PowerPoint Presentation · –31% by metformin –58% by lifestyle –39% lifestyle vs metformin *P

11/10/2014

1

30th

Annual meeting of Faculty of Medicine, KKU.

From Guideline to Real Practice

Chatlert Pongchaiyakul, M.D.

Professor of Internal Medicine,

Department of Medicine, Faculty of Meidince, KKU.

Case 1.

ผชายอาย 44 ป สมรสแลว อาชพแพทย

• มาปรกษาเนองจากผลตรวจสขภาพประจ าปผดปกต

• ผลตรวจ FPG 118 mg/dl, HbA1c 6.2%

• มารดาและพสาวเปนเบาหวาน ไมมโรคประจ าตวใดๆ และไมไดทานยาใดๆ เปนประจ า

• PE: BMI 27 kg/m2, Others: WNL

ค าถาม

1. ผปวยรายนเปนเบาหวานหรอไม

2. จะใหการรกษาอยางไร

Criteria for the Diagnosis of Diabetes

A1C ≥6.5%

OR

Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)

OR

2-h plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT

OR

A random plasma glucose ≥200 mg/dL (11.1 mmol/L)

ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.

Categories of increased risk for diabetes (Prediabetes)

FPG 100-125 mg/dl : IFG

or

2-h plasma glucose in the 75-g OGTT 140-199 mg/dl : IGT

or

A1C 5.7-6.4%

ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13.

Case 1.

ผชายอาย 44 ป สมรสแลว อาชพแพทย

• มาปรกษาเนองจากผลตรวจสขภาพประจ าปผดปกต

• ผลตรวจ FPG 118 mg/dl, HbA1c 6.2% • มารดาและพสาวเปนเบาหวาน ไมมโรคประจ าตวใดๆ และไมไดทานยา

ใดๆ เปนประจ า

• PE: BMI 27 kg/m2, Others: WNL

ค าถาม


2. จะใหการรกษาอยางไร

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Prevalence of IFG and DM in Thais

7 Aekplakorn W, et al. Diabetes Care 26:2758–2763, 2003

Lifestyle Interventions Can Prevent Type 2 Diabetes Onset

Several randomized trials have shown interventions (lifestyle, medications) can decrease rate of onset of diabetes

Lifestyle: Da Qing, Finnish Diabetes Prevention Study, Diabetes Prevention Program

Medications: Diabetes Prevention Program (metformin), The Stop-NIDDM (acarbose), DREAM (rosiglitazone), ACT-NOW (pioglitazone)

• 110,660 adults from 33 Da Qing, China, health care clinics screened in 1986 for IGT, type 2 diabetes mellitus

• 577 adults with IGT (WHO criteria) randomized to control (n=138) or one of three lifestyle interventions (n=438)

• Diet only

• Exercise only

• Diet + exercise

• Follow-up at 2-year intervals over 6 years to identify those who developed diabetes

Lifestyle Interventions Da Qing Study Methods

Pan XR, et al. Diabetes Care. 1997;20:537-544.

• Cumulative incidence of diabetes at 6 years was significantly decreased in the active intervention groups (P<0.05)

• When analyzed by clinic, each active intervention group differed significantly from the control (P<0.05)

Lifestyle Interventions Da Qing Study Results


Control 67.7% (95% CI, 59.8-75.2)

Diet 43.8% (95% CI, 35.5-52.3)

Exercise 41.1% (95% CI, 33.4-49.4)

Diet + exercise 46.0% (95% CI, 37.3-54.7)

• When stratified as lean or overweight (BMI < or ≥25 kg/m2), relative decrease in rate of development of diabetes in lifestyle intervention groups was similar

• After adjusting for differences in baseline BMI and fasting glucose, all interventions were associated with diabetes risk reduction

Lifestyle Interventions Da Qing Study Results


Diet 31% (P<0.03)

Exercise 46% (P<0.0005)

Diet + exercise 42% (P<0.005)

• Active intervention with diet and/or exercise led to a significant decrease in incidence of diabetes over a 6-year period (1986-1992) among those with IGT

• Diabetes incidence (per 100 person years) per year

• Control: 14.1 (95% CI 11.2-17.0)

• Lifestyle intervention: 7.9 (95% CI, 6.8-9.1)

Lifestyle Interventions Da Qing Study Conclusions


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Lifestyle Interventions Finnish Diabetes Prevention Study

• 522 subjects, 40-65 years of age • BMI ≥25 kg/m2; IGT: 2-h PPG 140-200 mg/dL

• Control group: general oral and written information diet and exercise

• Intervention group: individualized Reduce weight ≥5%

Decrease fat ≤30%, saturated fat ≤10% energy

Increase fiber to at least 15 g/1000 kcal

Moderate exercise ≥30 minutes/day

• Primary end point: diagnosis of diabetes

Tuomilehto J, et al for the Finnish Diabetes Prevention Study Group. N Engl J Med. 2001;344:1343-1350.

