt to prolong action of the insulin
subunit
Prevention of negative feedback
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Sodium-glucose-cotransporter-2 (SGLT2) inhibitors
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Hepatic targets Glucokinase activators
Stimulate insulin secretion and promote hepatic
glucose storage Will improve tolerance but can cause hypoglycemia
Fructose-1,6-bisphosphatase inhibitors
Inhibits gluconeogenisis, reduces serum glucose
Dose not induce hypoglycemia, nor cause hepaticsteatosis
Glycogen phosphorylase inhibitors
Can prevent hyperglycemia without affectingfasting glucose
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GIP antagonists Potentiates glucose-dependant insulin secretion,
just like GLP-1 agonists
It also promotes fat deposition by adipocytes, doesnot inhibit glucagon secretion, and has little effecton food intake, satiety, gastric emptying, orbodyweight
In animal studies:
Increased energy expenditure
Reduced fat deposition and lipotoxicity
Enhanced glucose uptake
Improved -cell function
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11-hydroxysteroid-dehydrogenase-1 (11BHD 1) inhibitors Converts cortisone to cortisol
Phenotypic similarities between metabolicsyndrome and Cushings syndrome Inhibition reduced insulin resistance, prevented
stress-induced obesity, improved tolerance, andenhanced insulin-secretory responsiveness in mice
200mg of a test drug (INCB13739) added tometformin: Reduced A1c by 0.6%
Reductions in total and LDL cholesterol andtriglycerides
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PPAR modulators
Dual PPAR- and PPAR-agonists (glitazars)
being developed for combo effect on lipidsand glucose
Potentially better side effect profile thanglitazones and fibrates
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Dopamine D2-receptor agonists
Bromocriptine
Produces effects on glycemic variableswithout increasing insulin concentrations
Bile acid sequestrants
Reduce glucose concentrations in DM II
patients Recent trial for colesevelam reduced A1c by
0.5-0.54% in combo with metformin
Unfortunately, it increases triglycerides
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Recent meta-analysis of 621 studies
135,246 patients
78.1% with DM II had resolution Additional 8.5% had improved glycemic
control
Issues
Resolution needs to be better defined, andneeds to be more consistant
A more detailed investigation is needed
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Promising new medications for the futuretreatment of DMII
Possible benefits of bariatric surgery are
exciting, and merit new research Level of Evidence: III B
Images and figures on slides 4, 14, and 18 wereobtained from the article being reviewed: Management of type 2 diabetes: new and future
developments in treatment
The Lancet, Vol 378. July 9 2011, 182-195