Overview of the Novel Diabetes

Therapies in Patients of T2DM

/

Classification and Diagnosis of

Diabetes

Criteria for the Diagnosis of

Diabetes

Categories of increased risk

for Diabetes (Prediabetes)

Correlation of A1C with

average glucose

Diabetes Care Vol. 37, Supplement 1, January 2014

Pharmacological Therapy for

Hyperglycemia in Type 2

Diabetes

PROPERTIES OF AVAILABLE

GLUCOSE-LOWERING

AGENTS

Diabetes Care 2016;39(Suppl. 1):S52S59

Pathogenic picture of type 2 diabetes- Ominous Octet

DeFronzo RA. Diabetes. 2009;58:773-795.

Class: Biguanides

Compound: Metformin

Cellular mechanism: Activates AMP-kinase (? other)

Primary physiological action: Hepatic glucose production

Advantages: Extensive experience; No hypoglycemia; CVD events (UKPDS)

Disadvantages: Gastrointestinal side effects (diarrhea, abdominal cramping);

Vitamin B12 deficiency

Contraindications: CKD, acidosis, hypoxia, dehydration, etc.

Lactic acidosis risk (rare)

Class: Sulfonylureas

Compound: 2nd Generation

Glyburide/glibenclamide, Glipizide, Gliclazide, Glimepiride

Cellular mechanism: Closes KATP channels on -cell plasma membranes

Primary physiological action: Insulin secretion

Advantages: Extensive experience ; Microvascular risk (UKPDS)

Disadvantages: Hypoglycemia; Weight

Class: Meglitinides (glinides)

Compound: Repaglinide, Nateglinide

Cellular mechanism: Closes KATP channels on -cell plasma membranes

Primary physiological action: Insulin secretion

Advantages:

Postprandial glucose excursions

Dosing flexibility

Disadvantages:

Hypoglycemia; Weight; Frequent dosing schedule

Class: TZDs

Compound: Pioglitazone, Rosiglitazone

Cellular mechanism: Activates the nuclear transcription factor PPAR-

Primary physiological action: Insulin sensitivity

Advantages: No hypoglycemia; Durability; HDL-C

Triglycerides (pioglitazone) ; CVD events (PROactive,pioglitazone)

Disadvantages: Weight; Edema/heart failure; Bone fractures; LDL-

C (rosiglitazone); ? MI (meta-analyses, rosiglitazone)

Class:-Glucosidase inhibitors

Compound: Acarbose, Miglitol

Cellular mechanism: Inhibits intestinal -glucosidase

Primary physiological action: Slows intestinal carbohydrate digestion/absorption

Advantages: ? CVD events (STOPNIDDM); Postprandial

glucose excursions; No hypoglycemia; Nonsystemic

Disadvantages: Generally modest A1C efficacy; Gastrointestinal side

effects (flatulence, diarrhea); Frequent dosing schedule

Class: DPP-4 inhibitors

Compound: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin

Cellular mechanism: Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations

Primary physiological action: Insulin secretion (glucose dependent)

Glucagon secretion (glucose dependent)

Advantages: No hypoglycemia; Well tolerated

Disadvantages: Angioedema/urticaria and other immune-mediated dermatological

effects

? Acute pancreatitis

? Heart failure hospitalizations

Class: SGLT2 inhibitors

Compound: Canagliflozin, Dapagliflozin, Empagliflozin

Cellular mechanism: Inhibits SGLT2 in the proximal nephron

Primary physiological action: Blocks glucose reabsorption by the kidney, increasing glucosuria

Advantages: No hypoglycemia; Weight; Blood pressure; Effective at all stages of

type 2 diabetes

Associated with lower CVD event rate and mortality in patients with CVD (EMPA-REG OUTCOME)

Disadvantages: Genitourinary infections; Polyuria; Volume depletion /hypotension/

dizziness; LDL-C; Creatinine (transient)