• 172 men, 350 women; mean age 55 y

• Mean BMI 31 kg/m2

• Mean duration of follow-up 3.2 years



Weight Loss, Kg Mean ± SD

Cumulative Incidence of Diabetes

After 4 Years Year 1 Year 2

Control 0.8±3.7 0.8±4.4 23%

(95% CI, 17-29)

Intervention 4.2±5.1* 3.5±5.5* 11% (95% CI, 6-15)

Risk Reduction 58%*

*P<0.001

• Reduction in incidence of type 2 diabetes was directly associated with changes in lifestyles of high-risk subjects (ie, those with IGT)

• Modifiable risk factors such as obesity, physical inactivity, suggested as main nongenetic determinants of diabetes

• These results demonstrate that 22 subjects with IGT must be treated with lifestyle intervention for 1 year (or 5 subjects for 5 years) to prevent 1 case of diabetes



3,234 nondiabetic persons in 27 clinical centers BMI ≥24 kg/m2 (≥22 kg/m2 in Asians)

IGT: FPG 95-125 mg/dL or 2-h PPG 140-199 mg/dL

From 1996-1999, randomly assigned to Standard lifestyle + placebo (n=1082)

Standard lifestyle + metformin, initiated at 850 mg orally once daily; at 1 month, increased to 850 mg twice daily (n=1073)

Intensive lifestyle intervention (n=1079)

Lifestyle Interventions Diabetes Prevention Program

Knowler WC, et al. for the Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

Goals of intensive lifestyle intervention

• 7% loss of body weight

• Dietary fat goal: 25% of calories from fat

• Calorie intake goal: 1200-1800 kcal/day based on initial body weight

• >150 minutes of physical activities weekly

– Similar in intensity to brisk walking; at least 700 kcal/week

• Group received 16-lesson curriculum



• Mean age 50.6 years

• 67.7% women; 45.3% members of minority groups

• Mean BMI 34.0 kg/m2

• 69.4% had a family history of diabetes

• Average follow-up: 2.8 years (range, 1.8-4.6)



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Lifestyle Metformin Placebo

5.6 kg 2.1 kg 0.1 kg

Results: average weight loss (P<0.001)

• Those assigned to lifestyle intervention had greater weight loss and increase in physical activity than participants receiving metformin or placebo

• Lifestyle intervention more effective in restoring normal post-load glucose values

Results: intensive lifestyle intervention



At 24 Weeks At Final Study

Visit

Weight loss ≥7% 50% 38%

Exercise >150 minutes/week

38% 58%


Medications DPP: Metformin Intervention

• Metformin, intensive lifestyle modification delayed or prevented type 2 diabetes vs placebo (11%/year incidence)

– Placebo: 11%/year incidence

– Metformin: 7.8%/year incidence*

– Lifestyle intervention: 4.8%/year incidence*

• Risk reduction:

– 31% by metformin

– 58% by lifestyle

– 39% lifestyle vs metformin

*P<0.001 vs placebo


Medications DPP: Metformin Intervention

• Intensive lifestyle intervention more effective than

either metformin or placebo

• By subgroup, metformin more effective if:

‒ FPG >110 mg/dL

‒ Age <60 years

‒ BMI >35 kg/m2

• Gender, ethnicity, 2-h PGG, NOT predictive of

response

• Use metformin in high-risk individuals

Medications The STOP-NIDDM: Acarbose

Chiasson JL, et al. Lancet. 2002;359(9323): 2072-2077; Chiasson JL, et al. JAMA. 2003;290(4):486-494.

Acarbose reduced risk of new

Hypertension >140/90; 5.3% absolute risk reduction (P=0.006)

Myocardial infarction (P=0.02)

Any CVD event: CHD, CV death or stroke, CHF, PVD (P=0.03)

Acarbose 100 mg TID

n=682

Placebo n=686

25% Relative Risk Reduction P=0.0022

DREAM Trial Investigators. Lancet. 2006;368(9541):1096-1105.

Medications DREAM: Rosiglitazone

60% Relative Risk

Reduction HR 0.40

(0.35–0.46) P<0.0001

• 5269 adults ≥30 years with IFG or IGT

• Rosiglitazone 8 mg or placebo

• 3 years

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DeFronzo RA, et al, for the ACT NOW Study. N Engl J Med. 2011;364:1104-1115.

Medications ACT NOW: Pioglitazone

602 adults with impaired glucose tolerance

pioglitazone (n=303) or placebo (n=299): F/U 2.4 years

Pioglitazone reduced risk of type 2 diabetes mellitus

by 72% vs placebo (HR 0.28; 95% CI 0.16–0.49 P<0.001)

Conversion to normal glucose tolerance: 48% of patients with pioglitazone vs 28% with placebo (P<0.001)

Pioglitazone reduced fasting glucose, 2-hour glucose, HbA1c

Weight gain, edema observed in the pioglitazone arm

DO PREVENTION INTERVENTIONS

HAVE SUSTAINED EFFECTS ?

• Combined lifestyle intervention vs control

• 51% lower incidence of diabetes during active intervention

• 43% lower incidence over 20 years

• 3.6 years fewer with diabetes

Lifestyle Interventions Da Qing Study 20-Year Follow-Up

Li G, et al. Lancet. 2008;371:1783-1789.

Average Annual Incidence

20-Year Cumulative Incidence

Controls 11% 93%

Combined lifestyle intervention

7% 80%

• No significant difference in rate of

• First CVD event (HR 0.98; 95% CI, 0-71-1.37)

• CVD mortality (HR 0.83; 0.48-1.40)

• All-cause mortality (HR 0.96; 0.65-1.41)

• Study had limited statistical power to detect differences in these outcomes

• Lifestyle interventions over 6 years can prevent, delay diabetes for up to 14 years after active intervention

• Unclear whether lifestyle interventions also lead to reduced CVD, mortality

Lifestyle Interventions Da Qing Study 20-Year Follow-Up

Li G, et al. Lancet. 2008;371:1783-1789.

