Barriers to Achieving Glycaemic Goals:

A Focus on Hypoglycemia and Weight Gain

Lobna F El toony

Head Of Diabetes & Endocrinology Unit

Internal Medicine Department Assuit

University

UEDA – Aswan 2012

Diabetes is the epidemic of the new century

Egypt will face explosive growth of diabetes

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

Egypt

Iran

Iraq

Saudi

Ara

bia

Alger

ia

Mor

occo

Syria

Sudan

UAE

Tunis

ia

Jord

an

Kuwai

t

Leba

non

Liby

a

Bahra

in

2003

2025

Due to a rapidly increasing & ageing population, Egypt will have the larg umber of people with diabetes in the region by 2025

Sourc

e:

Dia

bete

s A

tlas,

2nd e

ditio

n,

IDF

Type 2 Diabetes

IGT

Dual Defects in Type 2 Diabetes

Environment Genes Environment Genes

ß-cell Dysfunction Insulin Resistance

ADA and AACE/ACE Guidelines: Treatment Goals for A1C, FPG, and PPG

Parameter

Normal1,2

Level

ADA3

Goal

AACE/ACE2

Goal

FPG, mg/dL <100 90–130 <110

PPG, mg/dL <140 <180 <140

A1C, % 4–6 <7a ≤6.5

FPG=fasting plasma glucose; PPG=postprandial glucose; ADA=American Diabetes Association; AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology.

1. Adapted from Buse J et al. In: Williams Textbook of Endocrinology. 10th ed. 2003. Permission requested. 2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68. 3. ADA. Diabetes Care. 2007;30:S4–S41.

aThe goal for an individual patient is to achieve an A1C as close to normal (<6%) as possible without significant hypoglycemia.

Two thirds of individuals do not achieve target HbA1c

Saydah SH, et al. JAMA 2004; 291:335–342.

Liebl A, et al. Diabetologia 2002; 45:S23–S28.

Diabetes management guidelines: a sense of urgency

HbA1c “... the results of the UKPDS mandate that treatment of type 2 diabetes include aggressive efforts to lower blood glucose levels as close to normal as possible”

Diabetes must be… diagnosed earlier. And once diagnosed, all types of diabetes must then be managed

much more aggressively”

“

American Diabetes Association1

Canadian Diabetes Association2

1American Diabetes Association. Diabetes Care 2003; 26:S28–S32.

2Canadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl. 2):S1–S152.

Microvascular complications

Myocardial infarction

HbA1c

37%

14%

Deaths related to diabetes 21%

1%

Stratton IM, et al. BMJ 2000; 321:405–412.

• Hypoglycaemia

•Weigh gain Macrovascular

&

Microvascular

Risk Reduction

Tight Glycaemic

control

Barriers to Achieving Glycaemic Goals: A Focus on Hypoglycaemia

422HQ11NP 027

12

Classification of Hypoglycemic Episodes Based on whether individuals can treat themselves.

Symptomatic definitions:

Mild hypoglycemia: Adrenergic Symptoms (BG<70mg/dl)

(The patient is able to self-treat))

Moderate hypoglycemia: Cognitive impairment (BG<50mg/dl)

“Severe Hypoglycemia”: Unconscious (BG

???)

Unconsciousness and seizures.

The main cause of hypoglycaemia in people with type 2 diabetes is their diabetes medication

Hypoglycaemia occurs when there is an absolute or relative excess of therapeutic insulin in the presence of impaired counter-regulatory mechanisms

This commonly occurs with the use of insulin secretagogues or insulin, which raise insulin levels independently of blood glucose

Causes of hypoglycaemia

Amiel SA, et al. Diabet Med. 2008;25:245-54.

UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.

Pro

port

ion r

eport

ing a

t le

ast

one e

pis

ode o

f severe

hypogly

caem

ia

Error bars, 95% confidence interval.

