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MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE GUIDELINES
Dr SUNIL ZACHARIAH CONSULTANT ENDOCRINOLOGIST
INTRODUCTION
• The epidemic of type 2 diabetes and the recognition that achieving specific glycaemic goals can substantially reduce morbidity have made the effective treatment of hyperglycemia a top priority
• Intensive glycaemic control has been demonstrated to have a powerful beneficial effect on diabetes-specific microvascular complications, including retinopathy, nephropathy and neuropathy
• Development of new classes of blood glucose-lowering medications to supplement the older therapies has increased the number of treatment options
GLYCEMIC GOALS OF THERAPY
• DCCT (Diabetes Control and Complications Trial), UKPDS (UK Prospective Diabetes Study) and Stockholm Diabetes Study in Type 1 diabetes have helped to establish the glycaemic goals of therapy that result in improved long term outcomes
• Most recent glycemic goal recommended by the American Diabetes Association is HbA1c<7%, whereas International Diabetes Federation recommends HbA1c<6.5%
• Results of ACCORD study, which had the primary objective of decreasing CVD with interventions aimed at achieving HbA1c<6% vs. interventions aimed at achieving hbA1c<7.9%, showed excess CVD mortality in the intensive treatment group.
• ADVANCE study did not demonstrate any excess CVD mortality with HbA1c<6.5%
• Individualize target• Take into consideration factors such as life
expectancy, risk of hypoglycemia, presence of CVD
HbA1c
• Check 2-6 monthly (according to individual needs) until stable on unchanging therapy
• 6 monthly once blood glucose level and blood glucose-lowering therapy are stable
Lifestyle interventions
• Weight loss as little as 1 kg will ameliorate hyperglycemia
• ? Anti-obesity medications
• NICE guidelines regarding bariatric surgery
‘Diabesity epidemic’
• Increase in prevalence of diabetes is closely linked to marked increase in obesity
• Obesity lies in the causative pathway to glucose intolerance and is a major factor in progression from IGT to type 2 diabetes
• Every 1 kg increase in weight is associated with a 9% relative increase in diabetes prevalence
TRENDS IN INACTIVITY
Physical inactivity as 4th primary risk factor for all-cause mortality
Impact of bariatric surgery on type 2 diabetes
• 60 Obese patients (BMI>40), with recently diagnosed T2DM [Australia]
• Between 2002-2006• 30 received lifestyle interventions, 30 had gastric
banding, along with usual diabetes care• Remission of T2DM (HbA1c<6.2%) while taking
no medications occurred in 73% of surgical group but only 13% of conventional group.
• At 2 year follow-up surgical group lost 20.7% weight while conventional group lost 1.7%
• Impact of bariatric surgery on diabetes does not appear to be purely as a result of weight loss
• Significant improvements in insulin resistance are observed in the first week after surgery before any appreciable weight loss has occurred
• ?effects on gut hormones
PATIENT EDUCATION
• Structured education is an integral part of diabetes care
• Ideally offer it preferably through a group education programme, to every person and/or their carer at and around the time of diagnosis, with annual reinforcement and review
• Programme should meet the quality criteria laid down by DOH and Diabetes UK Patient Education Working Group
• Meet the local cultural, linguistic, cognitive and literacy needs
DIETARY ADVICE
• Integrate with diabetes management plan
• Sensitive to person’s needs, culture and beliefs
• Include high-fibre, low-glycemic index sources of carbohydrate
• Include low-fat dairy products and oily fish
• Control intake of foods containing saturated fats and trans fatty acids
SELF-MONITORING
• Self-monitoring of plasma glucose should be available
• To those on insulin treatment• To those on oral glucose-lowering medications
to provide information on hypoglycemia• To assess changes in glucose control resulting
from medications and lifestyle changes• To monitor changes during intercurrent illness• To ensure safety during activities, including
driving
METFORMIN
• Major effect is to decrease hepatic glucose output and lower fasting glycemia
• Typically metformin monotherapy will lower HbA1c by 0.8-1.5%
• Step up metformin over several weeks to minimize risk of gastrointestinal side effects
• Consider trial of Metformin SR if GI tolerability prevents the person continuing with metformin
• Interferes with B12 absorption, but is very rarely associated with anemia
• Weight stability or modest weight loss• UKPDS demonstrated a beneficial effect of
metformin on CVD outcome• Renal dysfunction with metformin use may
increase the risk of lactic acidosis (less than 1 case per 100000 treated patients)
• If eGFR <45 or creatinine >130, half the dose• If eGFR <30 or creatinine >150, stop metformin
SULFONYLUREAS
• Lower glycaemia by enhancing insulin secretion• Efficacy is similar to metformin • Major adverse effects are hypoglycemia and
weight gain (2 kg)• NICE guidelines• Prescribe a sulfonylurea with a low acquisition
cost (not glibenclamide) when an insulin secretagogue is indicated
• Educate the patient about the risk of hypoglycemia, particularly if he or she has renal impairment
THIAZOLIDINEDIONES
• Glitazones are peroxisome proliferator-activated receptor gamma modulators
• Increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin (“Insulin sensitizers”)
• As monotherapy reduces HbA1c by 0.5-1.4%• More durable effect on glycemic control,
particularly compared with sulfonylyureas
• Weight gain, fluid retention, with peripheral edema
• 2 fold increased risk of CCF• Increase in adiposity, largely subcutaneous, with
some reduction in visceral fat shown in some studies
• TZDs either have a beneficial (pioglitazone) or neutral (rosiglitazone) effect on atherogenic lipid profiles
• Recent meta-analysis on Rosiglitazone
NICE guidelines on Glitazones
• Do not start or continue TZDs if the person has heart failure or is at higher risk of fracture
• Continue TZD therapy only if there is a HbA1c reduction of >0.5% in 6 months
• TZD might be preferable to DPP4 inhibitor if the person has marked insulin insensitivity
GLINIDES
• 2 glinides currently available• Repaglinide and Nateglinide• As monotherapy reduces HbA1c by 1-1.5%• Like the sulfonylureas, the glinides stimulate
insulin secretion, although they bind to a different site within the sulfonylurea receptor
The action of repaglinide on -cells
ATP-sensitive K+ channel
Voltage-dependent Ca2+ channel
Membranepotential
Ca 2+
ATP
Insulin
Glucose
Ca2+-dependent K+ channel
MetabolismProteinsynthesis
Insulingranules
Na+ channel
Cl- channel
Repaglinide
NUCLEUS
PRANDIN SmPC Aug 2007
• The risk of weight gain is similar to sulfonylureas, but hypoglycemia may be less frequent
• Mainly to control post-prandial surge• [As patients get closer to HbA1c target, post
prandial glucose becomes the most significant contributing factor]
ACARBOSE
• NICE: Consider Acarbose for a person unable to use other oral glucose-lowering medications
• Alpha-Glucosidase inhibitor, which reduces the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post prandial glucose levels without causing hypoglycemia
• Increased delivery of carbohydrate to the colon results in increased gas production and GI side effects (25-45% stoppage)
INCRETIN-BASED THERAPIES
IR-i
nsu
lin (
mU
/l)
80
60
40
20
–10 –5 60 120 1800
** * * * * *
Time (min)
Incretineffect
Insulin response
Pla
sma g
luco
se (
mm
ol/l)
–10 –5 60 120 180
10
Time (min)
5
0
15Plasma glucose
Oral glucose load (50 g/400 ml) Isoglycaemic glucose infusion
• Insulin response is greater following oral glucose than i.v glucose, despite similar plasma glucose concentration
25
90
0
180
270
Pla
sma g
luco
se (
mg/d
l)
INCRETIN-EFFECT
• The augmented insulin response to oral glucose (the incretin response), is reported to be reduced or abolished in patients with T2DM
• Restoration of the incretin response could improve glycemic control in such patients
The incretin effect is reduced in patients with type 2 diabetes
0
20
40
60
80
Ins
uli
n (
mU
/L)
0 30 60 90 120 150 180
Time (min)
** *
** **
0
20
40
60
80
0 30 60 90 120 150 180
Time (min)
**
*
*P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia 1986;29:46–52.
Patients with type 2 diabetesControl subjects
Intravenous Glucose
Oral Glucose
Ins
uli
n (
mU
/L)
Incretins and glycaemic control
Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.
Active GLP-1 and
GIP
Release of incretin gut hormones
Pancreas
Bloodglucose control
GI tract
Glucagon from alpha cells
(GLP-1)Glucose
dependent
Alpha cells
Increased insulin and decreasedglucagon reduce hepatic glucose output
Glucose dependent Insulin
from beta cells(GLP-1 and GIP)
Beta cells
Insulinincreases peripheral glucose uptake
Ingestion of food
DPP-4enzyme rapidly
degrades
incretins
SITAGLIPTIN
• Licensed for use in T2DM at a dose of 100 mg once a day
• Can be added to metformin, a glitazone, a sulfonylurea or a sulfonylurea+metformin, when current regime does not achieve glycemic control
• HbA1c reduction of 0.5-1%• Weight neutral and low risk of hypoglycemia• Post prandial glucose also reduced (p<0.05) compared
to placebo• Slightly higher rates of constipation, nasopharyngitis and
dizziness
n=453
n=224
Weeks0 6 12 18 24
% H
bA
1c
7.0
7.2
7.4
7.6
7.8
8.0
8.2
Reduction in HbA1c
of 0.65%
p< 0.001 versus placebo
Placebo + metformin*
Sitagliptin 100 mg o.d. + metformin*
0
24-week Add-on Therapy to Metformin StudyMean change in HbA1c over time9
*Dose of metformin was ≥1,500 mg/day in both arms. All-patients-as-treated populationDiabetes Care, Vol. 29,2006; 2638–2643
VILDAGLIPTIN
• Licensed at a dose of 50 mg once or twice daily• In T2DM as dual oral therapy• Reduces HbA1c by 0.6-1.1%• Reduces postprandial glucose• Weight neutral and low risk of hypoglycemia• Main side effects are headache,
nosopharyngitis, dizziness
Vildagliptin produced an additional 1.1% reduction in HbA1c when added to metformin
Vildagliptin 50mg bd + metformin Placebo + metformin
Me
an
ch
an
ge
fro
m b
as
eli
ne
Hb
A1
C (
%)
Time (weeks of treatment)
-1.2
-1.0
-0.8
-0.4
-0.2
0.0
0.2
0.4
4 8 12 16 20 240
-1.1% vildagliptin
vs placebo(p<0.001)
n=n=
143 137 130 126 143143 143 143 143 143
from Bosi et al. Diabetes Care, 2007;30:890–895
Mean baseline HbA1c: 8.3-8.4%
-0.6
NICE: DPP-4 inhibitors
• Continue DPP-4 inhibitor therapy only if there is a reduction of >0.5% HbA1c in 6 months
• DPP-4 inhibitor is preferable to a Glitazone if• Further weight gain would cause significant
problems• TZDs are contraindicated• Person has a poor response or did not tolerate
TZDs in the past
Incretins and glycaemic control
Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.
