1. Management of Diabetes Treat to Target Approach (A1c <7%) by Professor Dr Intekhab Alam Department of Medicine Postgraduate Medical Institute Lady Reading Hospital, Peshawar.
This slide module will:
Discuss the importance of glycosylated haemoglobin A1c as a marker for blood glucose control in both type 1 and type 2 diabetes management
Review the Diabetes Control and Complications Trial, United Kingdom Prospective Diabetes Study, and other studies to identify the link between good glycaemic control and long-term clinical outcomes
Demonstrate the need for aggressive therapy to achieve glycaemic control, thereby reducing the risk of microvascular and macrovascular complications

2. Milestones in Diabetes Treatment
1920
1940
1960
1980
2000
Insulin glargine
NPH
insulin
A1c
DCCT
Metformin
Insulin discovered
First sulphonylureas
UKPDS
Insulin pump
Lente insulins
• It has been more than 80 years since the discovery of insulin, and as this timeline shows, there has been continuing progress. In fact, much of our current understanding of diabetes, its devastating consequences, and its effective management has been attained during the latter part of this timeline. As this presentation will discuss, despite the progress of science, there are still many challenges to be overcome
Researchers at the University of Toronto discovered insulin in 1921
The first sulphonylureas appeared during the early 1940s
Hans Christian Hagedorn’s delayed-action preparation, “neutral protamine Hagedorn,” appeared in 1946; we know it as NPH
The Lente series appeared in 1952
Metformin became available (outside the United States) in 1960
Portable insulin infusion pumps were introduced during the late 1970s
The Diabetes Control and Complications Trial was published in 1993
Rapid-acting insulin analogues became available in 1996
The United Kingdom Prospective Diabetes Study was published in 1998
Lantus (insulin glargine; the first long-acting insulin analogue) received US Food and Drug Administration approval in 2000
Rapid-acting insulin
DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.
1. Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.
2. US FDA Center for Drug Evaluation and Research. Available at: Accessed March 18, 2003.
3. Lantus Consumer Information. Available at: Accessed March 18, 2003.

3. Dual defect of type 2 diabetes: Treating a moving target
Insulin
Resistance
Type 2
Diabetes
b-cell
Dysfunction
Hyperglycaemia
Insulin Action
b-cell Failure
Insulin
Concentration
Insulin
Resistance
Dual defect of type 2 diabetes: treating a moving target
The pathophysiology of type 2 diabetes is complex, and characterised by remorseless progression of the dual metabolic defects of insulin resistance and b-cell dysfunction.
Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic.
As insulin resistance progresses, however, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Eventually, insulin secretion from the b-cell begins to decline and the severity of the hyperglycaemia increases further.
Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:
Euglycaemia
Normal
IGT ± Obesity
Diagnosis of type 2 diabetes
Progression of type 2 diabetes
DeFronzo et al. Diabetes Care 1992;15:318-68

4. Progressive hyperglycaemia in type 2 diabetes9
Diet 8
Insulin
Median HbA1C (%)
Metformin 7
Progressive hyperglycaemia in type 2 diabetes
All active therapies in the UKPDS reduced HbA1C, compared with placebo. However, the severity of hyperglycaemia increased at a similar rate in all treatment groups during the follow-up period. Current goals for glycaemic management set out by the International Diabetes Federation (Europe) and the American Association of Clinical Endocrinologists (USA) require control of HbA1C to 6.5% or less. The newly-diagnosed patients randomised to receive intensive glycaemic management in the UKPDS would, on average, have achieved this goal for only about 2 years following the initiation of treatment with oral antidiabetic monotherapy.
It should be remembered that the UKPDS was essentially an evaluation of oral antidiabetic therapy, and treatment was not intensified until fasting plasma glucose exceeded 15 mmol/L (270 mg/dL). The high levels of HbA1C in the later years of the UKPDS therefore reflect the study design, but nonetheless expose the limitations of oral antidiabetic monotherapy in achieving long-term glycaemic control.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:
HbA1C 6.5%
(IDF & AACE goal value)
Sulphonylurea 6 2 4 6 8 10
Time from randomisation (years)
UKPDS Group. Lancet 1998;352:854-65