Severe hypoglycaemic episodes increase with duration of treatment

The proportion of patients with type 2 diabetes experiencing severe hypoglycaemia was similar for those treated with sulphonylureas or insulin for <2 years (7% in both groups)

0.0

0.4

0.2

0.6

T2D sulphonylureas (n= 103) T2D <2 years insulin (n= 85) T2D >5 years insulin (n= 75) T1D <5 years (n= 46) T1D >15 years (n= 54)

Annual Prevalence = 7%

Treated with sulphonylurea

<2 yrs >5 yrs <5 yrs >15 yrs of insulin treatment of insulin treatment

Type 2 diabetes (T2D) Type 1 diabetes (T1D)

Consequences of hypoglycaemia

422HQ11NP 027

No. of Antecedent Severe

Hypoglycaemic Episodes

Adjusted Hazard Ratio* for Incident Dementia

(95% Confidence Interval)

≥1 1.44 (1.25-1.66)

1 1.26 (1.10-1.49)

2 1.80 (1.37-2.36)

≥3 1.94 (1.42-2.64)

History of severe hypoglycaemic episodes are associated with a significantly greater risk of dementia

*Adjusted for age (as time scale), BMI, race/ethnicity, education, sex, duration of diabetes, comorbidities, 7-year mean HbA1c level, diabetes treatment, and years of insulin use

History of hypoglycaemia and risk of cognitive decline in older type 2 diabetes patients

Whitmer RA, et al. JAMA. 2009;301:1565-72.

Prior event

HbA1c

HDL

Age

Hypoglycaemia

3.116 (1.744, 5.567)

1.213 (1.038, 1.417)

0.699 (0.536, 0.910)

2.090 (1.518, 2.877)

P Value Hazard Ratio

(confidence limits)

4.042 (1.449, 11.276)

<0.01

0.02

0.01

<0.01

0.01

12 0 2 4 6 8 10

Hazard ratio (confidence limits)

Hypoglycaemia was a major predictor of cardiovascular death in the VADT study

Duckworth W. Presented at the ADA 68th Scientific Sessions, 2008. Available at: http://professional.diabetes.org/presentations_details.aspx?session=3167. Accessed: 12 Nov, 2010.

Previous hypoglycaemia may impair cardiovascular autonomic function

Cardiovascular autonomic testing in 20 healthy subjects showed reduced baroreflex sensitivity and reduced mucsle response to vasodilation in those who had experienced a previous hypoglycaemic episode

Potential impact of hypoglycaemia

Likely consequences of hypoglycaemia include:

Physical and psychological morbidity and, in severe cases, fatality

Compromised physiological and behavioural defences against subsequent falling plasma glucose concentrations, causing a vicious cycle of recurrent episodes

Hypoglycaemia may preclude the maintenance of euglycaemia over a lifetime of diabetes and therefore

limits the vascular benefits from glycaemic control

Cryer PE. Diabetes. 2008;57:3169-76

Current guidelines generally recommend:1-4

HbA1c level ≤7.0% (53 mmol/mol) to lower the risk of micro and macrovascular complications

OR

HbA1c level ≤6.5% (48 mmol/mol) to achieve near normoglycaemic control

- Episodes of hypoglycaemia should be carefully titrated against this

- Individuals with hypoglycaemia unawareness or severe hypoglycaemia should

raise their glycaemic targets to avoid further episodes of hypoglycaemia

Selecting the most appropriate therapy and individualising treatment are key to reducing the prevalence of hypoglycaemia

Education and motivation are important to avoid hypoglycaemia

Current goals and the importance of individualisation

1. Canadian Diabetes Association. Can J Diabetes. 2008;32(Supp1):S1-S201. 2. American Diabetes Association. Diabetes Care. 2009;32(Suppl 1):S13-61. 3. Matthaei S, et al. Exp Clin Endocrinol Diabetes. 2009;117:522-57. 4. Rydén L, et al. Eur Heart J. 2007;28:88-136.

