update on the management of type 2 diabetes · update on the management of type 2 diabetes dr...
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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
www.endocrinologynz.com