Diabetes Mellitus II (Acute and chronic complications

Diabetes Mellitus II(Acute and chronic complications, long-

term treatment); Hypoglycemia

National Centre for Diabetes Care

Semmelweis University Faculty of Medicine,1st Department of Medicine

Budapest, 9th October, 2017

Ádám Gy. Tabák

Critical states in diabetes

o Hypoglycemia

o Diabetic ketoacidosis

o Hyperosmolar hyperglycemic state

o Lactic acidosis


o Hypoglycemia



o Lactic acidosis

Hypoglycemia – definition

o Blood glucose content fals < 3 mmol/l (the blood glucose value that could be reached during an extended fasting in healthy subjects)

o If the blood glucose is < 3 mmol/l and no symptoms are present – biochemical hypoglycemia

Hypoglycemia – autonomic symptoms

o palpitations

o tremor

o anxiety

o sweating

o hunger

o nausea

o paresthesia

Hypoglycemia – symptoms of neuroglycopenia

o decreased mental concentration

o headache

o weakness

o fatigue

o drowsiness

o heat sensation

o shivers, cold sensation, chills

o blurred vision, dizziness

o aggression

o disorientation

o convulsion

o coma

Hypoglycemia – frequency

o Severe hypoglycemia with loss of consciousness -10% (third party help is required 2-25% / yr)

o Conventional insulin treatment – mild - 1 / week(severe - 10% / year)

o Intensive insulin treatment – mild - 2 / week(severe - 25% / year)

o Sulfanilurea – mild - 20% / 6 months (severe – 0.2-4.2% /yr, 4-10% deaths)

Healthy

Insulin

(4.6 ± 0.2 mmol/l)

Blood glucose Blood glucose

glukagon

(3.8 ± 0.1 mmol/l)

adrenalin

(3.8 ± 0.1 mmol/l)

(glucose uptake in the brain -3.7 mmol/l)

growth hormone (3.7 ± 0.1 mmol/l)cortisol (3.2 ± 0.2 mmol/l)

(symptoms – 3.0 mmol/l; neuroglykopenia -2.7 mmol/l)

glucose autoregulation

(<2.8 >1.7 mmol/l)

other hormones,

neurtransmitters, other substrates

No / inadequate

insulin

Blood glucose Blood glucose

glukagon

adrenalin

?

DM1T

Counterregulatory response in healthy people and in type 1 diabetes

Type 1 diabetes patients are prone to hypoglycemia

o Insulin autoregulation is lost – the decrease of injected insulin is related to insulin pharmacokinetics

o The production of counterregulatory hormones is disturbed

o After 2 years glucagon response is decreased/absent

o Cathecolamin secretion is decreased

o Secretion of growth hormone and cortisol is decreased

o Neuroglycopenic symptoms are decreased/lost

o Repeat hypoglycemic events could cause hypoglycemia unawarness

Risk factors of hypoglycemic events

o Insulin overdose (timing, type of insulin)

o Carbohydrate intake (lower carbohydrate content/ skipped meal)

o Increased glucose utilisation (physical activity)

o Decreased endogenous glucose production (alcohol consumption, drugs)

o Increase insulin sensitivity (intensive insulin secretion, hypothyreoidism)

o Decreased insulin excretion (renal failure)

Treatment of hypoglycemia in type 1 dabetes

o Next meal is planned within 30 minutes –immediate start of the meal with fast absorbing carbohydrates

o Next meal is planned >30 minutes –intake of 10-20 g fast absorbing carbohydrate, check blood glucose after 15 minutes and repeat treatment as required (i.e. 1 – 2 dl sugar sweetened soda)

o In the case of loss of consciuosness

o 10-40 ml 40% glucose solution iv. (slowly), then oral glucose

o 1 mg glukagon injection (Glucagen Hypokit): sc., im., iv. – requires glikogen stores!

Treatment of hypoglycemia in type 2 diabetes

o If it is related to insulin treatment – as in T1DM

o Oral agent that can cause hypoglycemia (SU, glinid)

o continuous oral feeding

o acarbose treatment- glucose!

o loss of consciousness 10-40 ml 40% glucose solution iv. (slowly) then 5% glucose solution for an extended time period with oral feeding!

o glukagont is not recommended! – it can induce repeated events

o diazoxide, steroid


o Hypoglycemia



o Lactic acidosis

Epidemiology of DKA

o 1.25% of all hospital admissions in type 1 or type 2 diabetes cases

o 4-9% of hospital discharge letters mention DKA if the admission was related to diabetes

o Incidence has increased during the last 10 years in the US (35% over 10 years)

Epidemiology of DKA

o Prognosis

o in hospital mortality of DKA< 5 %, most recently <1%

o the most frequent cause of death among children and adolescents with T1DM

o most important prognostic factors

oolder age

osevere underlying / triggering illness

osevere hypothermia

Biochemical causes of ketosis

o Glucose deficiency (fasting ketosis): normal glucose

o Absolute or relative insulin deficiency: elevated glucose

o Counterregulatory hormones / insulin(stress-related ketosis – alcohol induced ketoacidosis)

elevated/normal/decreased glucose

Pathogenesis of DKA

Kitabchi AE et al Diabetes Care 32:1335-1343, 2009

Causes of DKA

o Insulin deficiency(skipped injection, newly manifested diabetes, pump treatment – tube obstruction)

o Acute stress(AMI, stroke, infection, premenstrual period, acute pancreatitis)

o Illicit drugs(cocaine, „disco-drugs”: ecstasy)

o Non-compliance

Diagnosis of DKA

o elevated blood glucose, usually >13.9 mmol/l

o arterial blood pH < 7.35

o plasma bicarbonate < 15 mmol/l

o increased anion-gap (Se Na – [Se Cl + Se bicarbonate])

o se ketone bodies > 5 mmol/l

o elevated amylase levels

o elevated serum creatinine (spurious due to ketone bodies)

o non-specific elevation of WBC count (10 000-15 000/μl)