5. ADA- and AACE/ACE-Recommended Goals for Glycaemic Control: A1c, FPG, and PPG
Biochemical Control1
Normal1
Goal1
A1c* (%)
<6.0
<7.0†
FPG (mg/dL) Average preprandial
<110
90-130‡
PPG (mg/dL)
<140
<180§
The goal of diabetes management is to achieve blood glucose levels as close to normal throughout the entire course of a day
To achieve this goal, the American Diabetes Association recommends a target A1cgoal of <7%. The World Health Association, the International Diabetes Federation, and the American Association of Clinical Endocrinologists/American College of Endocrinology have issued guidelines that recommend the more stringent A1c target of 6.5%
The Diabetes Control and Complications Trial, United Kingdom Prospective Diabetes Study, and other studies have shown that to intensively treat to target is to intensively treat diabetes comorbidity. These studies have proven that there is a link between good glycaemic control and long-term clinical outcomes
*Referenced to the nondiabetic range using a DCCT assay.1
†AACE/ACE recommendation: 6.5%.2
‡AACE/ACE recommendation: <110 mg/dL.2
§AACE/ACE recommendation: <140 mg/dL.2
ADA, American Diabetes Association; AACE/ACE, American Association of Clinical Endocrinologists/American College of Endocrinology; FPG, fasting plasma glucose; PPG, postprandial glucose; DCCT, Diabetes Control and Complications Trial.
1. ADA. Diabetes Care. 2003;26(suppl 1):S33-S50.
2. AACE/ACE. Endocr Pract. 2002;8(suppl 1):40-82.

6. A1c Reflects Overall Glucose Control
A1c is the glycated form of the abundant red blood cell protein1
A1c levels provide a 2- to 3-month index of glycaemic control2
The target A1c level for patients with diabetes is <7%1
Overall blood glucose control is best obtained by monitoring A1c3
Circulating serum glucose binds irreversibly to the N-terminal valine within the beta chain of the haemoglobin (Hb) molecule, creating A1c
It is currently accepted that A1c yields the best overall measurement of blood glucose control
A1c levels provide an objective index of glycaemic control for the past 2 to 3 months, based on the turnover of Hb in red blood cells
Importantly, increases in A1c levels reflect both the rise in fasting/preprandial blood glucose levels and postprandial glucose levels; thus, normalisation of A1c levels may require control of both pre- and postprandial glucose levels
1. Pickup JC. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.
2. Clark N. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
3. Cefalu WT. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.

7. Relationship of Mean Plasma Glucose and A1c
This slide shows mean plasma glucose (MPG) values at increasing levels of A1c derived from data from the Diabetes Control and Complications Trial
Using fasting plasma glucose alone as a gauge of long-term glycaemia tended to progressively underestimate A1c and 7-point MPG at increasing plasma glucose levels
Postprandial plasma glucose contributes appreciably to A1c, although not all post meal times are equal in their distribution; eg, post lunch levels and MPG show similar relationships to A1c levels, while post breakfast levels markedly overestimate A1c
MPG, mean plasma glucose.
Adapted from Rohlfing CL et al. Diabetes Care. 2002;25:
1. Rohlfing CL, Wiedmeyer H-M, Little RR, England JD, Tennill A, Goldstein DE. Defining the relationship between plasma glucose and HbA1c: analysis of glucose profiles and HbA1cin the Diabetes Control and Complications Trial. Diabetes Care. 2002;25:

8. A1c and Relative Risk of Microvascular Complications: DCCT20
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria 15 13 11 9
Relative Risk 7 5
Good glycaemic control is essential to reduce the risk of diabetic complications
Based on the Diabetes Control and Complications Trial data, the relative risk for microvascular complications such as diabetic retinopathy, nephropathy, neuropathy, and microalbuminuria increases with increasing levels of A1c
The relative risk of complications is set to “1” for an A1c of 6%
It is important to note that the risk gradient is continuous, with no glycaemic threshold for developing complications 3 1 6 7 8 9 10 11 12
A1c (%)
DCCT, Diabetes Control and Complications Trial.
1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:
2. DCCT. N Engl J Med. 1993;329:
3. DCCT. Diabetes. 1995;44:

9. Type 2 Diabetes Is a Progressive Disease: UKPDS
Cross-sectional median values
Conventional Treatment* (n=1138)
Intensive Treatment† (n=2729) 9 8
Median A1c (%) 7 6
United Kingdom Prospective Study was the largest study of newly diagnosed type 2 diabetes patients ever undertaken to examine the outcomes of treatment strategies over time
More than 4200 patients were eligible for randomisation to receive conventional or intensive treatment for 10 years
Conventional therapy consisted of dietary advice; in patients who developed marked hyperglycaemia, secondary sulphonylurea or insulin therapy was provided, with the additional option of metformin in overweight patients
Intensive therapy consisted of dietary advice, along with sulphonylureas or insulin therapy with once-daily Ultralente insulin or isophane insulin 3 6 9 12 15
Time From Randomisation (years)
*Diet, only.
†Insulin or sulphonylurea + diet.
UKPDS, United Kingdom Prospective Diabetes Study.
Adapted from UKPDS Group. Lancet. 1998;352:

10. Good Glycaemic Control Reduces Incidence of Complications
Risk reduction by decrease in A1c (%)
Complications DCCT1,2 Ohkubo3 UKPDS4
of diabetes mellitus (9% %) (9% 7%) (8% %)
Retinopathy -63% -69% -21%
Nephropathy -54% -70% -34%
Neuropathy -60% – –
Macrovascular disease -41%* – -16%*
A reduction in risk for organ damage due to diabetes was seen in 3 landmark trials—the Diabetes Control and Complications Trial (DCCT), Ohkubo, and the United Kingdom Prospective Diabetes Study.4 In each, good glycaemic control, reflected by reductions in A1c levels (noted for each study at the head of each column), reduces the long-term incidence of microvascular complications
Additionally, there was a strong trend toward reduction of macrovascular complications. The 41% reduction in macrovascular disease in DCCT was impressive, although it did not reach statistical significance due to the low number of events in the study
Thus, solid clinical evidence exists to support glycaemic control as a primary goal of therapy for patients with type 1 or 2 diabetes
*Not statistically significant.
DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.
1. DCCT Research Group. N Engl J Med. 1993;329:
2. DCCT Research Group. Diabetes. 1995;44:
3. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:
4. UKPDS Group. Lancet. 1998;352:

11. Correlation of A1c and Complication Risk: UKPDS
Type 2 DM
Risk reduction in complications per
each 1% reduction in mean A1c 43 37
Risk Reduction (%) 21 21 14
The United Kingdom Prospective Diabetes Study yielded:
A continuous and quantifiable correlation between decreased A1c measurements and a lower likelihood of diabetes-related macrovascular and microvascular complications, including peripheral vascular disease, stroke, and myocardial infarction
On average, each 1% reduction in A1c is associated with a 37% decrease in the risk of microvascular endpoints and a 21% decrease in the risk of any diabetes-related endpoint or death; even patients with A1c levels only moderately above normal show an increased vulnerability to complications
These data demonstrate the value of clinicians’ efforts to bring patients’ A1c levels as near normal as possible. However, even moderate reductions in A1c levels have the potential to prevent deaths from complications related to diabetes
Microvascular
Any Endpoint Related to Diabetes
Death Related
to Diabetes
Fatal and Nonfatal MI
Amputation or
Death From PVD
UKPDS, United Kingdom Prospective Diabetes Study; MI, myocardial infarction;
PVD, peripheral vascular disease.
Stratton IM et al. Br Med J. 2000;321:

12. Preservation of Benefit: EDIC Progression of Retinopathy
Type 1 DM
Conventional Treatment*
Intensive Treatment† 24 22 20 18 16 14
Cumulative Incidence (%) 12 10 8 6 4
The Epidemiology of Diabetes Interventions and Complications trial (EDIC) consisted of patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT) who were followed for an additional 4 years
Intensive therapy consisted of 3 injections of insulin daily or use of an insulin pump, combined with self-monitoring of blood glucose values, diet modification, and exercise. Conventional treatment consisted of 1 or 2 injections of insulin and 1 urine or blood glucose test each day
Those receiving intensive treatment during the DCCT/EDIC showed a lower risk of worsening retinopathy, including macular edema and proliferative retinopathy, and a need for laser therapy (P<.001) 2
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
EDIC (year)
*1-2 insulin injections and 1 urine/blood glucose test daily.
†3 insulin injections/pump treatments daily + SMBG + diet + exercise.
EDIC, Epidemiology of Diabetes Interventions and Complications trial; SMBG, self-monitored blood glucose.
DCCT/EDIC Research Group. N Engl J Med. 2000;342:

13. Risk of Death Related to A1c Levels6
A1c 7.0% 4
Relative Risk (%) 2
The relationship between A1c, diabetes, and mortality was investigated in 4662 men (aged years) in the Norfolk cohort of the European Prospective Investigation of Cancer and Nutrition
Results of the study showed that the relative risk of death increased through the range of A1c levels evaluated (<5.0%, 5.0%-5.4%, 5.5%-6.9%, 7.0%). It is important to note that between the levels of 5.0% to 5.4% and 5.5% to 6.9% the rise in risk of death is minimal; at A1c levels 7.0%, the risk increases dramatically
As can be seen, the higher the A1c level, the greater the relative risk of death from cardiovascular disease (CVD), ischaemic heart disease (IHD), or all causes
The study concluded that the increased risk of death from CVD, IHD, and all causes among men with diabetes could be largely explained by A1c concentration
Cardiovascular
Disease
Ischaemic Heart
Disease
All Causes
Note: A1c <5.0% was defined as a relative risk of 1.
Adapted from Khaw K-T et al. Br Med J. 2001;322:1-6.
Norfolk cohort of the European Prospective Investigation of cancer and Nutrition, n-4662