Behavioural Physiological Therapeutic

Missed or irregular meals

Alcohol or drug use

Exercise

Incorrect use of glucose-lowering medication

Advancing age

Longer diabetes duration

Presence of comorbidity

Deterioration of renal and hepatic function

Loss of awareness of hypoglycaemia

Glucose-lowering therapy

Concurrent medication (e.g. aspirin, warfarin, NSAIDs)

Risk factors for hypoglycaemia

Amiel SA, et al. Diabetic Med. 2008;25:245-54.

Glucose-lowering agents classified by risk of hypoglycaemia

1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Cefalu WT. Nature. 2007;81:636-49.

High risk1,2 Low risk1,2

Insulin Metformin

Sulphonylureas -glucosidase inhibitors

Glinides Pioglitazone

GLP-1 receptor agonists

DPP-4 inhibitors

Hypoglycaemia in elderly people with type 2 diabetes

422HQ11NP 027

Detection is more problematic

• Blunted symptoms (may be different from younger patients)

• Impaired cognition

Presence of multiple risk factors

•Multiple comorbidities and medication

•Renal impairment

•Poorly-adapted behaviour response

•Rare use of self-monitoring and lack of education

Potentially serious, sometimes life-threatening consequences

• Impairment in heart and brain function

• Cardiovascular events

• Falls and injury

• Cognitive decline

The problem of hypoglycaemia in elderly patients

Lecomte P. Diabetes Metab. 2005;31:5S105-5S111.

Symptoms of hypoglycaemia are not specific in nature:

Weakness

Unsteadiness

Sleepiness

Feeling faint

Feeling light-headed

Poor concentration

Neurological symptoms of hypoglycaemia may be misinterpreted as...

Transient cerebral ischaemia

Vertebrobasilar insufficiency

Vasovagal attacks

Cardiac dysrhythmia

Hypoglycaemia may be underestimated in elderly people with type 2 diabetes

McAulay V, et al. Diabet Med. 2001;18:690-705.

Summary 1 Hypoglycaemia is a potentially serious complication in type 2 diabetes, especially in the elderly Hypoglycaemic episodes may be associated with

cardiovascular death, MI, cardiac arrhythmias, nervous system abnormalities and cardiac ischaemia

Individualised treatment is key in order to avoid hypoglycaemia and glucose-lowering medication must be adapted to each person’s needs and lifestyle.

Several glucose-lowering agents (e.g. insulin secretagogues and insulin therapy) may increase the risk of hypoglycaemia

Fear of hypoglycaemia and the risks associated with treatment may cause individuals to stop taking their medication – a major barrier to achieving glycaemic control

Barriers to Achieving Glycaemic Goals:

A Focus on Weight Gain and Obesity

Cut-off points for overweight and obesity in European and Asian populations

BMI (kg/m2) European1

BMI (kg/m2) Asian2

Normal 18.5–24.9 18.5–22.9

Overweight (pre-obese) 25–29.9 23–24.9

Obese ≥30 ≥25

Overweight/obesity: classification

1. Tsigos C, et al. Obes Facts. 2008;1(2):106-16. 2. WHO Expert Consultation. Lancet. 2004 Jan 10;363(9403):157-63. 3. James WPT. J Intern Med. 2008;263:336-52.

The optimum population BMI is considered to be ~213

The vast majority of people with type 2 diabetes are overweight or obese

World Health Organization Fact sheet: Obesity and overweight. Available at: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed: 12 Nov, 2010.

A large proportion of people have metabolic

syndrome

Overweight/obese

10%

90%

Normal

Individuals with type 2 diabetes

Prevalence of Sedentary Life & Obesity in Egypt

Prevalence of sedentary lifestyle & obesity in the Egyptian population aged ≥ 20 years by residence and socio-economic status (1992-1994)

Prevalence of Obesity

(%)

Prevalence of Sedentary

Lifestyle

(%)

Residence &

Socio- economic

Status

16

37

49

27

52

73

89

63

Rural

Urban (Lower SES)

Urban (Higher SES)

Total

SES= Socio-economic status

Visceral fat independently predicts all-cause mortality in men

Kuk JL, et al. Obesity. 2006;14:336-41.