Clinical picture

o dry, warm skin, decreased skin turgoro polyuria, polydypsia, weight losso abdominal pain and tenderness

(differentiate from acute abdomen!)o Kussmaul-breathing – smell of aceton

(fruitlike)o symptoms of dehydration

(elevated heart rate, hypotension, decreased blood flow)

o normal or decreased body temperature

Severity of dehydration

o Mildo EC fluid loss ~10% (2l)o orthostatic increase in heart rate

o Moderateo EC fluid loss15-20% (3-4l)o orthostatic hypotension (blood pressure drop

>15/10 mmHg vérnyomásesés)o Severe

o EC fluid loss >20% (>4l)o hypotension even in the lying position

Symptoms of DKA

o acute dilatative gastritis, erosive gastritis

o hematemesis, coffee-ground emesis

o cerebral edema

o Lethargy, somnolence, coma with or without neurological symptoms

o hyperkalemia cardiac arrest

o hipokalemia arrhytmia

o fever

Differential diagnosis of DKA

Kitabchi AE et al Diabetes Care 24:131-153, 2001

Basic aspects of DKA treatment

o fluid

o ions(Na, K, Cl, PO3)

o insulin

o pH-correction

o antibiotics (skin test)

o cardiac support

o prevention of thromboembolic events

o secure iv. access

o urinary catheter

o nasogastric tube

infusion pump! / iv bolus

DKA treatment algorithm

o First hour: 1000 ml physiological saline solution

o Second hour: 1000 ml physiological saline + 2 g KCl8IU Human regular insulin (HRI) as iv. bolus + 8IU Human regular insulin in infusion or as iv.bolus

o pH: correction if pH <7.0 -

400 ml 4.2% NaHCO3 over 3-4 hours (parallel with sodium solution)

DKA treatment algorithmo Third hour and each subsequent hour (until blood glucose

is <13 mmol/l)500 ml physiological sodium solution + 1 gr KCl +8 IU HRI in infusion or as iv. bolus

o If baseline blood glucose is ~50 mmol/l when reaching 25 mmol/l, add 20 ml 40% dextrose to the sodium solution

o If blood glucose reaches 13 mmol/l sc. insulin injection is initiated

if the next planned insulin injection time is

- within 3 hours: 8-12 IU HRI sc.

- ove 3 hours: 12-16 IU HRI

Insulin treatment regimen following a DKA

5 times daily human regular insulin:

o 6.00: if blood glucose <7 mmol/l: 20 IU sc .

7-9 mmol/l: 24 IU sc.

>9 mmol/l : 28 IU sc.

o 12.00 :10-12 IU sc.

o 17.00 :16-20 IU sc.

o 22.00 :10-12 IU sc.

o 03.00 : 3-6 IU sc.

Recommended diet: 6.30 30g, 9.00 20g,12.15 50g, 14.45 20g, 17.15 40g, 19.45 20g, 22.15 15g CH


o Hypoglycemia



o Lactic acidosis

The epidemiology of HHS

o Mentioned on the discharge letter of hospitalised diabetic patients in <1%

o Mortality 15-20%

o Most important prognostic factors

oolder age

osevere underlying / triggering illness

osevere hypothermia

Pathophysiology of HHS

o not yet fully explored

o underlying abnormalities:

o excessive hyperglycemia in the extracellular space

o increased hepatic glucose production

o decreased peripheral glucose utilisation

o although intrecellular, intramitochondrial processes are disturbed, the level of ketone bodies is not elevated,because absolute insulin deficiency is not present and the level of counterregulatory hormones is less pronounced thus free fatty acid mobilisation is limited

Pathogenesis of HHS

o Early stages elevated sodium levelso hyperglycemia and hyperlipidemia cause

pseudohypernatremiao In later stages intracellular hyperhydration

develops that causes truly elevated sodiumlevelso osmotic diuresis related to hyperglycemia

causes water loss that worsens sodium levelso Mental status:

early stages cerebral dehydration causes confusion that temporarily improves then cerebral edema develops and mental status deteriorates to coma

Causes of HHS

o acute illness

o excessive intake of sugar sweetened beverages

o certain drugs (antipsychotics, steroids)

Diagnosis

o Blood glucose >40 mmol/l

o Osmolality >340 mosmol/l

Calculation of osmolality:Se osmolality (mosmol/l) = (SeNa + SeK(mmol/l))X2 + blood glucose (mmol/l) +urea (mmol/l)

BUN is also elevated due to prerenal asotemia

Spuriously elevated amylase and transaminases

o Effective osmolality >320 mosmol/l

(SeNa + SeK (mmol/l))X2 + blood glucose (mmol/l)

Clinical picture of HHS

o slow development of signs and symptoms

o extreme hyperglycemia may develop

o polyuria, polydypsia

o slowly worsening mental status

o progressive signs of dehydration

o prerenal uremia

o convulsions may develop

Therapy of HHS

o No clear cut recommendation

o Insulin treatment: similarly to DKA

o slow continuous decrease of blood glucose is recommended (4-5 mmol/l per hour)

o aim to reach 14 mmol/l during the first day

o after successful treatment some patients will not require insulin treatment

Outlineo Microvascular diabetes complications

o Retinopathyo Neuropathy

oautonomicosensory

o Nephropathyo Prevention of microvascular complications

o Macrovascular diabetes complicationso Ischemic heart diseaseo Strokeo Heart failureo Periferal vascular disease

Clinical Impact of Diabetes Mellitus

Diabetes

The leading cause of new cases of end stage renal

disease

A 2- to 4-fold

increase in cardio-

vascular mortality

The leading cause of new

cases of blindness in

working-aged adults

The leading cause of

nontraumatic lower

extremity amputations

Microvascular complications

Diabetic retinopathy

Retinopathy in Adults not Known to Have Diabetes Rationale for Diagnostic Criteria for DiabetesGlycemic Values in Deciles of Populations

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S19.

