Management of Type 2 Diabetes:New & future developments in treatment

Presented by Ben Sherrill Doctor of Pharmacy Candidate UGA College of Pharmacy Class of 2012

The Lancet Vol. 378 July 9, 2011 Pages 182 – 195

Introduction and Background on Type II Diabetes

DMII is a complex disease state› Multifaceted endocrine and metabolic disorder› Environmental and genetic factors play roles

in disease progression and severity Ex: Obesity; Genes PPARG, CAPN10, etc.

› Variable levels of insulin resistance and β-cell dysfunction

› Many other hormones play roles in insulin resistance, insulin secretion, and hyperglycemia Provide potential new targets for therapy

Introduction and Background on Type II Diabetes

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 β-cell function› Improve insulin action› Avoidance of negative side effects

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The image to the right depicts the various systems, locations, and mechanisms within the body that are being targeted in current, new, and future medications for the treatment of Type II Diabetes (DMII).

There are currently 8 classes of non-insulin medications used for DMII, each offering a different mechanism or approach for treating the disease. In the future, the number of classes available will potentially double, possibly even triple, as new research continues.

Introduction

Pancreatic contribution to serum glucose› α-cells

Secrete glucagon Suppresses hepatic glycogen synthesis Stimulates gluconeogenisis and glycogenolysis

Excess will prevent normal suppression of hepatic glucose output, leading to hyperglycemia

› β-cells Secrete insulin, C-peptide, and amylin

Bowels› L cells secrete incretins

Introduction

Renal contribution to serum glucose› Sodium-glucose-cotransporter-1 and -2

(SGLT1 & SGLT2) Reabsorb glucose

› Renal gluconeogensis contributes 20-25% of total glucose production

Hepatic contribution› Glycogen synthesis and metabolism

β-Cell Dysfunction: Incretin Based Treatments

Rationale:› High insulin response to glucose that is

administered orally is brought about by incretins 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

β-Cell Dysfunction

GLP-1 effects:› Potentiates glucose-dependant insulin

secretion and glucagon suppression› Slows gastric emptying› Reduces food intake› In animal studies, it increased mass and

decreased apoptosis of β-cells› Other potential effects:

Promote accumulation of glycogen in liver Increase glucose uptake Lower concentrations of triglycerides

β-Cell Dysfunction GLP-1

› Rapidly inactivated by dipeptidyl peptidase 4 (DPP-4)

› Short circulating t1/2 (<2 minutes)

GLP-1 mimetics› Exenatide (Byetta) and

liraglutide (Victoza)› GLP-1 receptor agonists that

are resistant to DPP-4 Achieved through different

methods of preparation

DPP-4 inhibitors› Highly specific, block DPP-4 to

increase endogenous GLP-1› Sitagliptin (Januvia),

saxagliptin (Onglyza), vildagliptin

β-Cell Dysfunction

GLP-1 Mimetics

Advantages› Weight loss› Low risk of

hypoglycemia› Possible effect on

β-cell survival and decline

Disadvantages› Unknown long-term

safety› Unconfirmed

association with pancreatitis and medullary cell carcinoma

› GI side effects (exenatide once-weekly)

› Avoid in renal failure

β-Cell Dysfunction

New GLP-1 mimetics in the pipeline:› Shortacting

Lixisenatide› Sustained-release

Exenatide once-weekly, taspoglutide, albiglutide, CJC-1134-PC

β-Cell Dysfunction

Other new/potential incretin-based therapies› 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 Linagliptin – low risk of hypoglycemia, no

renal adjustment Alogliptin – good GI tolerability

β-Cell Dysfunction: Non-incretin β-cell Stimulants Glucokinase Activators

(GAs)› Once it enters the β-cell,

glucose is phosphorylated by glucokinase

Affects the rate of glucose metabolism and ATP production

› Effects in animal and human DM II models: Increased insulin

concentrations Reduced glucose

concentrations Additional reduction of

glucose by effects on hepatic glucose metabolism

› Glucokinase activation is associated with increased triglycerides and risk of hypoglycemia

› Drugs being studied: Piragliptin Compound 14 R1511 AZD1656 AZD6370 Compund 6 ID1101

β-Cell Dysfunction: Non-incretin β-cell Stimulants

-Cell Dysfunction

Excess glucagon management› Incretin based treatments

Reduce secretion in a glucose-dependant manner (only in association with hyperglycemia)

Don’t compromise hypoglycemia counter-regulation

› Blocking of glucagon receptor or signaling pathway after binding with the hormone Models show significant reduction in basal

glycemia and improved glucose tolerance Might reduce body’s ability to counteract

hypoglycemia

Drugs Targeting Both -Cell and β-Cell Dysfunction

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 glucose concentrations

However, it increased glucagon concentration Oxyntomodulin

› Agonist at GLP-1R and Glucagon receptor› Induced weight loss, reduced food intake, and

increased energy expenditure in rats

Insulin-Action Enhancers

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 these approaches difficult

› Other potential mechanisms: Attempt to prolong action of the insulin β

subunit Prevention of negative feedback

Drugs Targeting Non-Insulin-Dependant Pathways

Sodium-glucose-cotransporter-2 (SGLT2) inhibitors

Drugs Targeting Non-Insulin-Dependant Pathways

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 hepatic

steatosis› Glycogen phosphorylase inhibitors

Can prevent hyperglycemia without affecting fasting glucose

Drugs Targeting Metabolic Syndrome

GIP antagonists› Potentiates glucose-dependant insulin

secretion, just like GLP-1 agonists It also promotes fat deposition by adipocytes,

does not inhibit glucagon secretion, and has little effect on food intake, satiety, gastric emptying, or bodyweight

› In animal studies: Increased energy expenditure Reduced fat deposition and lipotoxicity Enhanced glucose uptake Improved β-cell function

Drugs Targeting Metabolic Syndrome

11β-hydroxysteroid-dehydrogenase-1 (11 BHD 1) inhibitors› Converts cortisone to cortisol› Phenotypic similarities between metabolic

syndrome and Cushing’s syndrome Inhibition reduced insulin resistance, prevented

stress-induced obesity, improved tolerance, and enhanced insulin-secretory responsiveness in mice

› 200mg of a test drug (INCB13739) added to metformin: Reduced A1c by 0.6% Reductions in total and LDL cholesterol and

triglycerides

Drugs Targeting Metabolic Syndrome

PPAR modulators› Dual PPAR- and PPAR-γ agonists (glitazars)

being developed for combo effect on lipids and glucose Potentially better side effect profile than

glitazones and fibrates

Drugs With Unknown Mechanisms

Dopamine D2-receptor agonists› Bromocriptine

Produces effects on glycemic variables without 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

Metabolic Surgery

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, and needs to be more consistant

› A more detailed investigation is needed

Conclusion

Promising new medications for the future treatment 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 were obtained 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