Modeled data for odd ratios for mortality with increasing visceral fat mass after control for age and follow-up time

Odds r

atios f

or

mort

ality

0

Visceral Fat (kg)

2

6

0

5

4

1

3

0.25 0.5 0.75 1 1.25

N=291 p<0.05

Atherosclerosis in youth is linked to obesity

McGill HC, et al. Circulation. 2002;105:2712-8.

Mean extent of right coronary artery lesions by BMI and panniculus thickness in young men (N=2133)

<25 25-30 >30

Surf

ace a

rea involv

ed (

%)

0

12

10

8

6

2

Body mass index (kg/m2)

<25 25-30 >30

Surf

ace a

rea involv

ed (

%)

0

4

2

1

Body mass index (kg/m2)

Panniculus thickness ≤ median for sex and BMI

Panniculus thickness > median for sex and BMI

4

3

Fatty Streaks Raised Lesions

Abdominal obesity = cardiometabolic risk

Overweight/obesity is an important risk factor for cardiometabolic disease

Hamdy O, et al. Curr Diabetes Rev. 2006 Nov;2(4):367-73.

Excess body weight, especially intra-abdominal fat, adversely impacts many cardiometabolic risk factors, including:

Hypertension

Dyslipidaemia

Insulin resistance

Type 2 diabetes

Mechanisms linking excess body fat and obesity to disease

422HQ11NP057

Adipose tissue is a dynamic endocrine organ

↑IL-6

↓Adiponectin

↑Leptin

↑TNF

↑Adipsin (Complement D)

↑PAI-1

↑Resistin

↑FFA

↑Angiotensinogen

↑Leptin

Adipose tissue

↑Insulin

↑Insulin

↑Insulin

↑ Insulin

↑Insulin

↑Insulin

Inflammation

Thrombosis

Atherosclerosis Atherosclerosis

Type 2 Diabetes

Hypertension

Dyslipidaemia

Lyon CJ, et al. Endocrinology 2003;144:2195-200. Trayhurn P, Wood IS. Br J Nutr 2004;92:347-55.

Apoptosis

Angiogenesis

Fibrosis

Hypertrophy

Adiponectin has beneficial effects on the cardiovascular system

Shibata R, et al. Circ J 2009; 73: 608-14.

Adiponectin protects cardiovascular tissues under conditions of stress

TZDs

Caloric restriction

Inflammation

Cardiovascular protection

Adiponectin

In diabetes, elevated plasma FFAs fail to decline normally in response to insulin

Similar abnormalities in FFA metabolism are found in individuals with impaired glucose tolerance and in non-diabetic, insulin-resistant, obese individuals

Increased visceral fat is specifically related to FFA-associated insulin resistance

Visceral fat Subcutaneous fat

People with diabetes, especially obese individuals, are characterised by elevations in free fatty acids (FFAs)

Bays H, et al. J Clin Endocrinol Metab. 2004;89:463-78.

Involvement of adipose tissue, liver and muscle in obesity-induced CV disease

Van Gaal LF, et al. Nature. 2006;444(7121):875-80.

(visceral) adipose tissue

Macrophage recruitment

Ectopic fat Myocellular

ectopic fat

Endothelial dysfunction

Atherosclerosis

RBP-4

NEFAs

NEFAs

Diabetes Insulin resistance

MCP-1

TNF-

IL-6

Adiponectin

CRP PAI-1

VLDL

LDL-ox ICAM-1

ROS

INFLAMMATION

Cross-talk among adipocytes, macrophages and endothelial cells in inflamed adipose tissue

Local insulin resistance? Systemic insulin resistance?

Local angiogenesis

Adipokines

Macrophage

Proinflammatory cytokines/chemokines Angiogenic factors

MCP-1

IL-6

IL-1b

TNF-

Cross-talk

Adipocyte

Insulin resistance

CCL2

CCR2

Monocyte rolling Attachment Transendothelial migration

Neels JG, Olefsky JM. J Clin Invest. 2006;116:33-5.