Active GLP-1 and
GIP
Release of incretin gut hormones
Pancreas
Bloodglucose control
GI tract
Glucagon from alpha cells
(GLP-1)Glucose
dependent
Alpha cells
Increased insulin and decreasedglucagon reduce hepatic glucose output
Glucose dependent Insulin
from beta cells(GLP-1 and GIP)
Beta cells
Insulinincreases peripheral glucose uptake
Ingestion of food
DPP-4enzyme rapidly
degrades
incretins
GLP-1 Analogues
• Exenatide– Synthetic form of Exendin-4, derived from the
salivary secretions of the Gila monster lizard (Heloderma suspectum)
• Liraglutide– Novel long-acting analog obtained by
acylation of GLP-1 with fatty acid chain
Structure of native GLP-1 and two GLP-1 analogues
97% homology to native GLP-1
53% homology to native GLP-1
0.1
0.2
Pivotal phase III clinical studies – combined (ITT) exenatide lowered HbA1c
30-wk data; Mean (SE) 1DeFronzo RA, et al. Diabetes Care 2005;28:1092–1100; 2Buse JB, et al. Diabetes Care 2004;27:2628–2635; 3Kendall DM, et al. Diabetes Care 2005;28:1083–1091.
Placebo BD
-0.6
-0.8
247 245 241
8.5 8.5 8.5
0.1
-0.5
-0.9
123 125 129
8.7 8.5 8.6
-0.4
- 0.8-1
-0.5
0
0.5
Baseline
N 113 110 113
8.2 8.3 8.2
H
bA
1c (
%)
* P < 0.002 vs placebo * P < 0.001 vs placebo
*
*
*
*
*
*
* P < 0.0001 vs placebo
SU2MET1 MET + SU3
Exenatide 5 µg BD Exenatide 10 µg BD
Change in body weight over time, ITT populationExenatide with metformin
-0.3 ± 0.3 kg
-2.8 ± 0.5 kg
-1.6 ± 0.4 kg
Time (week)
ITT population, N = 336 (Placebo, N = 113; exenatide 5 µg, N = 110; exenatide 10 µg, N = 113)*P ≤ 0.05 ** P ≤ 0.001 compared to placeboDeFronzo RA, et al. Diabetes Care 2005;28:1092–1100.
PlaceboExenatide 5 µgExenatide 10 µg
5 10 15 20 25 300-4
-3
-2
-1
0
1
*
***
**
**** **
*
Mea
n (
±SE
) c
han
ge
in b
od
y w
eig
ht
fro
m b
asel
ine
(kg
)
Open-label extension study – combined 82-week completers data. Exenatide continued to reduce weight
82-wk completers; Mean (SE); Weight was a secondary endpoint Adapted from Blonde L, et al. Poster presented at the American Diabetes Association Meeting 2005 (Abstract 477P)
Baseline body weight98 kg
100 kg100 kg
0 10 20 30 40 50 60 70 80 90-5
-4
-3
-2
-1
0
Mea
n ∆
bo
dy
wei
gh
t (k
g)
Placebo BD (N = 128)Exenatide 5 µg BD (N = 128)Exenatide 10 µg BD (N = 137)
Open-label extension (all patients exenatide 10 µg BD)Placebo-controlled Trials
Time (week)
1
• 5 mcg or 10 mcg twice daily
• Main side effects are nausea and vomiting, developing antibodies to exenatide
NICE: EXENATIDE
• Continue exenatide only if a person has a reduction in HbA1c>1% and >3% of initial body weight in 6 months
• Discuss the benefits of exenatide to allow the person to make an informed decision
LIRAGLUTIDE
• 97% homologous with native human GLP-1• Half life of 11-15 hours• Permitting once daily injection• 1.2 and 1.8 mg/day• Added to metformin plus rosiglitazone, it reduces
HbA1c by 1.5% (p<0.01)• Main side effects are nausea and vomiting
Starting Insulin therapy
• If other measures do not keep HbA1c to <7.5% (or other agreed target), discuss benefits and risk of insulin treatment
• Initiate with structured programme