14. A Comprehensive Approach To Treat to Target
Type 2 DM
Conventional Treatment
Intensive Treatment 60
P=.007 50 40
Primary Composite Endpoint* (%) 30 20 10
Because hypertension and dyslipidaemia tend to be comorbid with type 2 diabetes, true treatment to target is not a matter of glycaemic control only. A multifactorial intervention is needed
The study from the Steno Diabetes Center in Denmark proves that optimal management in type 2 diabetes includes control of blood pressure (BP) to 130/80 mm Hg and reduction of low-density lipoprotein cholesterol
Patients were randomised to either conventional (n=80) or intensive treatment (n=80). Intensive treatment included insulin to control A1c to <6.5%, a diuretic to control BP, and an angiotensin-converting enzyme inhibitor, regardless of BP level. Additional therapies were as follows:
Intensive treatment: an angiotensin II receptor blocker to control BP to <130/80 mm Hg, dietary management of serum lipids (cholesterol: <190 mg/dL; fasting triglycerides: <150 mg/dL), and aspirin 150 mg/day
Conventional treatment: BP control to <135/85 mm Hg and serum lipid control (cholesterol <250 mg/dL; fasting triglycerides <180 mg/dL), with aspirin therapy reserved for patients with known ischaemia
At a mean follow-up of 7.8 years, patients receiving intensive treatment were about 50% less likely to have experienced cardiovascular disease, nephropathy, retinopathy, or autonomic neuropathy 12 24 36 48 60 72 84 96
Follow-up (months)
Number at Risk/Treatment
Conventional
Intensive 80 72 70 63 59 50 44 41 13 80 78 74 71 66 63 61 59 19
*Composite endpoint = cardiovascular death and amputation (with either therapy), and relative risk for organ damage (with intensive therapy).
Gaede P et al. N Engl J Med. 2003;348:
Steno diabetes center,Denmark. n 160.

15. Insulin Helps Achieve Control
Type 2 DM 60 * 47 50 40 35
Patients Achieving A1c <7% at 6 Years (%) 30 20 20 10
Conventional
Glucose Control
Insulin Alone
SU ± Insulin
A substudy of the United Kingdom Prospective Diabetes Study evaluated the efficacy of the addition of insulin therapy over 6 years in 826 newly diagnosed patients with type 2 diabetes randomised to either conventional control with diet alone or intensive control (insulin alone or insulin added to maximal sulphonylurea)
The aim of conventional control was to achieve the best possible fasting glucose; the aim of intensive control was to achieve and maintain fasting glucose <6.0 mmol/L (<108 mg/dL)
Significantly more patients in the combination group were able to achieve an A1c <7.0% than in the insulin-alone group (47% vs 35%, P=.011)
Thus, intensive insulin therapy, either alone or added to sulphonylurea, resulted in better control than diet alone
Intensive Glucose Control (FPG < 108 mg%)
Median A1c (IQR): % ( ) % ( )† % ( )†‡
*P=.011 sulphonylurea  insulin vs insulin alone; †P< insulin or sulphonylurea  insulin vs conventional glucose control policy; ‡P=.0066 sulphonylurea  insulin vs insulin alone.
SU, sulphonylurea; IQR, interquartile range.
Adapted from Wright A et al. Diabetes Care. 2002;25:

16. Treat to Target A1c A1c is a key marker of diabetes treatment efficacy
A1c levels correlate with a patient’s relative risk of death and of microvascular and macrovascular complications
The DCCT, UKPDS, and other major trials—as well as major diabetes organizations—support treatment-to-target A1c <7%
• A1c level is a key surrogate marker of the relative risk of both death and of microvascular and macrovascular complications in patients with diabetes
• The treat-to-target approach (A1c <7%) is supported by the Diabetes Control and Complications Trial, the United Kingdom Prospective Diabetes Study, other major trials, as well as major diabetes organizations
DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.