Lifestyle Interventions Finnish DPS 7-Year Follow-Up

Lindström J, et al. Lancet. 2006;368(9548):1673-1679.

43% Relative Risk

Reduction

• Brief (1-2 week) drug washout study at end of Diabetes Prevention Program trial

• DPP primary analysis: metformin decreased diabetes risk by 31%

• Washout: 26% accounted for by pharmacological effect of metformin

• Postwashout: diabetes reduced by 25%

DPP: Metformin Had Sustained Effect After Drug Washout

Diabetes Prevention Program Research Group. Diabetes Care. 2003;26:977-980.

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• During rosiglitazone vs placebo washout

– Primary outcome, new-onset diabetes or death: 10.5% vs 9.8% (P=0.59)

– Secondary outcome, regression to normoglycemia: 21.5% vs 23.8% (P=0.33)

– Median follow-up: 71 days (range, 63-86 days)

• Rosiglitazone substantially reduced incidence of type 2 diabetes (DREAM); however, when withdrawn, this effect is not sustained

Rosiglitazone Had No Sustained Effect After Drug Washout: DREAM

The DREAM Trial Investigators. Diabetes Care. 2011;34:1265-1269.

• Lifestyle intervention continues to have an effect; most drugs do not

Lifestyle Interventions Summary

Diabetes Care. 1997;20:537-544; N Engl J Med. 2002;344:1343-1350; N Engl J Med. 2002;346;393-403; Diabetes Care. 2011;34:1265-1269;

Lancet. 2002;359(9323): 2072-2077 N Engl J Med. 2011;364:1104-1115.

Study N Intervention Treatment Risk Reduction

DPP IGT 3324 Metformin 3 years 31%

DREAM IGT 5269 Rosiglitazone 3 years 60%

STOP-NIDDM IGT 1429 Acarbose 3 years 21%

ACT NOW IFG ~600 Pioglitazone 3 years 81%

Study N Intervention Treatment Risk Reduction

Da Qing IGT 577 Lifestyle 6 years

20 years 34% - 69%

Finnish DPS IGT 523 Lifestyle 3+ years 7 years

58%

DPP IGT 3324 Lifestyle 3 years 58%

Lif

es

tyle

P

ha

rma

co

log

ic

• Data analyzed from 1,402 adults without diabetes

– 2005–2006 NHANES participants

– Valid fasting plasma glucose, oral glucose tolerance tests

• Almost 30% of the US adult population had

prediabetes in 2005–2006; only 7.3% were aware

they had it

• Adoption of risk reduction behaviors suboptimal

Most People with Diabetes Are Unaware of Their Condition

Geiss LS, et al. Am J Prevent Med. 2010;38:403-409.

Recommendations: Testing for Diabetes in Asymptomatic Patients

• Consider testing overweight/obese adults with one or more additional risk factors

– In those without risk factors, begin testing at age 45 years

• If tests are normal

– Repeat testing at least at 3-year intervals

• Use A1C, FPG, or 2-h 75-g OGTT

• In those with increased risk for future diabetes

– Identify and, if appropriate, treat other CVD risk factors

ADA. II. Testing in Asymptomatic Patients. Diabetes Care. 2012;35(suppl 1):S13.

Screening for diabetes 1. ผทอาย 35 ปขนไป

2. ผทอวน (BMI >25 kg/m2 และ/หรอ WC 90 cm. ในผชายหรอ 80 cm. ในผหญง หรอ

มากกวาสวนสงหารสองในทงสองเพศ (อตราสวนรอบเอวตอสวนสง >0.5) และม พอ

แม พ หรอ นองเปนโรคเบาหวาน

3. เปนโรคความดนโลหตสงหรอก าลงรบประทานยาควบคมความดนโลหตสง

4. มระดบไขมนในเลอดผดปกต (TG >250 mg/dL and/or HDL-C <35 mg/dL)

5. มประวตเปนโรคเบาหวานขณะตงครรภหรอเคยคลอดบตรน าหนกเกน 4 kg.

6. เคยไดรบการตรวจพบวาเปน IGT หรอ IFG

7. มโรคหวใจและหลอดเลอด (cardiovascular disease)

8. มกลมอาการถงน าในรงไข (polycystic ovarian syndrome)

Thai CPG of DM, 2014

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Managing Prediabetes

For those found to have prediabetes, provide support or referral to encourage

Weight loss of at least 7%

Moderate exercise of at least 150 minutes per week

Consider metformin for certain patients

Obese (BMI ≥35 kg/m2)

<60 years (most effective, 25-44 years)

Lifestyle interventions feasible, more cost-effective than medications

American Diabetes Association, 2014.

