Update on the Management of Type 2 Diabetes

Dr Richard Carroll Endocrinologist

Why Do We Treat Diabetes?

• ‘Well being’

• Symptoms

– Polyuria, thirst, polydipsia, weight loss

• Complications of chronic hyperglycaemia

• Complications of acute hyperglycaemia

“Diabetes” is Not a Diagnosis

1. Type 1 • Autoimmune • Idiopathic

2. Type 2 3. Other specific types

• Genetic defects of β-cell function • MODY 3 (Chromosome 12, HNF-1α) • MODY 1 (Chromosome 20, HNF-4α) • MODY 2 (Chromosome 7, glucokinase) • Other very rare forms of MODY (e.g.,

MODY 4: Chromosome 13, insulin promoter factor-1; MODY 6: Chromosome 2, NeuroD1; MODY 7: Chromosome 9, carboxyl ester lipase)

• Transient neonatal diabetes (most commonly ZAC/HYAMI imprinting defect on 6q24)

• Permanent neonatal diabetes (most commonly KCNJ11 gene encoding Kir6.2 subunit of β-cell KATP channel)

• Mitochondrial DNA • Others

• Genetic defects in insulin action • Type A insulin resistance, Leprechaunism, Rabson-

Mendenhall syndrome, Lipoatrophic diabetes, Others

• Diseases of the exocrine pancreas • PancreatitisTrauma/pancreatectomy, Neoplasia,

Cystic fibrosis, Hemochromatosis, Fibrocalculous pancreatopathy, Others

• Endocrinopathies • Acromegaly, Cushing's syndrome, Glucagonoma,

Pheochromocytoma, Hyperthyroidism, Somatostatinoma, Aldosteronoma, Others

• Drug or chemical induced • Vacor, Pentamidine, Nicotinic acid,

Glucocorticoids, Thyroid hormone, Diazoxide, β-Adrenergic agonists, Thiazides, Dilantin, γ-Interferon, Others

• Infections • Congenital rubella, Cytomegalovirus, Others

• Uncommon forms of immune-mediated diabetes • “Stiff-man” syndrome, Anti-insulin receptor

antibodies, Others • Other genetic syndromes sometimes associated with

diabetes • Down syndrome, Klinefelter syndrome, Turner

syndrome, Wolfram syndrome, Friedreich ataxia, Huntington chorea, Laurence-Moon-Biedl syndrome, Myotonic dystrophy, Porphyria, Prader-Willi syndrome, Others

4. Gestational diabetes mellitus

ADA Classification of diabetes. Diabetes Care

January 2013 vol. 36 no. Supplement 1 S67-S74

When to Think Outside of the Box?

Atypical features

Type 1 Diabetes • GAD antibody negative within five years

of diagnosis • Robust C-peptide levels or >200 pmol/L

after five years

Type 2 Diabetes • Not obese • No evidence of insulin resistance (HTN,

lipids, PCOS, AN)

Family History Syndromic features

• Presented at NZSSD and NZ Paediatric Endocrinology conference 2012

• Discussions with Exeter (A Hattersley, S

Ellard)

• Peer reviewed article • Carroll RW, Murphy R (2013)

Monogenic diabetes: A diagnostic algorithm for clinicians. Genes 4, 522-535

• http://nzssd.org.nz/education/2013%20Monogenic_diabetes_card_with_forms_18%20Dec%20copy.pdf

Diabetes

Microvascular Retinopathy Nephropathy Neuropathy

Macrovascular Cardiovascular

Cerebrovascular Peripheral vascular

Diabetic Nephropathy

Commence screening at five years (T1DM) and immediately (T2DM). Annual screening thereafter

ACR

(mg/g)

ACR

(mg/mmol)

24 hour

(mg)

Normal < 30 < 3.4 < 30

Microalbuminuria 30 – 300 3.4 – 34 30 – 300

Overt Nephropathy > 300 > 34 > 34

• Largest cause of End Stage Renal Failure (ESRF) worldwide

• Associated with ↑ risk of atherosclerosis

Progression of Nephropathy

Normotensive Normoalbuminuric Patients

Possible role for ACE inhibition to reduce progression to microalbuminuria (ABCD) but insufficient evidence at present

Hypertensive Normoalbuminuric Patients

ACE inhibition reduces progression to microalbuminuria and may increase likelihood of regression (BENEDICT / ADVANCE)

Verapamil unlikely to be effective

Patients with Evidence of Nephropathy

Hypertensive patients benefit from Angiotensin II receptor blockade with reduced progression of nephropathy (IDNT / RENAAL)

ACE therapy likely to be as effective (DETAIL)

Combination therapy may be more effective in reducing proteinuria (CALM)

Sensory Motor

Autonomic

Laing 1999

United Kingdom Prospective Diabetes Study (UKPDS)

Conventional

Intensive

0 3 6 9 12 15 0

10

20

30

0

10

20

30

Myocardial infarction p=0.052

Stroke p=0.52

Time from randomisation (years)

0

10

20

30

Microvascular endpoints p=0.0099

0 3 6 9 12 15

Time from randomisation (years)

Patients

with e

vents

(%

)

Patients

with e

vents

(%

) Pa

tien

ts w

ith

eve

nts

(%

)