Increased body weight is associated with increased death rates for cancer

Calle EE, et al. N Engl J Med 2003;348:1625-38.

For each relative risk, the comparison was between men in the highest body-mass-index (BMI) category (indicated in parentheses) and men in the reference category (body-mass index, 18.5 to 24.9). Asterisks indicate relative risks for men who never smoked. Results of the linear test for trend were significant (P≤0.05) for all cancer sites

Type of Cancer (highest BMI category)

Prostate (35)

Non-Hodgkin’s lymphoma (35)

All cancers (40)

All other cancers (30)

Kidney (35)

Multiple myeloma (35)

Galbladder (30)

Colon and rectum (35)

Oesophagus (30)

Stomach (35)

Pancreas (35)

Liver (35)

Relative Risk of Death (95% Confidence Interval)

7

Mortality from cancer according to BMI for men

1 2 3 4 5 6

4.52

2.61*

1.94

1.91*

1.84

1.76

1.71

1.70

1.68*

1.52

1.49

1.34

1. Young T, et al. J Appl Physiol. 2005;99:1592-9. 2. Tasali E, et al. Chest. 2008;133;496-506. 3. Foster GD, et al. Diabetes Care. 2009;32:1017-9.

Obstructive sleep apnoea (OSA) associated with type 2 diabetes and obesity

Excess weight is an important risk factor for OSA1

41–58% of OSA is estimated to be attributable to excess weight

Increasing evidence suggests that OSA has adverse effects on glucose metabolism and risk of diabetes, independent of degree of obesity2

OSA is also a significant risk factor for CV disease and mortality2

Physicians should be aware of the extremely high prevalence (>86%) of undiagnosed OSA

in obese individuals with type 2 diabetes3

Mechanistic Links: Sleep Apnea and Metabolic Dysfunction

Type 2 Diabetes Sleep Apnea

Intermittent

Hypoxemia

Sleep Fragmentation

Sympathetic Activation

HPA dysregulation

Systemic Inflammation

Insulin

Resistance

b-cell

Dysfunction

?

Weight gain as a consequence of treatment

422HQ11NP057

Glucose-

lowering therapy

Diabetes

Weight gain/

obesity

Peters AL. Cleve Clin J Med. 2009 Dec;76 Suppl 5:S20-7.

Treatment-related weight gain, and/or weight gain through “defensive snacking”

because of hypoglycaemia

Increases CV risk

+

-

+

Inter-relationship between overweight/obesity, diabetes and CV risk: potential impact of treatment-related weight gain

CV risk

Decreases CV risk

Years

Insulin (n=409)

0

1

5

0 3 6 9 12

8

7

6

4

3

2 Conventional (n=411)*

* Conventional treatment; diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L (>270 mg/dL) n=at baseline

UKPDS: up to 8 kg in 12 years1

ADOPT: up to 4.8 kg in 5 years2

Annualised slope (95% CI) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2) Glibenclamide, -0.2 (-0.3 to 0.0)

Glibenclamide (n=277)

Metformin (n=342)

Treatment difference (95% CI) Rosiglitazone vs metformin 6.9 (6.3 to 7.4); P<0.001 Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1); P<0.001

Weig

ht

(kg)

Years

96

92

88

0

100

0 1 2 3 4 5

Change in w

eig

ht

(kg)

Most current therapies result in weight gain over time

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. 2. Kahn SE, et al (ADOPT). N Engl J Med. 2006;355:2427-43.

On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisations for rosiglitazone

Range of weight change (kg) in response to diabetes medications

Glucose-lowering medications and weight profile

Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8:573-84.

Range of weight change (kg)

Sulphonylureas

Glinides

Thiazolidinediones

Insulin

DPP-4 inhibitor (sitagliptin)

Metformin

GLP-1 receptor agonist (exenatide)

-6 -4 -2 0 2 4 6 8 10

Combination therapy and weight gain

Rodbard HW, et al. Endocr Pract. 2009;15:540-59.