DKA, urinary tract infections leading to urosepsis, pyelonephritis

Class: GLP-1 receptor agonists

Compound: Exenatide, Exenatide extended release, Liraglutide, Albiglutide, Lixisenatide, Dulaglutide

Cellular mechanism: Activates GLP-1 receptors

Primary physiological action: Insulin secretion, Glucagon secretion (glucose dependent)

Slows gastric emptying; Satiety

Advantages: No hypoglycemia; Weight; Postprandial glucose excursions;

Some cardiovascular risk factors

Disadvantages: Gastrointestinal side effects(nausea/vomiting/diarrhea); Heart

rate; ? Acute pancreatitis; C-cell hyperplasia/medullary thyroid tumors in animals; Injectable; Training requirements

Class: Insulin

2 2015

NOVEL DIABETES THERAPIES IN

REVIEW -- FOCUS ON DPP-4

INHIBITORS, GLP-1 RECEPTOR

AGONISTS, AND SGLT2 INHIBITORS

DPP-4 INHIBITORS IN THE

MANAGEMENT OF TYPE 2

DIABETES MELLITUS

Incretins

In 1900s, the concept of incretins emerged---

Certain factors

1. produced by the intestinal mucosa in response to nutrient ingestion

2. stimulate the release of substances from the endocrine pancreas

3. reduce blood glucose levels

The term incretin subsequently was used to denote these glucose-lowering, intestinal-derived factors.

To date, only GIP and GLP-1 fulfill the definition of an incretin hormone in humans.

Incretins: Glucagon-like peptide 1 (GLP-1) and

glucose-dependent insulinotropic polypeptide (GIP)

Released from the GI tract after a meal

This incretin effect: approximately 60% of the insulin

secreted after a meal in a healthy person.

The incretin effect in a patient with T2DM is markedly

reduced: < 20% of the postprandial insulin response.

GLP-1 and GIP have a half-life of approximately 2

minutes--- metabolized rapidly by the serine protease

enzyme dipeptidyl peptidase-4 (DPP-4).

DPP-4 inhibitors are highly selective, competitive, and

potent inhibitors of the DPP-4 enzyme and have been

shown to increase GLP-1 concentrations by approximately

4-fold.

Incretin effect

DMIncretindiminished, but preserved

(50%70% of

the total insulin)

Intravenous GLP-1 infusion in T2DM patients

*P

DPP-4 inhibitors

Dipeptidylpeptidase-4 inhibitors enhances GLP-1

levels through inhibition of DPP-4

GLP-1 t =12 mininactive

Currently Available DPP-4 Inhibitors Approved by the EMA and

US FDA for Use in Patients With T2DM

What Reductions in A1C Should

We See With DPP-4 Inhibitors?

In general, a DPP-4 inhibitor is likely to provide

a 0.4%-0.5% decrease in A1C.

When used in combination with other

antidiabetic compounds, the fall in A1C is

variable

eg, with sitagliptin + metformin, A1C reduction:

0.65%-1.1% from baseline 7.2%-8.7%.

Are There Any Body Weight, Blood Pressure, or

Lipid Benefits With DPP-4 Inhibitors?

Neutral effect on body weight

The effects of DPP-4 inhibitors on lipid profiles

and blood pressure are inconsistent

Is Hypoglycemia Commonly

Seen With DPP-4 Inhibitors? DPP-4 inhibitors have an antihyperglycemic effect only when

glucose levels are raised. Thus, the incidence of hypoglycemia

with this class of drugs is very low !

The effect of GLP-1 on glucagon is glucose-dependent.

The counterregulatory response to hypoglycemia-- raising

glucagon to counteract low blood glucose levels--are not

affected.

Results of CV Safety Trials With

DPP-4 Inhibitors Three large CV safety trials have recently reported on 3

different DPP-4 inhibitors: saxagliptin (SAVOR-TIMI

53); alogliptin (EXAMINE) and sitagliptin (TECOS).

These major studies suggest that DPP-4 inhibitors do

not increase the risk for CV events, but neither do they

provide cardioprotective benefit.