FPG

2hPG

HbA1c

Ret

inop

ath

y (

%)

15

10

5

0

US (NHANES III)

42- 87- 90- 93- 96- 98- 101- 104- 109- 120-

34- 75- 86- 94- 102- 112- 120- 133- 154- 195-

3.3- 4.9- 5.1- 5.2- 5.4- 5.5- 5.6- 5.7- 5.9- 6.2-

FPG (mg/dL)

2hPG (mg/dL)

HbA1c (%)

Retinopathy and Blindness in Diabetes Patients

o It is estimated that retinopathy affects 80%-97% of patients with diabetes of >15 years’ duration

o Diabetes is the leading cause of new cases of blindness in adults*

o Diabetic retinopathy accounts for the majority of these cases

o Minimum cost of blindness for working-age adult is estimated at $12,769 per year

Klein R, Klein BEK. In: Diabetes in America. 2nd ed. 1995:293-338.

*Blindness is defined as visual acuity 20/200

Diabetic retinopathy

None Non-Proliferative Proliferative

Mild Moderate Severe

ETDRS: Early Treatment Diabetic Retinopathy Study

Maculopathy

Diabetic maculopathy

None Maculopathy(hard exsudate)

Mild Moderate Severe

44

• Retinal thickening in the area around the

fovea within 500 microns

• Hard exsudates in the area around the

fovea within 500 microns with oedema

• Retinal thickening at least one papilla in

diameter around the fovea within 1

papilla distance

Definition of „clinically significant”

macula oedema (ETDRS)

ETDRS: Early Treatment Diabetic Retinopathy Study

45

Ischemic maculopathy

o Absence of capillary blood flow in the region of sharp-sight

o Irreversible loss of function

o No effective treatment

(Fluorescein angiographia)

Diabetic neuropathy

Sensory neuropathy

Foot Ulcers and Amputations in Diabetes Patients

o >50% of lower limb amputations in the US

o 67,000/yr (1993 -1995)

o Foot ulcers occur in 15% of diabetes patients over a lifetime

o Cost of diabetes-related amputation: $27,000

National Diabetes Fact Sheet. November 1, 1997:1-8.

Reiber GE et al. In: Diabetes in America. 2nd ed. 1995:409-428.

Boulton AJM et al. Lancet 2005; 366: 1719-1724.

The epidemiology of foot ulcers

Annual incidence 2 – 6 %

Prevalence 3 – 8 %

Recurrence rate within 5 years 50 – 70 %

Average healing rates 11 – 14 weeks

1-year amputation rate 15 %

Relationship Between Hyperglycemia and Neuropathyo Slowly progressive disease preferentially affecting the

long axons

o 30% to 40% of all diabetics are symptomatic

o 60% have neuropathy (symptomatic or asymptomatic)

o Peripheral symptoms:

o numbness/tingling in the feet, cramps, sensitivity/ insensitivity to touch, loss of balance/coordination

o Autonomic symptoms:

o urinary incontinence, loss of sexual response, gastric stasis, orthostatic hypotension

o Exact etiology unknown

Diabetic Neuropathy. July 1995 (updated 1996). NIDDK publication NIH 93-3185.

Vinik AI et al. In: Diabetes Mellitus. 1996:737-751.

“Positive“ Symptoms

• Persistent burning or dull pain

• Paroxysmal electric, shooting, stabbing pain

• Dysesthesias (painful paresthesias)

• Evoked pain (hyperalgesia, allodynia)

• Numbness

“Negative“ Symptoms (deficits)

• Hypoalgesia, analgesia

• Hypoesthesia, anesthesia

• Thermal, vibration, pressure sensation, reflexes

A paradox of diabetic neuropathy

Hyperalgesia Allodynia

Signs of Neuropathic Pain

An increased response

to a stimulus that is

normally painful

Pain due to a

stimulus that is

normally not painful

Stimulus-Evoked Pain (Elicited bythe Physician on Examination)

Small fiber neuropathy

o Classical symptoms of diabetic neuropathy + minimal or no signs of neuropathy

o Results of different diagnostic tests are usually normal

Silent foot ulcer present for a few

months

Zick R., Brockhaus KE. Diabetes mellitus.

Fußfibel, Kirchheim, Mainz 2000.

Autonomic neuropathy

Ziegler D. Diabetes Metab Rev 1994; 10: 339-383.