ผหญงไทยอาย 55 ป สมรสแลว อาชพพนกงานธนาคาร

• มารดาเปนเบาหวาน ไมมโรคประจ าตวใดๆ และไมไดทานยาใดๆ เปนประจ า

• มน าหนกลด 4 kg. ปสสาวะบอย กระหายน ามาก ปรกษาเพอนทท างาน บอกอาการเหมอนเลยแนะน าใหลองไปตรวจเลอดด

• ผลตรวจ FPG 196 mg/dl, HbA1c 8.1%

ค าถาม


2. ทานจะตรวจรางกาย และตรวจทางหองปฏบตการใดเพมเตม

3. จะใหการรกษาและตดตามผปวยรายนอยางไร

Case 2.

IFG=impaired fasting glucose; IGT=impaired glucose tolerance. Representative depiction of time course and function.

Kendall DM et al. Am J Med. 2009;122(6A):S37-S50.

Pathophysiology and Progression of Type 2 Diabetes

Years

0

-15 -10 -5 0 5 10 15 20 25 30

200

150

100

50

250

Insulin resistance

Insulin level

Re

lati

ve A

mo

un

t

β-cell function

Incretin effect

Diagnosed diabetes

Prediabetes (IFG, IGT)

Diabetes Onset

350

300

250

200

150

100

Postmeal glucose

Fasting glucose

Glu

cose

(mg

/dL)

50

In early stages, as insulin resistance rises, there is a compensatory increase in insulin secretion and glucose levels remain normal

As β-cell dysfunction worsens, insulin secretion falls, IGT and hyperglycemia become apparent, and overt type 2 diabetes develops

Glucose levels, both pre- and postprandially, increase steadily as the individual progresses from normoglycemia to IGT and, finally, type 2 diabetes

39

Pathophysiology of Hyperglycemia in T2DM:

DeFronzo RA. Diabetes. 2009;58:773-795.

Multiple drugs in combination may be required to improve glucose homeostasis

Treatment should target underlying pathophysiology

Poor

Glucose

Homeostasis

Glucose production

Glucose uptake

Insulin secretion

B

Increased hepatic glucose production

De Fronzo RA. Diabetes 2009;58:773-95.

Basal H

GP (

mg/k

g m

in)

T2DM CON 11.1

2.0

FPG (mmol/l) 16.7 5.6

2.8

2.4

1.6

Basal HGP(left) in control and type 2 diabetic (T2DM) patients. The relationship between basal hepatic glucose production (HGP) and fasting plasma glucose (FPG) (right).

2.5

4.0

3.5

2.0

3.0

Control T2DM

R=0.85, p<0.001 P<0.001





Poor

Glucose

Homeostasis

Glucose production

Glucose uptake

Lipolysis

Insulin secretion

B

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Accelerated lipolysis

• Fat cells are resistant to the antilipolytic effect of insulin in type 2 diabetes leading to elevated plasma free fatty acid concentrations and increased levels of toxic lipid metabolites, and thus lipotoxicity

• These toxic lipid metabolites cause insulin resistance in muscle and liver and promote β-cell failure

De Fronzo RA. Am J Med. 2010;123:S38-S48.





Poor

Glucose

Homeostasis

Glucose production

Glucose uptake

Lipolysis

Incretin effect

Insulin secretion

B

Incretin Effects Was Diminished in Type 2 Diabetes

*p0.05 vs. respective value after oral load IR=immunoreactive

Adapted from Nauck M et al Diabetologia 1986;29:46–52.

Diminished incretin effect

Normal incretin effect

Oral glucose (50 g/400 ml)

Isoglycemic IV glucose

0

–10

10

15

20

Ven

ou

s p

lasm

a g

lucose

(mm

ol/L

)

5

60 120 180

Time (minutes)

0

40

60

80

IR in

su

lin (

mU

/L)

20

Healthy controls (n=8) Type 2 diabetes (n=14)

0

10

15

20

5

Time (minutes)

0

40

60

80

IR in

su

lin (

mU

/L)

20

–5 –10 60 120 180 –5

–10 60 120 180 –5 –10 60 120 180 –5

* * * * * *

* * *

*

Ven

ou

s p

lasm

a g

lucose

(mm

ol/L

)





Poor

Glucose

Homeostasis

Glucagon secretion

Glucose production

Glucose uptake

Lipolysis

Incretin effect

Insulin secretion

A

B





Poor

Glucose

Homeostasis

Neurotransmitter dysfunction

Glucose reabsorption

Glucagon secretion

Glucose production

Glucose uptake

Lipolysis

Incretin effect

Insulin secretion

A

B

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SGLT2 SGLT1

Normal Physiology of Renal Glucose Homeostasis

Proximal tubule

S1

Glomerulus Distal tubule

Loop of Henle

Collecting duct

Glucose

filtration

Glucose

reabsorption Minimal

glucose

excretion

S3

Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35.

Rahmoune H, et al. Diabetes 2005;54:3427–34.

0

500

1000

1500

2000

2500

0

1

2

3

4

5

6

7

Transporter protein expression Glucose uptake into

tubular epithelial cells †

Norm

aliz

ed levels

AM

G u

pta

ke (

CP

M)

SGLT2 GLUT2 Healthy Type 2 diabetes

mellitus

Healthy

Type 2 diabetes

mellitus

*p<0.05; †from human exfoliated proximal tubular epithelial cells (HEPTECs)

In Type 2 Diabetes Mellitus, Counterproductive Increases in SGLT2 Upregulation and Glucose Reabsorption Occur

*

*

*

SGLT2 Inhibition Reduces Renal Glucose Reabsorption

Proximal tubule

SGLT2 SGLT1

S1

S3

Glomerulus Distal tubule

Loop of Henle

Collecting duct

Glucose

filtration

Reduced glucose

reabsorption Increased

glucose

excretion

SGLT2 inhibitor

Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35;

Han S. Diabetes 2008;57:1723–9.