For patients with renal impairment

Summary of Properties of DPP4

Inhibitors

GLP-1 RECEPTOR AGONISTS

IN THE MANAGEMENT OF

TYPE 2 DIABETES MELLITUS

GLP-1 RAs: How Do They Work?

Human GLP-1 has a short half-life and is broken down

rapidly by DPP-4.

GLP-1 receptor agonists (GLP-1 RAs) are resistant to

proteolysis by DPP-4.

GLP-1 RAs

stimulate GLP-1 receptors at pharmacologic doses

increasing insulin & decreasing glucagon release

inhibit gastric emptying & decrease appetite (ie, increase

satiety)

beneficial effects on glycemic control and additional benefits

on body weight, blood pressure, cholesterol levels, and beta-

cell function.

Additional physiological benefits are observed at pharmacological levels of GLP-1

DPP-4is, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonistsAdapted from Holst et al1

1. Holst JJ et al. Trends Mol Med 2008;14:161168; 2. Flint A et al. Adv Ther 2011;28:213226

Physiological GLP-1 levels

Pharmacological GLP-1 levels

GLP-1 effects

Incre

asin

g p

lasm

a G

LP-1

concentr

ations

GLP-1RAs

DPP-4is

Insulin Glucagon= Plasma glucose2

Appetite Food intake= Weight loss2

Gastric emptying

37

Exenatide Exendin-Based GLP-1

53% identical to native human GLP-1

The first GLP-1 RA (exenatide twice daily)

Approved in Europe in 2006.

Gila monster Exendin-4

Liraglutide :Human GLP-1

Knudsen et al. J Med Chem 2000;43:16649; Degn et al. Diabetes 2004;53:118794

97% GLP-1

C-16 ( )

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Glu

Arg

7 9

36

Liraglutide

DPP-4 13

GLP-1

7

36

9

Lys

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

DPP-4

= 1.5 2.1

DPP-4: -4

What Reductions in HbA1c

Should We See With GLP-1 RAs?

GLP-1 RAs produce superior glycemic control

compared with orally available diabetes

medications (eg, DPP-4 inhibitors and--in most

studies--sulfonylureas.

In head-to-head clinical trials, liraglutide and

dulaglutide caused the greatest and equivalent

reductions in HbA1c levels.

Benefits Beyond Glycemic

Control With GLP-1 RAs

GLP-1 RAs cause a decrease in body weight of

approximately 3 kg

GLP-1 RAs have positive effects on blood

pressure and lipid parameters.

Safety and Adverse Effects of

GLP-1 RAs GLP-1 RAs have a low risk for hypoglycemia

GLP-1 RAs most frequently cause AEs of nausea,

vomiting, and diarrhea

These GI side effects tend to be transient and generally mild

to moderate in severity

Pancreatitis is a rare event and has been reported

with the use of GLP-1 Ras

they should be discontinued if pancreatitis is

suspected and used cautiously in patients with a

history of pancreatitis

Results of CV Safety Trial With

GLP-1 RA

Results from the first cardiovascular outcomes

trial with a GLP-1 RA, lixisenatide

Neutral. Not increase cardiovascular risk or provide

cardiovascular benefit.

Victoza(Liraglutide) Significantly Reduced the

Risk of Major Adverse Cardiovascular Events in

the LEADER Trial (Mar 04, 2016)

The detailed results are planned to be presented at

the 76th Scientific Sessions of the American Diabetes

Association in June 2016.

SGLT2 INHIBITORS IN THE

MANAGEMENT OF TYPE 2

DIABETES MELLITUS

SGLT2 Inhibitors: How Do They Work?

SGLT2 inhibitors have an insulin-independent mechanism of action.

SGLT2 inhibitors increase urine glucose excretion and produce osmotic diuresis.

Therapeutic SGLT2 inhibition has shown reductions in blood glucose, A1C, body weight, and blood pressure.