6%

29%

0

10

20

30

40

50

n=708 n=495

Morta

lity

(%

)

Autonomic neuropathy

– +

The natural history of autonomic neuropathy in diabetesMortality rates after 5.8 years of follow-up (metaanalysis)

Painless or silent myocardial infarction

should always be suspected in every diabetic patients suffering from

o acute heart failure / pulmonary oedema

o collapse

o vomiting

o ketoacidosis of unknown origin / unexplained hyperglycaemia

If in a diabetic patient with tachycardia

o hyperthyreodism

o anaemia

o infection can be excluded,

the tachycardia is most likely due to

autonomic neuropathy

Gastrointestinal autonomic neuropathy

o Gastroparesis

o Paroxysmal nocturnal diarrhoea

o Obstipation

o Gallbladder hypomotility / increased risk of gallstones

o Silent / painless acute abdomen

Symptomatic

treatment

Pathogenetically

oriented treatment

The aim of pathogenetically oriented treatment is to

slow down, stop, or even reverse the progression of

neuropathy

Choices of pathogenetically oriented therapy of neuropathy in diabetes mellitus

o Optimal glycaemic control

o Management of risk factors

o Aldose – reductase inhibitors

o Benfotiamin

o Alpha-lipoic acid

*All criteria have to be fulfilled

Treatment of symptomatic diabetic polyneuropathy with α-lipoic acid: a meta-analysis

Included trials in the meta-analysis

o Randomised, double-masked trial

o Placebo-controlled, parallel-group trial

o ALA infusion 600 mg iv per day

o Duration of iv treatment – 3 weeks, weekends excepted

o Daily assessment of Total Symptom Score (TSS), weekends excepted

o Diabetic patients with symptomatic polyneuropathy

Ziegler D et al. Diabet Med 2004; 21: 114-121

Total Symptom Score (TSS)

ALADIN I

ALADIN III

SYDNEY

NATHAN II

Meta-analysis

-40 -20 0 20 40 60 80

GM with 95% CI

%

Favours alpha.lipoic acid; p<0.05

Treatment of symptomatic diabetic polyneuropathy with α-lipoic acid: a meta-analysis

Ziegler D et al. Diabet Med 2004; 21: 114-121

Treatment-Painful neuropathyGeneral MeasuresImprove glycaemic control

Exclude or treat other contributory factors

•Alcohol excess

•Vitamin B12 deficiency/Folate

•Uraemia

Simple analgesia-NSAID/Paracetamol

Explanation, empathy and reassurance

Choose drugs according to dominant symptoms

Burning pain

Tricyclics

Anticonvulsants

Duloxetine

Lancinating pain

Tricyclics

Anticonvulsants

Duloxetine

Other symptomsAllodynia

•Plastic film

•Leg cradle at night

Restless legs

•Ropinirole

Painful Cramps

•Quinine sulphate

Diabetic nephropathy

Kidney Disease in Diabetes Patients

o 27,851 new cases of ESRD in diabetes patients in 1995

o 40% of all new cases in the US

o Nearly 99,000 diabetes patients required dialysis or kidney transplantation that year

o Annual cost of ESRD:

o $45,000 in diabetic patients ages 45-64

National Diabetes Fact Sheet. November 1, 1997:1-8.

U.S. Renal Data System, USRDS 1997 Annual Data Report.

0

5

10

15

20

25

30

1980 1990 1997 2000

international

hungarian

The proportion diabetes among ethiological

factors of end-stage renal disesase

%

Relationship Between Hyperglycemia and Nephropathyo Diabetic nephropathy: persistent proteinuria

(total excretion >500 mg/day), resulting in ESRD

o 25% to 50% of diabetes cases

o mortality from all causes in ESRD patients 20X to 40X higher than in those without renal dysfunction

o Preceded by microalbuminuria (protein excretion 30–300 mg/day)

o 20X higher risk of nephropathy than in normoalbuminuric patients

O’Meara YM et al. In: Harrison’s Principles of Internal Medicine. 14th ed. 1998:1545-1553.

Trevisan R, Viberti GC. In: Diabetes Mellitus. 1996:727-737.

Diabetic nephropathy– clinical symptoms

o No specific clinical symptoms

o Progression of nephropathy is characterized by decrease of glomerular filtration rate (GFR), development of proteinuria (microalbuminuria followed by macroalbuminuria), and hypertension

Proteinuria and mortality in type 1 diabetes years after onset of proteinuria

Reprinted from Jemsen T., Borch-Johnson K., Kofoed-Evevoldsen A., Deckert T.

Diabetologia 30: 144-8; 1987.

Prevalence of cardiovascular diseases in 40-year-old

patients with type 1 diabetes onset in child-hood

Sarti et al. Diabetologia 1998; 41: A350.

4%2%

7%

13%

20%

43%

0

10

20

30

40

50

ischaemic heart disease stroke total cardiovascular

diseases

without diabetic nephropathy

with diabetic nephropathy

n=5148; follow-up: 10-24 years

End-Stage

Progression

Initiation

“At Risk”

Cardiovascular

disease

CHF

Arteriosclerotic

cardiovascular

disease events

Coronary artery disease

Left ventricular hypertrophy

Elderly,

DM, BP

Chronic Renal

disease

ESRD

Chronic renal

insufficiency ( GFR)

Albuminuria

Proteinuria

Elderly,

DM, BP

Adapted from Sarnak and Levey, Am J Kidney Dis 2000;35:S117–31.

Cardiovascular and renal disease continuum

Stage III.

Diabetic nephropathy

Stage V.

Stage IV.

Stage II.

Stage I.

Endstage renal disease

(after 20-25 years)

• MACROALBUMINURIA(> 200 ug/min.)