ผหญงไทยอาย 55 ป สมรสแลว อาชพพนกงานธนาคาร

• มารดาเปนเบาหวาน ไมมโรคประจ าตวใดๆ และไมไดทานยาใดๆ เปนประจ า

• มน าหนกลด 4 kg. ปสสาวะบอย กระหายน ามาก ปรกษาเพอนทท างาน บอกอาการเหมอนเลยแนะน าใหลองไปตรวจเลอดด

• ผลตรวจ FPG 196 mg/dl, HbA1c 8.1% ค าถาม


2. ทานจะตรวจรางกาย และตรวจทางหองปฏบตการใดเพมเตม

3. จะใหการรกษาและตดตามผปวยรายนอยางไร

Case 2.

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Recommendation for 1st diagnosis DM

ประวตการเจบปวย • อายทเรมเปนเบาหวาน

• อาการเมอแรกตรวจพบ

• อปนสยการทานอาหาร

• กจกรรมเคลอนไหว ออกก าลงกาย

• ประวตการรกษาทผานมา ยาทเคยหรอก าลงไดรบ

ยา steroid

• อาการของโรคแทรกซอน เชน ตามว ชาปลายมอ

ปลายเทา ปสสาวะเปนฟอง เดนแลวปวดนอง

• ความรความเขาใจเกยวกบเบาหวาน

การตรวจรางกาย

• BW, HT, WC

• BP, HR

• Systemic

• Eye and retina

• Foot, skin, corn, ulcer

• Sensation

• Peripheral pulse

Recommendation for 1st diagnosis DM

Laboratories

• HbA1c

• Lipid (chol, Tg, HDL-c)

• Liver function tests

• Serum creatinine

• Urine exam (if no proteinuria microalbuminuria)

Refer • นกโภชนาการ

• จกษแพทย

• อายรแพทยโรคไต ถาไตผดปกต

• อายรแพทยโรคหวใจ เมอมความผดปกตของ EKG

• ทนตแพทย เมอตรวจพบความผดปกตของเหงอกและฟน

Class Mechanism Advantages Disadvantages Cost Biguanides Activates AMP-kinase

↓ Hepatic glucose production

Extensive experience No hypoglycemia Weight neutral ? ↓ CVD

Gastrointestinal Lactic acidosis B-12 deficiency Contraindications

Low

SUs / Meglitinides

Closes KATP channels ↑ Insulin secretion

Extensive experience ↓ Microvasc. risk

Hypoglycemia Weight gain Low durability ? Ischemic preconditioning

Low

TZDs PPAR-γ activator ↑ insulin sensitivity

No hypoglycemia Durability ↓ TGs, ↑ HDL-C ? ↓ CVD (pio)

Weight gain Edema / heart failure Bone fractures ? ↑ MI (rosi) ? Bladder ca (pio)

High

α-GIs Inhibits α-glucosidase Slows carbohydrate absorption

No hypoglycemia Nonsystemic ↓ Post-prandial glucose ? ↓ CVD events

Gastrointestinal Dosing frequency Modest ↓ A1c

Mod.

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages Cost DPP-4 inhibitors

Inhibits DPP-4 Increases GLP-1, GIP

No hypoglycemia Well tolerated

Modest ↓ A1c ? Pancreatitis Urticaria

High

GLP-1 receptor agonists

Activates GLP-1 R ↑ Insulin, ↓ glucagon ↓ gastric emptying ↑ satiety

Weight loss No hypoglycemia ? Beta cell mass ? CV protection

GI ? Pancreatitis Medullary ca Injectable

High

SGLT2 inh inh. Renal glucose reabsorption

Weight loss No hypoglycemia ↓ blood pressure

UTI Genital tract infection

High

Insulin Activates insulin receptor ↑ peripheral glucose uptake

Universally effective Unlimited efficacy ↓ Microvascular risk

Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements “Stigma”

Vary

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Antihyperglycemic agents and

HbA1c reduction

Drugs HbA1c reduction

Metformin 1-2%

Sulfonylureas 1-2%

Glinides 1-1.5%

TZDs 0.5-1.4%

-glucosidase inh. 0.5-0.8%

DPP-4 inhibitors 0.8%

SGLT2 inh, 0.8-1.0%

GLP1 analog 1%

Insulin 1.5-3.5% or more

11/10/2014

11

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

Healthy eating, weight control, increased physical activity

Metformin

high

low risk

neutral/loss

GI / lactic acidosis

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+


+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high


Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low


T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012

At diagnosis

FPG < 180 mg/dl or HbA1c < 8%

FPG > 180 mg/dl or HbA1c > 8%

ปรบเปลยนพฤตกรรมชวต โภชนบ าบด ออกก าลงกาย เรยนรโรคเบาหวานและ

การดแลตนเอง 1-3 เดอน ถายงคมไมไดตามเปาหมาย ใหเรมการรกษาดวยยา

ใหยา metformin ยาทเปนทางเลอก : SU, Glitazone, DDP-4 inh, alpha-glucosidase inh or

