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Clinical Practice Guidelines: Management of �Type 2 Diabetes Mellitus�2015

Topic :

Targets for Individualised Control

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40

15

13

10

4

5

0

10

20

30

40

50

Ischemic

heart disease

Other heart disease

Diabetes

Malignant neoplasms

Cerebrovascular disease

Pneumonia/

influenza

All other

Deaths (%)

Causes of Death in People With Diabetes

WHO Report 1997. World Health Organisation. Geneva 1997

of Diabetic Patients Deaths

are from CV Causes

65%

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UKPDS and myocardial infarction

0

10

20

30

0

3

6

9

12

15

% of patients with MI

Years after randomisation

Intensive

Conventional

p=0.06

Risk reduction 16%

(CI 95%: 0-29%)

UKPDS 33 Lancet. 1998;352:837-853

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Post-Trial Changes in HbA_1c

UKPDS results�presented

Mean (95%CI)

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Any Diabetes-related Endpoint

Intervention Trial�Median follow-up 10.0 years

Intervention Trial + Post-trial monitoring�Median follow-up 16.8 years

RR=0.88 (0.79-0.99)

P=0.029

Conventional

Sulfonylurea/�Insulin

Conventional

Sulfonylurea/�Insulin

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Myocardial Infarction Hazard Ratio

(fatal or non-fatal myocardial infarction or sudden death)

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

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All-cause Mortality Hazard Ratio

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

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UKPDS: Legacy Effect of Earlier Glucose Control

After median 8.5 years post-trial follow-up�

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.0099 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log Rank

N Eng J Med 2008

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Glucose lowering?

1. The presence of a legacy effect argues for early intensive glucose lowering

2. Target HbA_1cto 6.5% except where this requires complex treatment regimens or life expectancy is less than 5 years

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Question 1:

Does treatment-directed lowering HbA1c (below 6.0 to 6.5%) reduce CV endpoints

ACCORD ^{P, S}

ADVANCE ^{P, S}

VADT ^{P, S}

Questions addressed in RCT of Type 2 diabetes treatment

UKPDS ^P

^{P, primary prevention; S, secondary prevention}

UKPDS ^P

Long-term follow-up

After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival.

N Engl J Med 2015 Jun 4; 372: 2197-2206.

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0.9

0.7

1.1

1.5

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Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear

13

Study	Diabetes Duration (mean)	Antihyperglycemic Medication^a	Follow-up�(median)	A_1c: Baseline, Between-arm Difference	Microvascular	CVD	Mortality
ADVANCE³	8 years	Intensive glucose control including gliclazide vs standard treatment	5 years	7.5% (both arms)^b, �–0.8%^d	↓	↔	↔
ACCORD^4,5	10 years	Multiple drugs in both arms	3.4 years	8.1% (both arms)^e, �–1.1%^c	↓	↔	↑
VADT⁶	11.5 years	Multiple drugs in both arms	5.6 years	9.4% (both arms)^b, �–1.5%^d	↔	↔	↔

^cMedian between-arm difference; ^dMean between-arm difference; ^eMedian baseline HbA_1c.

CV = cardiovascular; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD =

Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE

Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6.

Duckworth W et al. N Engl J Med. 2009;360:129–139.

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a study of 11,140 patients randomized to receive intensive glucose control (HbA_1c target ≤6.5%) with addition of gliclazide (or substitution of gliclazide for other sulfonylurea therapy) or standard glucose control (HbA_1c target defined by local guidelines). Patients in the standard treatment group who were receiving gliclazide when they entered the study substituted this drug with another sulfonylurea. At the end of the follow-up period, mean HbA_1c values were 6.5% in the intensive-control group and 7.3% in the standard-control group (–0.8% between-arm difference). Intensive control resulted in a reduced risk for major microvascular events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.77–0.97; P=0.01) but not for major macrovascular events (HR 0.94, 95% CI 0.84–1.06; P=0.32) or death from any cause (HR 0.93, 95% CI 0.83–1.06; P=0.28), including death from cardiovascular (CV) causes.³

Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a randomized multicenter study that investigated the incidence of cardiovascular events among 10,251 diabetic patients receiving multiple antihyperglycemic medications as intensive therapy (target HbA_1c <6%) vs standard therapy (target HbA_1c 7.0–7.9%). An absolute between-treatment difference in HbA_1c levels of –1.1% was observed in favor of the intensive therapy group.⁴ Intensive therapy did not significantly affect advanced measures of microvascular outcomes but did delay the onset of albuminuria and some measures of eye complications and neuropathy.⁵ The trial reported no significant differences in the rate of nonfatal stroke (HR 1.06, 95% CI 0.75–1.50; P=0.74) but found a significant reduction in incidence of nonfatal MI in the intensive-therapy group (HR 0.76, 95% CI 0.62–0.92; P=0.004). A concomitant increase in CV deaths (HR 1.35, 95% CI 1.04–1.76; P=0.02) and all-cause mortality (HR 1.22, 95% CI 1.01–1.46; P = 0.04) in this group led to its early termination in 2008, 17 months before the study conclusion.⁴

