New DMII Treatments

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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

New DMII Treatments

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