UKPDS 1998

Long-term Benefit

Glucose Lowering Therapies

Class Generic name Brand name Company

Biguanide Metformin* Glucophage SR® Merck Serono

Secretagogues SUs

Glibenclamide*

Gliclazide*

Glimepiride*

Tolbutamide

Glibenclamide Diamicron MR®

Amaryl® Tolbutamide

Wockhardt UK Servier Laboratories

Sanofi-aventis Sovereign Medical

Class Generic name Brand name Company

Biguanide Metformin* Glucophage SR® Merck Serono

Secretagogues SUs

Meglitinides

Glibenclamide*

Gliclazide* Glimepiride*

Glipizide*

Glipizide*

Tolbutamide Nateglinide

Repaglinide

Glibenclamide Diamicron MR®

Amaryl®

Glibenese®

Minodiab® Tolbutamide

Starlix®

Prandin®

Wockhardt UK Servier Laboratories

Sanofi-aventis

Pfizer

Pfizer Sovereign Medical

Novartis

Daiichi Sankyo

α-glucosidase inhibitors Acarbose Glucobay® Bayer

Incretin mimetic Exenatide

Liraglutide

Byetta®

Victoza®

Eli Lilly & Co

Novo Nordisk

TZDs Pioglitazone

Actos® Takeda

Dipeptidyl peptidase-4 (DPP-4) inhibitors Saxagliptin

Sitagliptin

Vildagliptin

Onglyza®

Januvia®

Galvus®

AZ/BMS Alliance

MSD

Novartis

Biguanide/TZD FDC Metformin/rosiglitazone Avandamet® GSK

Biguanide/DPP-4 inhibitor FDC Metformin/vildagliptin Eucreas® Novartis

SGLT-2 inhibitor Canagliflozin Johnson and Johnson

Amylin mimetic Pramlinitide Symlin®

Amylin pharmaceuticals

Intestinal GIP and GLP-1

Production

Carbohydrate delivery to duodenum

Brain

Increases satiety and

reduces appetite

Liver

Reduced glucose output

Stomach

Slows gastric emptying

Pancreatic α cells

Reduces post prandial

Glucagon secretion

Pancreatic β cells

Enhances glucose

dependent insulin

production

Pancreatic α cells

Reduces post prandial

Glucagon secretion

GLP-1 and GIP are Degraded by the DPP-4 Enzyme

Meal

Intestinal

GLP-1 and GIP

release

GLP-1 and GIP

Actions

DPP-4

Enzyme

GLP-1 and GIP

Intact

GLP-1, GIP

Metabolites Rapid Inactivation

Half-life

incretins ~ 2 minutes

Deacon CF et al. Diabetes. 1995;44:1126–1131.

*Meier JJ et al. Diabetes. 2004;53:654–662.

DPP-4 inhibitor

X

Exenatide (Byetta)

• Exendin-4

• Found in saliva of Gila monster

• Approved in combination with oral

agents

• Can be used alongside insulin

• Average weight loss of 2.3kg over 6/12

• Long acting once weekly injection in

development

Exenatide versus insulin glargine in patients with suboptimally

controlled type 2 diabetes: a randomized trial". Ann Intern Med.

2005 October 18;143(8):559

Liraglutide (Victoza)

• Long acting GLP-1 analog

• GLP-1 bound to albumin with

gradual release

• Half life of 11-15 hour

Types of Insulin

Duration of action Insulin Commercial name

Rapid acting Lispro Humalog

Aspart Novorapid

Glulisine Apidra

Short acting Regular Actrapid

Intermediate acting NPH Protophane

Insulatard

Humulin N

Long acting Detemir Levemir

Glargine Lantus

Types of Insulin Available

Novorapid/Humalog/Epidra

Glargine

Detemir

Pla

sm

a I

nsulin

Levels

0 24 18 12 6 Time (Hrs)

Actrapid

Protophane

Contribution of fasting hyperglycaemia to overall glycaemia increases with worsening diabetes

ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.

Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.

290 patients with T2DM treated with diet or OHAs

100

0

50

Rela

tive c

ontr

ibuti

on (

%)

<7.3 7.3―8.4 8.5―9.2 9.3―10.2 >10.2

HbA1c (%) quintiles

70%

30%

Post Prandial

Fasting

Rapid-acting insulin mimicking endogenous bolus insulin

Long-acting insulin mimicking endogenous basal insulin

Rapid-acting insulin matching individual insulin requirements via a pump

When does your patient need insulin

Relative mortality and glycated haemoglobin (HbA1c) levels in type 2 diabetes in a large United Kingdom general practice observational study.

Opie L H et al. Heart 2011;97:6-14

©2011 by BMJ Publishing Group Ltd and British Cardiovascular Society

Aspirin

• Two certainties:

– Adults (Men < 50 and women < 60) with no risk factors for CVD do not benefit from Aspirin for primary prevention

– Adults (Men > 50 and women > 60) with risk factors for CVD do benefit from Aspirin

• At present evidence is insufficient to direct management of other groups

Benefits of coronary risk factor reduction in diabetics and non-diabetics. Yudkin BMJ 1993; 306

Management Goals for Diabetes

• Glycaemic Control • HbA1c 50 – 60 mmol/mol

• Blood Pressure • <130/80 (125/75)

• Lipids • TC<4.0mmol/L

• LDL<2.5

• HDL>1.0

• TG<1.7mmol/L

Dr Richard Carroll Endocrinologist

027 583 3242

Richard.carroll@ccdhb.org.nz

www.endocrinologynz.com