repaglinide


อาจพจารณาเรมยา 2 ชนดรวมกน

ใชยารวมกน 2 ชนด (เพมเสรมกบ metformin) ยาชนดท 2 ทควรใช ไดแก SU

ยาทเปนทางเลอก :TZD, DDP-4 inh, alpha-glucosidase inh, repaglinide, basal insulin


มอาการจากน าตาล ในเลอดสง

ไดรบการรกษาอย แต FPG > 300 mg/dl

or HbA1c > 11% + มโรคหรอภาวะอน

OHA รวมกบ NPH กอนนอน (21.00-23.00) หรอ LAA หรอรวมกบ premixed human

insulin หรอ premixed insulin analog วนละ 1-2 ครง กอนอาหารเชาหรอเยน

OHA 3 ตว

ฉดอนซลนวนละหลายครงเลยนแบบการตอบสนองในคนปกต NPH กอนนอน / LAA และ RI / RAA กอนอาหารแตละมอ

หรอสงตอผเชยวชาญ

ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา

ไมไดเปาหมาย


ไมไดเปาหมาย ไมไดเปาหมาย

At diagnosis






repaglinide











OHA 3 ตว



ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา




CONSIDERATIONS

• Age

• Weight

• Comorbidities Coronary artery disease

Heart Failure

Chronic kidney disease

Liver dysfunction

Hypoglycemia

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

11/10/2014

12

Age: Older adults - Reduced life expectancy

- Higher CVD burden

- Reduced GFR

- At risk for adverse events from polypharmacy

- More likely to be compromised from hypoglycemia

Less ambitious targets

HbA1c <7.5–8.0% if tighter

targets not easily achieved

Focus on drug safety



Weight

- Majority of T2DM patients overweight / obese

- Intensive lifestyle program

- Metformin

- GLP-1 receptor agonists

- ? Bariatric surgery

-



Medication class Weight effects GLP-1 analogs

Metformin

-Glucosidase inhibitors

DPP-4 inhibitors

Insulin

Sulfonylureas

Glinides

Thiazolidinediones

SGLT2 inhibitors

↓

+ or ↓

+

+ or ↓ ↑

↑

↑

↑ ↓

DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide 1,;SGLT2, Sodium glucose cotransport 2

Weight effects of glucose lowering medications

Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia

Metformin: CVD benefit (UKPDS)

Avoid hypoglycemia

? SUs & ischemic preconditioning

? Pioglitazone & CVD events

? Effects of incretin-based therapies



Metformin: May use unless condition is unstable or

severe

Avoid TZDs

? Effects of incretin-based therapies



Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia

Increased risk of hypoglycemia

Metformin & lactic acidosis

US: stop @SCr ≥ 1.5 (1.4 women)

UK: ↓ dose @GFR <45 & stop @GFR <30

Caution with SUs (esp. glyburide)

DPP-4 inh – dose adjust for most

Avoid exenatide if GFR <30


Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia


11/10/2014

13

Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis

Insulin best option if disease severe


Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia


Emerging concerns

regarding association with

increased mortality

Proper drug selection in the hypoglycemia prone


Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia


Risk for hypoglycemia associated with

different antihyperglycemic agents

11/10/2014

14

Glycemic targets - - HbA1c < 7.0% (mean PG 150-160 mg/dl)

- - Pre-prandial PG <130 mg/dl

- - Post-prandial PG <180 mg/dl

Individualization is key: - Tighter targets (6.0 - 6.5%) - younger, healthier - Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc.

- - Avoidance of hypoglycemia

PG = plasma glucose Diabetes Care, Diabetologia, 2014


ผหญงไทยอาย 60 ป เปน T2DM และ hypertension มา 3 ป

• ไดรบการรกษาดวย

Metformin (500) 1x3 oral pc Enalapril (5) 1x2 oral pc

• PE: BMI 24 kg/m2

Blood pressure 160/100 mmHg , no complications

• Lab: FPG 234 mg/dL, HbA1c 9.1%

Tg 220 mg/dL, HDL-C 30 mg/dL, direct LDL-C 164 mg/dL

BUN 14 Cr 0.8

ค าถาม

จะใหการรกษาและตดตามผปวยรายนอยางไร

Case 3.






• Lab: FPG 234 mg/dL, HbA1c 9.1%


BUN 14 Cr 0.8

ค าถาม


Case 3.

11/10/2014

15

HbA1c 9.1% BMI 24






• Lab: FPG 234 mg/dL, HbA1c 9.1% Tg 220 mg/dL, HDL-C 30 mg/dL, direct LDL-C 164 mg/dL

BUN 14 Cr 0.8

ค าถาม


Case 3.