The Veterans Affairs Diabetes Trial (VADT), conducted in 1,791 veterans with poorly controlled T2DM, was designed to achieve an overall difference of –1.5% between intensive and standard glucose therapy arms. Microvascular complications were minimally affected by intensive glucose control, as no significant differences in retinopathy, major nephropathy, or neuropathy were seen. A nominally significant reduction (P=0.05) in any worsening of albumin excretion was observed in the intensive-therapy group. No significant differences were observed between the 2 groups in the incidence of major CV events (HR 0.88, 95% CI 0.74–1.05; P=0.14) or death from any cause (HR 1.07, 95% CI 0.81–1.42; P=0.62).⁶

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Di Angelantonio E et al, The Emerging Risk Factors Collaboration, JAMA 311: 1225-1233, 2014

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

Hazard ratios for incident CVD by baseline levels of glycemia measures

73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline

adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c and CVD risk

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A1c Targets

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Individualised A1c Targets and Patients’ Profile
Tight (6.0 – 6.5%)	6.6 – 7.0%	Less tight (7.1 – 8.0%)
Newly diagnosed Younger age Healthier (long life expectancy, no CVD complications) Low risk of hypoglycaemia	All others	Comorbidities (coronary artery disease, heart failure, renal failure, liver dysfunction) Short life expectancy Prone to hypoglycaemia

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Treatment Strategies: Glucose Triad

Treatment strategy should target all 3 components

Ceriello A, Colagiuri S. Diabet Med. 2008;25(10):1151-1156.

HbA_1c

PPG

FPG

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As Patients Get Closer to A1C Goal, the Need to Manage PPG Significantly Increases

17

Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and �postprandial plasma glucose increments to the overall diurnal hyperglycemia �of Type 2 diabetic patients: variations with increasing levels of HBA(1c). �Diabetes Care. 2003;26:881-885.

Increasing Contribution of PPG as A1C Improves

% Contribution

0

20

40

60

80

100

A1C Range (%)

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Contribution of FPG and PPG to A1c

Landmark study using 4-point glucose measurement (290 T2DM subjects)

PPG accounted for ~70% overall glycaemic exposure when A1c is low (<7.3%)

Contribution from the fasting hyperglycaemia increasing as A1c increases

With A1c >10.2%, contributions reversed;

PPG contributed ~30% and FPG ~70%

Monnier L et al.Diabetes Care 26:881–885, 2003

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Steno-2 Study

Glycosylated�haemoglobin �<6.5%

Patients Reaching Intensive-Treatment Goals at Mean 7.8 y, (%)

Intensive Therapy

Cholesterol�<3.8 mmol/l

Triglycerides�<1.7 mmol/l

Systolic BP�<130 mm Hg

Diastolic BP�<80 mm Hg

Conventional Therapy

P=0.06

P<0.001

P=0.19

P=0.001

P=0.21

Gæde P et al. N Engl J Med 2003;348:383-393

Slide Source

Lipids Online Slide Library

www.lipidsonline.org

Efficacy of multiple risk factor intervention in high-risk subjects (type 2 diabetes with microalbuminuria): Steno-2

The Steno-2 study showed the effect of a multiple risk factor intervention strategy in 160 subjects with type 2 diabetes with microalbuminuria. Although all these subjects had type 2 diabetes, the results suggest that multiple risk factor intervention may also be highly beneficial in subjects with the metabolic syndrome. Subjects in the intensive therapy group were to follow a reduced-fat diet and exercise regularly, offered smoking cessation counseling, prescribed an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II–receptor blocker (ARB) regardless of blood pressure, and received vitamin supplementation and aspirin; stepwise antiglycemic and antihypertension medications were also prescribed as well as lipid-modifying therapy with a statin and/or fibrate. Subjects receiving intensive therapy were much more likely to reach their total cholesterol goal (<175 mg/dL) and systolic blood pressure goal (<130 mm Hg) and to routinely use ACE inhibitors or ARBs (data not shown). Note that it was much more difficult to achieve systolic blood pressure goal than diastolic blood pressure goal. The difference between intensive and conventional therapy for hemoglobin A1c (glycosylated hemoglobin) was only 0.6%.

Reference:

Gæde P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393.

