MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE GUIDELINES Dr

1
MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE
GUIDELINES

• Dr SUNIL ZACHARIAH
• CONSULTANT
  ENDOCRINOLOGIST

2
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

3
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 HbA1clt7,
  whereas International Diabetes Federation
  recommends HbA1clt6.5

4

• Results of ACCORD study, which had the primary
  objective of decreasing CVD with interventions
  aimed at achieving HbA1clt6 vs. interventions
  aimed at achieving hbA1clt7.9, showed excess CVD
  mortality in the intensive treatment group.
• ADVANCE study did not demonstrate any excess CVD
  mortality with HbA1clt6.5
• Individualize target
• Take into consideration factors such as life
  expectancy, risk of hypoglycemia, presence of CVD

5
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

6
Lifestyle interventions

• Weight loss as little as 1 kg will ameliorate
  hyperglycemia
• ? Anti-obesity medications
• NICE guidelines regarding bariatric surgery

7
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

8
TRENDS IN INACTIVITY
9
Physical inactivity as 4th primary risk factor
for all-cause mortality
10
Impact of bariatric surgery on type 2 diabetes

• 60 Obese patients (BMIgt40), with recently
  diagnosed T2DM Australia
• Between 2002-2006
• 30 received lifestyle interventions, 30 had
  gastric banding, along with usual diabetes care
• Remission of T2DM (HbA1clt6.2) 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

11

• 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

12
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

13
DIETARY ADVICE

• Integrate with diabetes management plan
• Sensitive to persons 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

14
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

15
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

16

• 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 lt45 or creatinine gt130, half the dose
• If eGFR lt30 or creatinine gt150, stop metformin

17
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

18
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

19

• 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

20
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 gt0.5 in 6 months
• TZD might be preferable to DPP4 inhibitor if the
  person has marked insulin insensitivity

21
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

22
The action of repaglinide on ? -cells
Glucose
Ca2-dependent K channel
Protein
Metabolism
synthesis
NUCLEUS
Insulin
granules
Cl- channel
ATP
2
Ca
Membrane
potential
Na channel
Insulin
Voltage-dependent Ca2 channel
ATP-sensitive K channel
PRANDIN SmPC Aug 2007
23

• 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

24
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)

25
INCRETIN-BASED THERAPIES
Isoglycaemic glucose infusion
Oral glucose load (50 g/400 ml)
Insulin response
Plasma glucose
80
15
270
60
10
180
Incretineffect
IR-insulin (mU/l)
40
Plasma glucose (mmol/l)
Plasma glucose (mg/dl)

5

90



20


0
0
0
10
5
60
120
180
10
5
60
120
180
Time (min)
Time (min)

• Insulin response is greater following oral
  glucose than i.v glucose, despite similar plasma
  glucose concentration

25
26
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

27
The incretin effect is reduced in patients with
type 2 diabetes
Intravenous Glucose
Oral Glucose
Control subjects
Patients with type 2 diabetes
80
80
60
60
Insulin (mU/L)
Insulin (mU/L)
40
40
20
20
0
0
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Time (min)
Time (min)
P .05 compared with respective value after oral
load. Nauck MA, et al. Diabetologia
1986294652.
28
Incretins and glycaemic control
Bloodglucose control
DPP-4enzyme rapidly degrades incretins
Adapted from 7. Drucker DJ. Cell Metab.
20063153165. 8. Miller S, St Onge EL. Ann
Pharmacother 2006401336-1343.
29
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 sulfonylureametformin, 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 (plt0.05)
  compared to placebo
• Slightly higher rates of constipation,
  nasopharyngitis and dizziness

30
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 population Diabetes
Care, Vol. 29,2006 26382643
31
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

32
Vildagliptin produced an additional 1.1
reduction in HbA1c when added to metformin
Mean baseline HbA1c 8.3-8.4
0.4
0.2
-1.1 vildagliptin vs placebo (plt0.001)
0.0
-0.2
-0.4
Mean change from baseline HbA1C ()
-0.6
-0.8
-1.0
-1.2
4
8
12
16
20
24
0
Time (weeks of treatment)
143
137
130
126
143
n
143
143
143
n
143
143
Vildagliptin 50mg bd metformin
Placebo metformin
from Bosi et al. Diabetes Care, 200730890895
33
NICE DPP-4 inhibitors

• Continue DPP-4 inhibitor therapy only if there is
  a reduction of gt0.5 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

34
Incretins and glycaemic control
Bloodglucose control
DPP-4enzyme rapidly degrades incretins
Adapted from 7. Drucker DJ. Cell Metab.
20063153165. 8. Miller S, St Onge EL. Ann
Pharmacother 2006401336-1343.
35
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

36
Structure of native GLP-1 and two GLP-1 analogues
97 homology to native GLP-1
53 homology to native GLP-1
37
Pivotal phase III clinical studies combined
(ITT) exenatide lowered HbA1c
MET1
SU2
MET SU3
0.5
0.2
P lt 0.002 vs placebo
P lt 0.001 vs placebo
P lt 0.0001 vs placebo
0.1
0

• HbA1c ()

-0.5
-0.4
-0.5
-0.6



-0.8
- 0.8
-1
-0.9



123 125 129
247 245 241
N
113 110 113
8.7 8.5 8.6
8.5 8.5 8.5
Baseline
8.2 8.3 8.2
30-wk data Mean (SE) 1DeFronzo RA, et al.
Diabetes Care 20052810921100 2Buse JB, et al.
Diabetes Care 20042726282635 3Kendall DM, et
al. Diabetes Care 20052810831091.
38
Change in body weight over time, ITT
populationExenatide with metformin
Placebo Exenatide 5 µg Exenatide 10 µg
-0.3 0.3 kg
-1.6 0.4 kg
Mean (SE) change in body weight from baseline
(kg)
-2.8 0.5 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
placebo DeFronzo RA, et al. Diabetes Care
20052810921100.
39
Open-label extension study combined 82-week
completers data. Exenatide continued to reduce
weight
Baseline body weight
98 kg
Placebo BD (N 128) Exenatide 5 µg BD (N
128) Exenatide 10 µg BD (N 137)
100 kg
100 kg
Open-label extension (all patients exenatide 10
µg BD)
Placebo-controlled Trials
1
0
-1
-2
Mean ? body weight (kg)
-3
-4
-5
0
10
20
30
40
50
60
70
80
90
Time (week)
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)
40

• 5 mcg or 10 mcg twice daily
• Main side effects are nausea and vomiting,
  developing antibodies to exenatide

41
NICE EXENATIDE

• Continue exenatide only if a person has a
  reduction in HbA1cgt1 and gt3 of initial body
  weight in 6 months
• Discuss the benefits of exenatide to allow the
  person to make an informed decision

42
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 (plt0.01)
• Main side effects are nausea and vomiting

43
Starting Insulin therapy

• If other measures do not keep HbA1c to lt7.5 (or
  other agreed target), discuss benefits and risk
  of insulin treatment
• Initiate with structured programme