At diagnosis






repaglinide











OHA 3 ตว



ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา




At diagnosis






repaglinide











OHA 3 ตว



ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา




Combination

ขอด

Insulin secretagogue +

metformin

- ลดปญหาการเกด weight gain จาก sulfonylurea

- ลดปญหาการเกด hypoglycemia จาก sulfonylurea

- ลดปญหาตอทางเดนอาหารจากยา metformin

Sulfonylureas + acarbose - ชวยลดระดบน าตาลหลงอาหารไดดกวายา

sulfonylurea อยางเดยว

Sulfonylureas +

thiazolidinediones

- ลดภาวะด ออนซลนและปจจยเสยงอนๆ ตอโรคหลอดเลอดแดงและหวใจ

Thiazolidinediones +

metformin

- ลดปญหาการเกด weight gain จาก thiazolidinedione

- ลดปญหาตอทางเดนอาหารจากยา metformin

- ไมมปญหาการเกด hypoglycemia

- เพมประสทธภาพในการลดปจจยเสยงตอโรคหวใจและหลอดเลอด

DPP-4 inhibitors +

metformin /

thiazolidinediones

- ไมมปญหาการเกด hypoglycemia

- ไมเพมปญหา weight gain จาก thiazolidinedione

- ลดระดบน าตาลโดยใชกลไกตางกน

11/10/2014

16


Parameters Targets

Lipid LDL-C Triglyceride HDL-C

< 100 mg/dL (< 70 if CAD or multiple risk factors for CAD) < 150 mg/dL > 40 mg/dL (men), > 50 mg/dL (women)

Systolic BP Diastolic BP

< 140 mmHg < 80 mgHg

BMI Waist circumference

18.5-22.9 kg/m2 or near < 90 cm (men), < 80 cm (women) or < Height/2

Thai Guideline 2014

Case 4.

ผปวยชายไทยอาย 62 ป เปน T2DM 12 ป HT 10 ป

• ไดรบการรกษาดวย glipizide (5) 2x2 oral ac, Metformin (850) 1x3 oral pc, losartan (100) 1x1 oral pc

• มารพ.วนนพบ

FPG 190 mg/dl, 2-hr postprandial 240 mg/dl HbA1c 9.2%,

BUN 22, Cr 1.4, Na 138 K 5.2 HCO3 20 Cl 95

Chol 180, Tg 305, HDL-c 42, direct LDL-c 100,

urine microalbumin 250

• PE: BP 150/85 mmHg, non-proliferative DR

ค าถาม

ทานจะดแลรกษาและตดตามผปวยรายนอยางไร

Case 4.

ผปวยชายไทยอาย 62 ป เปน T2DM 12 ป HT 10 ป

• ไดรบการรกษาดวย glipizide (5) 2x2 oral ac, Metformin (850) 1x3 oral pc, losartan (100) 1x1 oral pc

• มารพ.วนนพบ

FPG 190 mg/dl, 2-hr postprandial 240 mg/dl HbA1c 9.2%,

BUN 22, Cr 1.4, Na 138 K 5.2 HCO3 20 Cl 95

Chol 180, Tg 305, HDL-c 42, direct LDL-c 100,

urine microalbumin 250

• PE: BP 150/85 mmHg, non-proliferative DR

ค าถาม

ทานจะดแลรกษาและตดตามผปวยรายนอยางไร


Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs


Metformin

high

low risk

neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight


Costs

high

low risk

gain


high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable



Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+


+


+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§





or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high


Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low


T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012

11/10/2014

17

At diagnosis






repaglinide











OHA 3 ตว



ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา




At diagnosis






repaglinide











OHA 3 ตว



ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา




Adding Prandial Insulin in Clinical Practice

• Identify the main meal by monitoring BG 1–2 hrs after meal.

• Start prandial insulin 4 U once daily with this largest meal

– Monitor pre-prandial glucose of next meal or 2h post-prandial glucose

– Target pre-prandial < 70-130 mg/dl or 2h post-prandial 180 mg/dl*

– Titrate 1-2 U every 3 days

– If A1C ≥7% after 3 months, recheck pre-meal blood glucose levels and if out of range, may need to add another injection

– Decrease 10% of rapid insulin dose if hypoglycemia

• Implication for existing OADs:

– Metformin should be continued (at discretion of physician)

– SU should be discontinued

– TZD should be continued

*Nathan DM, et al. Diabetologia 2006;49:1711–21.

11/10/2014

18

• เจาะ DTX 3 วน ใน 1 สปดาห • เจาะกอนอาหารเชา และกอนอาหารเยน • เลอกคาต าสดมาใชในการปรบขนาด insulin • ผลเลอดเชา-ปรบเยน / ผลเลอดเยน-ปรบเชา • ปรบตามตาราง..Keep 80-110 mg/dl • ใหเร มจาก 6-0-6 ( 6 units เชา - 6 units เยน) • สามารถนามาใชกบ once daily regimen ได

Titration algorithm

Any episodes of hypoglycaemia should be taken into account prior to titration

Blood sugar level before meal

Insulin dose adjustment

mmol/L mg/dL Units

< 4.4 < 80 -2

4.4-6.1 80-110 No adjustment

6.2-7.8 111-140 +2

7.9-10.0 141-180 +4

> 10.0 >180 +6

The lowest SMPG value on any 3 days in a week prior to next site visit/phone contact

Twice daily titration example

SMPG 1

SMPG 2

SMPG 3

Bre

akfa

st

Before Before

8.2

8.0

150

145

6 10

Din

ne

r

8.2

150

8.0

145

7.9

141

6.2

111

mmol/L

mg/dL

units

units




mmol/L mg/dL Units

< 4.4 < 80 -2


6.2-7.8 111-140 +2

7.9-10.0 141-180 +4

> 10.0 >180 +6

7.9

141

6.2

111

Lowest before breakfast

SMPG

Lowest before dinner

SMPG

Prescribed doses (units)