17. Treat to Target A1c
Aggressive therapy is often necessary to achieve control
Treat to target requires a comprehensive approach: control of blood pressure and control of LDL-c, bolstering a concerted attack on A1c levels
Treat to target reduces risk of complications and its associated costs
• Aggressive therapy helps achieve control
• Treat to target requires a comprehensive approach: control of blood pressure and low-density lipoprotein cholesterol, and a concerted attack on A1c levels
Treat to target A1c levels reduces the risk of complications, thereby reducing the cost associated with these complications
Early diagnosis, along with effective therapeutic agents, may result in more patients reaching and maintaining target A1c goals, thereby maintaining a low-cost state for an extended period of time
LDL-C, low-density lipoprotein cholesterol.

18. Pitfalls In HbA1C Estimation
False high HbA1C:
Hb F, Acetylated Hb, Cabamoylated Hb.
False low HbA1C:
Hb S or C, Hemolytic anemias, Hemmorhage.
Reliability in diagnosing Diabetes:
sensitivity 85%
specificity 91%.
Fructosamine levels:
nonenzymatic glycosylation of serum proteins esp Albumin
1.5-2,4 mmol/l with 5gm/dl of Albumin.

19. The ABC of Diabetes Management
Effective management of diabetes requires
A – Control of A1c
B – Control of Blood pressure
C – Control of Cholesterol
The effective management of diabetes requires control of
A - A1c
B –Blood pressure
C –Cholesterol

20. ADA Glycemic Targets Normal Goal Action Level
HbA1c (%) <6 <7 >8
Fasting and preprandial blood glucose (mg/dL) < to >140
The ADA recommendations for glycemic targets is as follows
Normal
Goal
Action Level
HbA1c (%)
< 6
<7
> 8
Fasting and prandial blood glucose (mg/dl)
< 110
80 to 120
> 140
American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41.

21. ADA Blood Pressure Targets
Goal (mm Hg)
Usual patient <130/85
Isolated systolic hypertension If ≥180 < If 160 to 179 Reduce by 20
The ADA recommendations for blood pressure targets is as follows
Goal (mm Hg)
Usual patient
< 130/ 85
Isolated systolic hypertension
If  180
If 160 to 179
<160
Reduce by 20
American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41.

22. ADA LDL-Cholesterol Targets (mg/dl)
Medical Nutrition Therapy Drug Therapy Begin Rx Goal Begin Rx Goal
With CV disease >100 ≤ > ≤100
No CV disease > ≤ > ≤100
The ADA recommendations for LDL – cholesterol targets is as follows
Medical Nutrition therapy
Begin Rx Goal
Drug therapy
Begin Rx Goal
With CV disease
>100 mg/dl  100 mg/dl
>100 mg/dl  100 mg/dl
No CV disease
>100 mg/dl  100 mg/dl
>130 mg/dl  100 mg/dl
American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41 & S56-S59.

23. European Diabetes Policy Group Desktop Guide
‘Providing a greater emphasis on arterial risk factor management rather than just good blood glucose control’
The European Diabetes Policy Group Desktop Guide recommends
“Providing a greater emphasis on arterial risk factor management rather than just good blood glucose control”
European Diabetes Policy Group (1998–1999)

24. European Diabetes Policy Group Desktop Guide
At each assessment
Set individual targets for blood glucose, blood lipid and blood pressure
Targets should incorporate an assessment of risk and the patient’s needs
Set realistic objectives within a time period
Evaluate individual targets at least yearly in the light of past successes and if clinical circumstances change
The European Diabetes Policy Group Desktop Guide also recommends that at each assessment
Set individual targets for blood glucose, blood lipid and blood pressure
Targets should incorporate an assessment of risk and the patient’s needs
Set realistic objectives within a time period
Evaluate individual targets at least yearly in the light of past successes and if clinical circumstances change
European Diabetes Policy Group (1998–1999)

25. Assessment Measure HbA1c every 2-6 months
blood lipid profile (total, LDL- and HDL-cholesterol, and triglycerides) every 2-6 months if previously above assessment levels otherwise annually
blood pressure at each consultation unless known to be below assessment levels
One should measure
HbA1c every 2-6 months
blood lipid profile (total, LDL- and HDL-cholesterol, and triglycerides) every 2-6 months if previously above assessment levels otherwise annually
blood pressure at each consultation unless known to be below assessment levels
European Diabetes Policy Group (1998–1999)

26. European Diabetes Policy Group advice
‘Failure to attempt to reach agreed targets is inadequate care’
The European Diabetes Policy Group advises that
‘Failure to attempt to each agreed targets is inadequate care’
European Diabetes Policy Group (1998–1999)