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Steno-2 follow up primary endpoint

Gaede P et al. N Engl J Med 2008;358:580-591

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Steno-2 primary outcome

Primary Composite Endpoint (%)

Months of Follow-up

0

24

48

60

96

36

84

72

12

Conventional �Therapy

Intensive �Therapy

P=0.007

Hazard ratio = 0.47 (95% CI, 0.24–0.73; P=0.008)

Gæde P et al. N Engl J Med 2003;348:383-393

Slide Source

Lipids Online Slide Library

www.lipidsonline.org

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Steno-2 Follow up

Gaede P et al. N Engl J Med 2008;358:580-591

Slide Source

Lipids Online Slide Library

www.lipidsonline.org

Figure 2. Changes in Selected Risk Factors during the Interventional Study and Follow-up Period. Panel A shows mean ({+/-}SE) values for selected risk factors during the interventional part of the study for all patients (solid lines) and during the follow-up period (dashed lines). In the conventional-therapy group, mean values were obtained at baseline, at 3.8 years, at 7.8 years, and at 13.3 years. At these intervals, the total numbers of patients in both study groups were 160, 149, 130, and 93, respectively. Panel B shows the percentage of patients in each group in whom the treatment goals for the intensive-therapy group were reached at the end of the study. Only one patient (in the intensive-therapy group) reached all five treatment goals at the end of follow-up. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. LDL denotes low-density lipoprotein.

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Steno-2 follow up secondary endpoint

Gaede P et al. N Engl J Med 2008;358:580-591

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Treating the ABCs Reduces �Diabetic Complications

Strategy	Complication	Reduction of Complication
Blood glucose control	Heart attack	↓ 37%¹
Blood pressure control	Cardiovascular disease Heart failure Stroke Diabetes-related deaths	↓ 51%² ↓ 56%³ ↓ 44%³ ↓ 32%³
Lipid control	Coronary heart disease mortality Major coronary heart disease event Any atherosclerotic event Cerebrovascular disease event	↓35%⁴ ↓55%⁵ ↓37%⁵ ↓53%⁴

¹UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853.

²Hansson L, et al. Lancet. 1998;351:1755-1762.

³UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713.

⁴Grover SA, et al. Circulation. 2000;102:722-727.

⁵Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

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Glucose lowering – �waste of time?

Glucose lowering, started early, may have long term cardiovascular benefits

Multifactorial risk reduction is imperative

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Self-monitoring of Blood Glucose (SMBG)

SMBG, self-monitoring of blood glucose.

When and how should glucose monitoring be used?

Noninsulin Users

Insulin Users

Introduce at diagnosis
Personalize frequency of testing
Use SMBG results to inform decisions about whether to target FPG or PPG for any individual patient

All patients using insulin should test glucose

≥2 times daily
Before any injection of insulin

More frequent SMBG (after meals or in the middle of the night) may be required

Frequent hypoglycemia
Not at A1C target

Testing positively affects glycemia in T2D when the results are used to:

Modify behavior
Modify pharmacologic treatment

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SMBG Frequency vs A1C

When and how should glucose monitoring be used?

Miller KM, et al. Diabetes Care. 2013;36:2009-2014.

1-13 years

13-26 years

26-50 years

50+ years

SMBG per day

0-2

3-4

5-6

7-8

9-10

11-12

≥13

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

10.5

11.0

Mean A1C

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Targets for Control

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Parameters		Levels
Glycaemic control*	Pasting or pre-prandial	4.4 – 7.0 mmol/L
	Post-prandial**	4.4 – 8.5 mmol/L
	A1c⁺⁺	≤6.5%
Lipids	Triglycerides	≤1.7 mmol/L
	HDL-cholesterol	>1.0 mmol/L (male)
	HDL-cholesterol	>1.2 mmol/L (female)
	LDL-cholesterol	≤2.6 mmol/L^#
Blood pressure		≤135/75 mmHg^$
Exercise		150 minutes/week
Body weight	If overweight or obese, aim for 5-10%weight loss in 6 months

Modified from the NICE guideline: Type 2 diabetes: The management of type 2

diabetes, 2009. (Level III). Glycaemic target should be individualised to minimise

risk of hypoglycaemia. (Level I). The committee acknowledges the increased CVD

death in the intensive group of the ACCORD study. (Level I). However, the

committee believes it is due to the overall treatment strategies that were employed

to achieve the A1c target rather than the reduction in A1c. This is also collaborated

by the ADVANCE study. (Level I).

** Measured at least 90 minutes after meals.

⁺⁺A1c ≤6.5% is advocated for patients with a shorter duration of diabetes,

no evidence of significant CVD and longer life expectancy and have minimal risk of

hypoglycaemia. There are strong benefits for reduction of nephropathy (ADVANCE)

and retinopathy (ACCORD/ACCORD Eye Study Group) at or below this level of

A1c. (Level I)

^#In individuals with overt CVD, LDL cholesterol target is <1.8 mmol/L.�^$In children and adolescents, blood pressure (BP) should be <95th percentile for age and sex. 49 (Level III)