SMPG 1

SMPG 2

SMPG 3 B

reak

fast

Before Before

8.2

8.0

150

145

6 10

Din

ne

r

8.2

150

8.0

145

7.9

141

6.2

111

mmol/L mg/dL

units units

= +4 14 10 = +2 8 6

Once daily titration example

SMPG 1

SMPG 2

SMPG 3

Bre

akfa

st

Before Before

8.2

8.0

150

145

Din

ne

r

6.2

111

mmol/L mg/dL units

12

10.0

8.5

180

148

7.9

141

11/10/2014

19




mmol/L mg/dL Units

< 4.4 < 80 -2 units


6.2-7.8 111-140 +2 units

7.9-10.0 141-180 +4 units

> 10.0 >180 +6 units

6.2

111

Lowest before breakfast

SMPG

Prescribed Insulin dose (Units)


SMPG 1

SMPG 2

SMPG 3

Bre

akfa

st

Before

8.2

8.0

150

145

6.2

111

mmol/L mg/dL

units

Before

Din

ne

r

12

10.0

8.5

180

148

7.9

141

= +2 14

12

Slide No. 110

ALL TO TARGET EFFICACY

A1C (%)

6.5

7.5

8.5

9.5

Premixed Basal + 1 shot

Basal + 0-3 shot

* *

* P < 0.05 vs. Premixed

39

49 45

14

0

20

40

60 *

24 *

*

24 *


Basal + 0-3 shot

% Patients with A1C <7%

Baseline <7% without hypo 60 weeks

ALL TO TARGET SYMPTOMATIC HYPOGLYCEMIA

Event-rates per person-yr


Basal + 0-3 shot

* P < 0.05 vs. Premixed

0

5

10

15

*

*

*

*

BG < 70 mg/dl BG < 50 mg/dl

Basal + prandial Insulin had better efficacy and less hypoglycemia compare to Premixed

Case 5.

ผปวยหญงอาย 55 ป เปน T2DM 8 ป, HT & dyslipidemia 5 ป

• ไดรบการรกษาดวย glicazide MR (60) 2x1 oral ac เชา,

Metformin (500) 2x3 oral pc, pioglitazone (30) 1X1 oral pc,

Insulin glargine 16 U Sc. ac เยน, Amlodipine (5) 1x1 oral pc,

Enalapril (20) 1/2 x 2 oral pc, Simvastatin (40) 1x1 oral pc เยน,

ASA (81) 1x1 oral pc

• ในชวง 1 เดอนทผานมา FPG 180-240 mg/dl ในชวง 1 ปทผานมา HbA1c 7.9-8.6%

• Good control for HT and Dyslipidemia

ค าถาม

ทานจะดแลรกษาผปวยรายนอยางไร

Case 5.

ผปวยหญงอาย 55 ป เปน T2DM 8 ป, HT & dyslipidemia 5 ป

• ไดรบการรกษาดวย glicazide MR (60) 2x1 oral ac เชา,

Metformin (500) 2x3 oral pc, pioglitazone (30) 1X1 oral pc,

Insulin glargine 16 U Sc. ac เยน, Amlodipine (5) 1x1 oral pc,

Enalapril (20) 1/2 x 2 oral pc, Simvastatin (40) 1x1 oral pc เยน,

ASA (81) 1x1 oral pc

• ในชวง 1 เดอนทผานมา FPG 180-240 mg/dl ในชวง 1 ปทผานมา HbA1c 7.9-8.6%

• Good control for HT and Dyslipidemia

ค าถาม

ทานจะดแลรกษาผปวยรายนอยางไร

11/10/2014

20


Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs


Metformin

high

low risk

neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight


Costs

high

low risk

gain


high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable



Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+


+


+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§





or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high


Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low


Breakfast

200

100

0

Glucose (mg/dl)

Basal Glucose

Lunch Dinner

Basal Insulin

Insulin (mU/ml)

50

25

0

Breakfast Lunch Dinner

Physiologic Insulin Therapy

Rapid Rapid Rapid, Long MDI with Analogs

Physiologic Profile

Basal Insulin

Insulin (mU/ml)

50

25

0 Breakfast Lunch Dinner

Regular+NPH/Lente Regular+NPH/Lente

At diagnosis






repaglinide











OHA 3 ตว



ปรบ

เปลยน

พฤต

กรรม

พรอม

กบ

เรม

ยา




11/10/2014

21

Challenges to Achieving Glycemic Goals

Physician related

Failure of some clinicians to adopt a treat-to-target approach1

Suboptimal dosing of available therapies1

Medication related

Inability of any single agent’s mechanism of action to target all

core defects of type 2 diabetes2

Patient related

Concern over adverse effects3

Suboptimal adherence to lifestyle measures1

Underuse of medications as a result of costs4 or complexity of

therapy1

9

1. Blonde L. Clin Cornerstone. 2005;7(Suppl 3):S6–S17. 2. Van Gaal LF et al. Diabetologia. 2003;46(Suppl 1):M44–M50.

3. McDonald HP et al. JAMA. 2002;288:2868–2879. 4. Piette JD et al. Diabetes Care. 2004;27:384–391.

“All of science is nothing more than the refinement of everyday thinking.” - Albert Einstein

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