• Decreased GFR

• Hypertension

Overt nephropathy

(after 15-20 yrs)

• MICROALBUMINURIA

• Normal or low GFR

• Normal or high blood pressure

Incipient nephropathy

(after 5-15 yrs)

• Thickening of the glomerular basal

membrane

• Expansion of the mesangial matrix

Clinically silent renal disease

(after 2-5 yrs)

• Enlarged kidneys

• Increased GFR

Glomerular hypertrophy and

hyperfiltration

GFR: glomerular filtration rate

20-200 mg/min

or

30-300 mg/24 hours

Microalbuminuria

Urinary albumin excretion:

Proteinuria

o It’s generally accepted that diabetic nephropathy is the cause of the proteinuria, if

o Duration of diabetes is > 10 years

o Diabetic retinopathy is present

o No other causes of proteinuria indicated by clinical data

Prevention of microvascular disease

UKPDS MAIN STUDY

Effect of Treatment on HbA1c

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53.

Conventional(10-y cohort)

9

8

7

6

00 3 6

6.2% upper limit of normal range

ADA goal

ADA action

9 12 15Time From Randomization (y)

Intensive(all patients)

Conventional(all patients)

Intensive(10-y cohort)

Med

ian

Hb

A1

c(%

)

UKPDS MAIN STUDY

Risk Reduction of Various Endpoints

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

Risk Reduction (%)

P=0.000054

P=0.015

P=0.052

P=0.0099

P=0.029

0 5 10 15 20 25 30 35

Diabetes-related

end points

Myocardial

infarction

Albuminuria

Retinopathy

Microvascular 25%

21%

16%

33%

12%

UKPDS HYPERTENSION SUBSTUDY

Risk-Reduction of Microvascular Endpoints

UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:

UKPDS 38. BMJ 1998;317:703-13.

Years from Randomization

0

Pati

ents

Wit

h E

ven

ts (

%)

20

1 2 3 4 5 6 7 8 9

10

0

Less Tight Control

Tight Control

Risk-Reduction 37%P=0.0092

Macrovascular complications

Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64)

109

20

11

9 63819

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total CVD CHD Cardiac

failure

Intermittent

claudication

Stroke

Risk

ratio

P<0.001 for all values except *P<0.05.

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.

Ruderman N et al, eds. Oxford; 1992.


Risk-Reduction of Stroke


UKPDS 38. BMJ 1998;317:703-13.

0

Pati

ents

Wit

h E

ven

ts (

%)

20

1 2 3 4 5 6 7 8 9

10

0



Less Tight Control

Tight Control


Diabetes-Related Deaths


UKPDS 38. BMJ 1998;317:703-13.


0

Mo

rta

lity

(%

)40

1 2 3 4 5 6 7 8 9

20

0

30

10

Less Tight Control

Tight Control


SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY (4S)

Diabetes Subgroup AnalysisReduction of Major Recurrent CV Events

Pyorala K et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care

1997;20:614-20.

Years Since Randomization

Pro

po

rtio

n W

ith

Ma

jor

CH

D E

ven

t

0.60

0

0.50

0.40

0.30

0.20

0.10

0.001 2 3 4 5 6

Placebo Simvastatin

Diabetes

Years Since Randomization

Pro

po

rtio

n W

ith

Ma

jor

CH

D E

ven

t

0.60

0

0.50

0.40

0.30

0.20

0.10

0.001 2 3 4 5 6

No Diabetes

Placebo Simvastatin

Risk Reduction 32%P=0.0001

Risk Reduction 55%P=0.002

CV Risk-Reduction With Antiplatelet TherapyHigh-Risk PatientsDiabetes Subgroup Meta-analysis

Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy I: prevention of death, myocardial

infarction, and stroke by prolonged antiplatelet therapy in various categories of patient. BMJ 1994;308:71-2.

No Diabetes Diabetes

n 21,197 21,136

Vascular eventsControl 16.4% 22.3%

Antiplatelet Rx(usually ASA) 12.8% 18.5%

Risk Reduction 28% 21%

Multifactorial treatment of type 2 diabetes – Steno-2

n = 160, DM2T, Gaede P et al. N Engl J Med 348:383-393, 2003

Intenzív

Konvencionális

<4.5 mmol/l <1.7 mmol/l

Multifactorial treatment of type 2 diabetes – Steno-2

n = 160, DM2T, Gaede P et al. N Engl J Med 348:383-393, 2003

Mikrovaszkuláris szövődmények Makrovaszkuláris szövődmények

RR 0.47 (95% CI 0.22-0.74, P=0.01)

Outlineo The effect of glycemic treatment on

complicationso microvascular diseaseo macrovascular disease

o Pathophysiology of hyperglycemiao Treatment targetso Selecting the right treatmento Non-pharmacological therapyo Pharmacological therapyo Treatment algorithm

The effect of glycemic treatment on complications

o Microvascular disease

o Macrovascular disease

KUMAMOTO STUDY

The effect of intensive therapy on HbA1c

Ohkubo Y, et al. Diab Res Clin Pract 1995;28:103-17.

Conventional

Intensive

Years

9

0

Hb

A1

c(%

)12

11

10

8

6

5

7

1 2 3 4 5 6

2.3%

HbA1c

target: fasting< 7.8, pp < 11.1 mmol/l

KUMAMOTO STUDY

Risk of microvascular complicationsC

um

ula

tiv

e p

rog

ress

ion

(%)

50

40

30

20

10

0

50

40

30

20

10

0

40

30

20

10

0

40

30

20

10

0

Évek

0 1 2 3 4 5 6

Évek

0 1 2 3 4 5 6

Retinopathy

Primary prevention

Nephropathy

Primary prevention

Retinopathy

Secondary intervention

Nephropathy

Secondary intervention

-62%P=0.032

-70%P=0.039

-52%P=0.049

-52%P=0.044

Conventional

Intensive

Ohkubo Y, et al. Diab Res Clin Pract 1995;28:103-17.