Sodium- Glucose Cotransporters

SGLT1 SGLT2

Site Mostly intestineSome kidney

Almost exclusively kidney

Sugar Specificity Glucose or galactose Glucose

Affinity for glucose HighKm= 0.4 Mm

Low Km = 2 Mm

Capacity for glucose transport

Low High

Role Dietary glucose absorptionRenal glucose reabsorption

Renal glucose reabsorption

Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

Normal Renal Glucose Physiology

180 g of glucose is filtered each day

Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation

SGLT2 reabsorbs about 90% of the glucose

SGLT1 reabsorbs about 10% of the glucose

Virtually no glucose excreted in urine

The Kidneys Play an Important Role in Glucose Control

Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Targeting the Kidney

Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

Renal Glucose Transport

Altered Renal Glucose Control in Diabetes

Thats Why Renal Glucose be targeted !

Gluconeogenesis is increased > 2X in postprandial relative to the postabsorptive states in T2DM patients

Renal contribution to hyperglycemia

3-fold increase relative to patients without diabetes

Glucose reabsorption

Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemicindividuals

Marsenic O. Am J Kidney Dis. 2009;53:875-883. Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277. Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434.

Reductions in HbA1c With

SGLT2 Inhibitors Mean Change From Baseline With SGLT2 and DPP-4 Inhibitors

Stratified by Baseline HbA1c Levels: Patients With T2DM Had Mean

eGFR of 94 mL/min/1.73 m2

Body Weight, Blood Pressure, or Lipid

Benefits With SGLT2 Inhibitors

Osmotic diuresis causes fluid loss and volume depletion

and a short-term weight loss but does not contribute to

weight loss over the long term, which is related to a loss

of calories linked to glycosuria.

SGLT2 inhibitors increase fat oxidation and decrease waist

size loss of body fat

BW loss: 2-3 kg --- reaches a maximum after a few

months, maintained over the long-term

a fall in SBP ( 3-4 mm Hg), DBP (2 mm Hg) (without HR

increase)

HDL -C, TG , LDL-C, little or no change in HDL-

C/LDL-C ratio (Mechanisms unknown)

Safety and Adverse Effects With

SGLT2 Inhibitors? SGLT2 inhibitors have a low rate of hypoglycemic

events

AEs:

Genital infections (10-15% in women, 1-4% in men),

Repeated UTI

Polyuria and volume depletion postural dizziness,

hypotension, dehydration, fainting

Transient decrease in eGFR of 3%-10%

A signal for an increase in risk for bladder, prostate, and

breast cancer in the dapagliflozin clinical trials (no evidence

for carcinogenic or genotoxic activity in preclinical studies)

Diabetic ketoacidosis, rare adverse event ---

mechanisim may be:

Lowering the insulin dose to reduce the risk for hypoglycemia

in insulin-treated patients can contribute to ketoacidosis, as

there is insufficient insulin to suppress lipolysis and

ketogenesis

SGLT2 inhibitors cause glucagon secretion, which can

stimulate ketogenesis

SGLT2 inhibitors may decrease renal clearance of ketone

bodies, increasing plasma ketone body levels

Other contributing factors could be major illness and/or

reduced food and fluid intake

Safety and Adverse Effects With

SGLT2 Inhibitors?

Results of CV Safety Trials With SGLT2i

--- EMPA-REG OUTCOME trial

A 14% reduction in the primary endpoint

The primary outcome was: death from

cardiovascular causes, nonfatal myocardial

infarction, or nonfatal stroke (3-point major adverse

cardiac event [MACE])

A 35% reduction in heart failure hospitalization

In a patient population with established cardiovascular disease,

empagliflozin reduced the risk for death from CV and all-cause

mortality, and the benefit appeared early in the first few months

of the trial and continued to grow until study end

Results of CV Safety Trials With SGLTi :

38% reduction in CV death, 32%

reduction in all-cause mortality

Sulfonylureas (and insulin) Metformin

Thiazolidinediones

GLP-I analogs &DPP IV inhibitorsSGLT2 inhibitors

SUMMARY

Drugs used in diabetes