Consensus statements from the AACE-ACE

Combined use of any 2 or all 3 of these agents may result in an

increased risk of weight gain

Insulin + SUs Insulin + TZDs SUs + TZDs

AACE: American Association of Clinical Endocrinologists ACE: American College of Endocrinology

- Blocks +Promotes

Foley JE, et al. Vasc Health Risk Manag. 2010 Aug 9;6:541-8.

DPP-4 inhibitors have weight-neutral effect in T2D patients, either as monotherapy and as add-on therapy to other oral agents

DPP-4 inhibitors

Some medications have a weight-neutral effect

FFA

+ Lipolysis

+ Fat oxidation

Apo B-48 Intestinal TG absorption -

Defensive snacking as a potential mechanism for weight gain in diabetes

Russell-Jones D, Khan R. Diabetes Obes Metab. 2007;9:799-812.

In the DCCT, insulin-treated patients with severe hypoglycaemia had a significantly (P<0.05) greater increase in weight than those without severe hypoglycaemia during the study

A potential explanation for this is “defensive snacking” – an increase in a patient’s carbohydrate intake following hypoglycaemia due to their fear of further events

Patients with severe hypoglycaemia

Patients without severe hypoglycaemia

0 2 4 6 8

Weight gain (kg)

+6.8 kg

+4.6 kg

Beneficial effects of modest and major weight reduction

422HQ11NP057

1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Knowler WC, et al. N Engl J Med. 2002;346:393-403. 3. Bouldin MJ, et al. Am J Med Sci. 2006;331:183-93.

Weight loss: a cost-effective means of controlling diabetes

The advantages of weight loss are its pleiotropic benefits, safety profile and low cost1

Body w

eig

ht

Reduces the risk of progression from pre-diabetes to overt diabetes2

May help to avoid other comorbidities associated with obesity (e.g. degenerative joint disease and urinary incontinence)3

Improves blood glucose, blood pressure and lipids1

Needs to be maintained in the long term1

Major weight reduction (>10-15%): Recommendations for bariatric surgery

1. IDF position statement. Available at:http://www.idf.org/webdata/docs/IDF-Position-Statement-Bariatric-Surgery.pdf. Accessed 2 Aug 2011.

*In Asian and some other ethnicities of increased risk, BMI action points may be reduced by 2.5 kg/m2

Surgery should be considered: For patients with a BMI of 30−35* kg/m2

whose diabetes is not adequately controlled by optimal medical regimens, especially when there are other major co-morbidities

Surgery should be an accepted option: For individuals with type 2 diabetes and

a BMI of 35 kg/m2 or more

Different bariatric procedures

*With a BMI of approximately 40 kg/m2 Recovery based on fasting plasma glucose <7.0 mmol/l and not receiving hypoglycaemic therapy

1. Colquitt JL, et al. Cochrane Database Syst Rev. 2009;(2):CD003641 2. Buchwald H, et al. Am J Med. 2009;122:248-256.e5. 3. Sjostrom L, et al. N Engl J Med. 2004;351:2683-93.

Major weight loss may be associated with recovery of type 2 diabetes in some individuals1,2

Recovery of type 2 diabetes in severely* obese individuals receiving either bariatric surgery or conventional therapy2

Patients

with d

iabete

s r

em

issio

n (

%)

20

0 Surgical (N=342)

72%

40

60

80

100

Control (N=248)

21%

Surgical (N=118)

Control (N=84)

36%

13%

N = 2037

2 Years 10 Years

p<0.001

p<0.001

Most people with type 2 diabetes (T2D) are overweight or obese

T2D as a result of obesity is responsible for a significant proportion of obesity-related disability and life-years lost

Abdominal obesity is most strongly associated with a constellation of risk factors linked with diabetes and cardiovascular disease

Other comorbidities such as obstructive sleep apnoea and depression may be associated with obesity in type 2 diabetes

Glucose-lowering medications provide options to choose weight-neutral or weight-loss drugs

Bariatric surgery should be considered for severely obese patients with T2DM

Summary 2

THANK YOU FOR TRYING

TO STAY AWAKE

Lobna F El Toony