Turner RC, et al. JAMA 1999;281:2005–2012.

Time since randomization

HbA1c <8%

HbA1c <7%

3 years 48–55% 41–46%

6 years 35–38% 25–27%

9 years 16–21% 10–18%

Bottom line: All type 2 diabetes patients will require combination therapy

or insulin treatment eventually

UKPDS: Limitations of monotherapy

DCCT Research Group, N Eng J Med 1993;329;977-986

DCCT/EDC Research Group, JAMA 2002;287:2563-2569.

HbA1c values in the DCCT and EDIC studies

n=1441, 3-4x injections/day, SMBG ≥ 4x/day

Fasting/preprandial target: 3.9-6.7 mmol/l

Postprandial target < 10 mmol/l

Risk of macrovascular complications in the DCCT/EDIC studies

Risk Reduction 42% (9-63%)

Log-Rank P=0,02Risk Reduction 57% (12-79%)

Log-Rank P=0,02

DCCT/EDC Research Group, NEJM 2005; 353:2643-2653.

Summary

o Intensive treatment (aiming at an HbA1c<7%) significantly reduces the risk of microvascularcomplications

o There is no glycemic threshold, all reduction in HbA1c are effective

o Type 2 diabetes is a progressive disease, eventually all patients will require combination therapy

o Among type 1 diabetes patients intensive glycemic control reduces the risk of macrovascular complications

Summary

o Type 2 diabetes is a heterogeneous disease

oOne extreme is predominant insulin resistance with relative insulin deficiency

oThe other extreme is predominant insulin secretory failure sometimes with mild insulin resistance

ADA: Diabetes Care: 20, 1183-1197; 1997

ADA. Diabetes Care 30 (Suppl 1):S4-S41; 2007

Treatment targets in type 2 diabetes - ADA

Value

HbA1c (%) < 7%*

Fating blood glucose (mmol/l) 5 – 7,2

Postprandial blood glucose (mmol/l) < 10

Blood pressure < 130 / < 80

* DCCT normalised methods (reference 4-6%). More or less stringent

goals may be appropriate in individual patients.

Selecting the right glycemic treatment

o Blood glucose lowering effect

o Side effects

o Nonglycemic effects

o weight,

o blood pressure,

o lipids,

o insulin sensitivity,

o β-cell function

o Cost of therapy

Nathan DM et al. Diabetes Care 29:1963-1972

Nonpharmacological therapy

Results

Glycemic effectiveness 1-2% (HbA1c)

Side effects Rare

Nonglycemic effects Beneficial

Cost Cheapest

CommentEffectiveness decreases after 1 year

The role of diet (medical nutrition therapy)

o Dietary advice is not prohibitive any more

o Diabetes patients in general should follow

current dietary guidelines aimed at the general

population

o However the freedom to choose does not equal

mean that certain rules related to timing and

carbohydrate content should not be followed

Medical nutrition therapy recommendations

Component Recommendation

Carbohydrate*

saccharose

45-60%

< 10%

Protein 0,8 g/ttkg

Fat

saturated fat

trans fat

cis-fat*

unsaturated fats

< 10%

minimal

10-25%

< 10%

Sodium < 6 g

Alcohol 1-3 E (15-45 g)

* 60-70% of total calories should come from carbohydrates and cis-fats

The standard weight loss diet

o Moderate restriction (500-1000 kcal/day reduction) compared to weight maintenance dieto women 1000-1200 kcalo men 1200-1600 kcal

o Expected weight loss 0.5-1 kg / weeko Weight loss of up to 10% is frequently achieved however 1/3 of

weight loss is regained within a year

o Basal metabolic rateo men 900 + 10 x weighto women 700 + 7 x weight

Nutrition Subcommittee of the Diabetes Care Advisory Committee of Diabetes UK. Diabet Med 2003;20:786-807


Metformin

Results

Glycemic effect 1,5% (HbA1c)

Side effecgtsGI side effects

Lactic acidosis (extremely rare)

Nonglycemic effects Weight neutral

Cost Cheap

Effects of metformin treatment

Intensive therapy with metformin in obese diabetes patients - UKPDS

o Metformin monotherapy compared to other intensive treatmentso More effectively reduced the risk of all diabetes

related endpoints, diabetes related mortality, and all-cause mortality compred to sulfanylureas (SU) and insulin

o Less weight gain and hypoglycemia compared to SU and insulin

o No difference on microvascular risk compared to other intensive treatments

o In combination with SUo Increased mortality compared to SU monotherapy

(this was not confirmed later)

UKPDS Group. Lancet 352:854-865, 1998

ADA/EASD: Titration of Metformin

ADA/EASD: Titration of Metformin (cont’d)


-glucosidase inhibitors

Results

Glycemic effects 0,5-0,8% (HbA1c)

Side effectsGI symptoms

3x/day

Nonglycemic effects Weight neutral

Cost Relative expensive

Acarbose effectively reduces postprandial glucose

Favours FavoursCV event p Acarbose Placebo

Coronary mortality 0.4368

Myocardial infarction 0.0120

Angina 0.3883

Heart failure 0.2251

Revascularisation 0.6784

Peripheral vascular disease 0.4558

Stroke/cerebrovascular event 0.5269

Any of the above CV events 0.0061

Acarbose reduces cardiovascular risk in type 2 diabetes

CV - cardiovascularHanefeld M et al. Eur Heart J 2004

Meta-analysis: 7 double blind, placebo controlled study; n=2,180 T2DM

0 0.5 1.0 1.5 2.0


Glitazones

Results

Glycemic effect 0,5-1,4% (HbA1c)

Side effects

Fluid retention,weight gain,osteoporosisCV side effects (?)

Nonglycemic effectsBeneficial effect on lipids, antiinflammatory effects

Cost Expensive

Summaryo Glitazones seems to be most effective in early stages

of type 2 diabetes considering their beneficial effects on insulin secretion and their side effects

o In overweight diabetes patients in combination with maximally tolerated dose of metformin in combination

o In case of metformin intolerance (side effects) or contrainidcation (e.g. renal failure) glitazones could be given as monotherapy

o Individualised treatment is recommended based on effectiveness and risks


Sulfanilureas

Results

Glycemic effects 1,5% (HbA1c)

Side effectsWeight gain

Hypoglycemia

Nonglycemic effects Lot of experience

Cost Very cheap

The sulfanilurea receptor

Sulfanilureas – advantages and disadvantages

Benefits

o long experience, large range of compounds

o individualised therapy

o good combination with acarbose

Disadvantages

o limited durability

o hypoglycemia risk

o potential cardiovascular effects

o renal or liver disease is a relative contraindication


Glinides

Results

Glycemic effects 1-1,5% (HbA1c)

Side effects 3x / day

Nonglycemic effects

Cost Expensive

Prandial glucose regulators advantages and disadvantages

Benefits

o Rapid onset and short duration effect on insulin secretion

o low risk of hypoglycemia

o no dose adjustment in elderly, renal or liver disease

o flexible lifestyle

Disadvantages

o moderate effect on fasting glucose

o less effective that SUs

o expensive


Drugs acting through incretin effects

Results


Side effects Gstrointestinal

Nonglycemic effectsWeight loss

Preservation of β-cells

Cost Expensive

The effects of GLP-1 in humans

GLP-1 secretion begins

from jejunal and ileal

L-cells

Subsequently…

•Increases glucose-dependent

insulin secretion and production

• Inhibits glucagon secretion

• Slows gastric emptying and

small bowel motility

(„ileal brake”)

• Decreases hunger and food intake

After a meal…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412

Drucker DJ. Mol Endocrinol 2003; 17:161-171

Postprandial GLP-1 secretion is decreased in IGT and type 2 diabetes

Data from: Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723

* P <0.05 T2DM vs. NGT.

20

15

10

5

00 60 120 180 240

Time (min)

Mean (SE)

GLP-1 (pmol/L)

* * * **

**

*

Meal NGT subjects

IGT subjects

T2DM patients

Possible ways to increase GLP-1 effects

DPP IV resistant compounds:

o GLP-1 analogues

oliraglutide; NN2211 (acilated) → 12 h

oCJC-1131 (reactive side chain)

o GLP-1 receptor agonists („incretin mimetics”): exendin-4 (exenatide), sc., 2,5 h

DPP IV (dipeptidyl-peptidase) inhibitors:

o vildagliptin, sitagliptin

Comparison of incretin-based therapies

*Significant compared to active comparator

Adapted from Drucker and Nauck, Lancet 2006;368:1696-705.

Hb

A1

c c

hange (

%)

1.0

0.5

0

–0.5

–1.0

–1.5

–2.0

*

*

Exenatide BIDHeine, 2005

Liraglutide ODVilsbøll, 2006

*

SitagliptinAschner, 2006

Fasti

ng

glu

co

se

change

(mg/d

L)

20

0

–20

–40

–60

–80

*

* *

3

2

1

–2

–3

–5

*

*

0

–1

–4

Weig

ht

change (

kg)

• based on studies that showed the highest effectiveness

Combination therapy – expected glycemic effect

DeFronzo, et al. N Engl J Med 1995;333:541-549; Horton, et al. Diabetes Care. 1998;21:1462-1469;

Coniff, et al. Diabetes Care. 1995;18:817-824; Moses, et al. Diabetes Care 1999;22:119-124;

Schneider, et al. Diabetes 1999; 48 (Suppl 1): A106; Egan, et al. Diabetes 1999; 48 (Suppl 1):A117.

Fonseca, et al. Diabetes 1999:48 (Suppl 1):A100.

Treatment HbA1c fasting glucose

Sulfanilurea + metformin ~1.7% ~3.5 mmol/l

Sulfanilurea + troglitazone ~0.9-1.8% ~2.8-3.3 mmol/l

Sulfanilurea + pioglitazone ~1.2% ~3.3 mmol/l

Sulfanilurea + acarbose ~1.3% ~2.2 mmol/l

Repaglinide + metformin ~1.4% ~ 2.2 mmol/l

Pioglitazone + metformin ~0.7% ~ 2.2 mmol/l

Rosiglitazone + metformin ~0.8% ~2.8 mmol/l

Insulin + OADs Dose dependent Dose dependent


Insulin

Results


Side effectsInjection, SMBG, Hypoglycemic risk,weight gain

Nonglycemic effects Improving lipid profile

Cost Relatively cheap

Absolute indications for insulin therapy in type 2 diabetes

o Significant hyperglycemia (HbA1c>10%)o Hyperglycemia present if maximal dose of oral

antidiabetic treatment is giveno Metabolic decompensation

o acute injury, stress, infectiono severre hyperglycemia with ketonemia or ketonuriao significant weight loss (symptomatic hyperglycemia)

o Surgeryo Pregnancyo Severe renal diseaseo Allergy to oral antidiabetic drugs


Combination therapy:Oral antidiabetic drugs and insulin

o Basis

o Combination of drugs with different modes of action

o Decrease the risk of side effects, more convenient

o Sulfanilurea + Insulin

o Bedtime insulin and daytime SU

o Could be used immediately after diagnosis

o Metformin + Insulin

o Improves insulin sensitivity

o α-glucosidase inhibitor (acarbose) + Insulin

o Decrased postprandial peaks

Initiation of bedtime insulin therapy

o OADs could be continued

o Initiate bedtime insulin (appr. 10 IU)

o NPH (at bedtime)

o 70/30 (before dinner)

o Basal analogue insulin (any time)

o Dose titration based on fasting glucose

o Every 2-3 days dose could be increased by

o 4 IU if fasting glucose >7.8 mmol/l

o 2 IU if fasting glucose = 6.6 to 7.8 mmol/l

o Target fasting glucose (4.0-6.0 mmol/l)

6-59

CSII

Insulin analogue bolus and basal ×4-5

Insulin analogue bolus human insulin basal ×4-5

Human insulin basal bolus ×4-5

Analogue high-mix ×3

Analogue low-mix ×2

Human premix ×2

Basal insulin analogue ×1-2

Human NPH or lente insulin ×1-2

Lindholm A.: Best Pract Res Clin Gastroent 2002

convenient

physiological

Pyramid of insulin treatment

Twice daily insulin therapy(Conservative insulin treatment)

o Premix insulins and pen devices simplify these treatments.

o After oral treatment (except for metformin) is stopped a mixture of intermedier and rapid acting insulin is injected (morning –before 7:00, evening before 18:00)

o During titration the different insulin preparations should be given separately for easier modification

o When the required dosage is found, it could be changed to premix insulins

o The usual rate of morning to evening insulin dose is 2:1 – 3:2

o Morning insulin usually contains 20-30% rapid acting insulin, evening mixture contains 0-10%

o The resimes are simple, usually patient compliance is good

o major disadvantage is the rigidity of the regime

Four times daily insulin(Intensive conservative therapy)

o Recommended for younger patients with type 2 diabetes that follow an active lifestyle

o Recommended therapy in pregnancy

o If the required insulin dosage is >60-80 IU

o If severe renal failure or intercurrent infection is present

ADA/EASD: Initiation and Adjustment of Insulin Regimens

Overviewo Glycemia and diabetes complicationso The effect of glycemic treatment on

complicationso microvascular diseaseo macrovascular disease

o Pathophysiology of hyperglycemiao Treatment targetso Selecting the right treatmento Non-pharmacological therapyo Pharmacological therapyo Treatment algorithm

Causes of hypoglycaemias I

o Insulin treatment; SU treatment (long-term observation !);

o Deficiency/low levels of contrainsular hormones:

Sheehan sy; panhypopituitarism;

M. Addison

McQuarrie sy (low levels of catecholamines)

Absence of glucagon (pancreatectomy,

pancreas diabetes);

Enzymopathies:

Gierke disease (Ø Glucose-6-phosphatase)

impaired gluconeogenesis

hereditary fructose intolerance

Causes of hypoglycaemias II

o Alcohol intoxication (in SU or insulin treated DM patients)

o Leucine-induced hypoglycaemia

o PP hypoglycaemia:

1. in Dumping sy

2. hyperreactive B-cells (relatively common !)

Newborns of diabetic mothers (hyperinsulinaemia)

Diffuse B-cell hyperplasia (nesidioblastosis)

Genetic failure of the KATP-channel (closed channel)

(neonatal hyperinsulinaemia)

Insulin receptor autoantibodies

INSULINOMA

o Hypoglycaemia in the fasting state (early in the morning)

o High insulin levels (before breakfast)

o Unconsciousness (in the morningpatient will not awake)

o Dg: 4-hour OGTT (glucose and insulin determinations)

typically: insulin levels are high and the insulin profile does not follow the glucose profile

other diagnostic tools: 72-hour fasting, regular glucose measurement; abdominal sonography, CT,

angiography

Therapy: surgical removal of the adenoma

Blood glucose and insulin levels due to hyperreactive insulin responses and to insulinomas during the 4-hour OGTT

o Time Functional hyperinsulinaemia Organic hyperinsulinaemia glucose Insulin glucose Insulin

o 0 min 5,8 (mM/L) 7,8 (mU/ml) 3,9 (mM/L) 19,4 (mU/ml)

o 30 min 7,2 19,1 5,5 30,5

o 60 min 8,1 30,4 6,1 51,4

o 90 min 7,4 28,5 4,4 90,7

o 120 min 6,3 26,3 4,1 79,2

o 150 min 5,9 25,2 3,3 69,4

o 180 min 4,3 24,0 2,8 66,3

o 210 min 3,9 18,1 2,1 68,4

o 240 min 4,6 13,9 2,2 55,4

o in organic hyperinsulinaemia (due to insuloma) the insulin levels do not follow the blood glucose levels and they remained high corresponding to the automacy of insuloma;

Hypoglycaemia in other tumors

o Mesenchymal sarcomas

o Mesotheliomas

o Severe hypoglycaemia can develop

o Insulin and C-peptide levels are normal

o IGF-I and IGF-II are elavated

o Therapy is surgical removal of te sarcomas (if it is possible)

Factitious hypoglycaemias

o Münchausen’s syndrome

o Non-diabetic patient is injecting insulin

o The patient will not acknowledge insulininjections

o Symptomes (hypoglycaemia, low blood glucose, hiogh insulin levels) suggestive for insuloma

o However, C-peptide levels are normal !!

Documents

Diabetes Mellitus II (Acute and chronic complications