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1

Main findings in UKPDS re glycaemic control:

establish that retinopathy, nephropathy, and possibly neuropathy are benefited by lowering blood glucose levels in type 2 diabetes with intensive therapy, which achieved a median HbA1c of 7.0% compared with conventional therapy with a median HbA1c of 7.9%. #

The overall microvascular complication rate was decreased by 25%.

3. The results demonstrate that the risks of complications can be significantly lowered even in the range of hyperglycemia where HbAlc levels are <8.0%. 


Nonetheless, the UKPDS did not prove definitively that intensive therapy that lowered blood glucose levels reduced the risk of cardiovascular complications compared with conventional therapy. Thus, the role of hyperglycemia in cardiovascular complications still unclear.

2

UKPDS findings re BP control

The study showed that lowering blood pressure to a mean of 144/82 mmHg significantly reduced strokes, diabetes-related deaths, heart failure, microvascular complications, and visual loss.

Epidemiological analysis showed a continuous relationship between the risk of all the above outcomes and systolic blood pressure. There was no evidence of a threshold of BP for these complications.

“Tight blood pressure control,” as achieved in the UKPDS, significantly reduced the risks of virtually all cardiovascular and microvascular outcomes, with risk reductions ranging from 24 to 56%.
A reduction seen in myocardial infarction was not significant.

UKPDS also compared antihypertensive treatment with an ACE inhibitor to that with a β-blocker. Both drugs were about equally effective in lowering blood pressure, #

3

overall, UKPDS conclusions re BP and glycaemic control

Thus, both hyperglycemia and hypertension should be vigorously treated when they occur together with an expectation that reductions in microvascular and cardiovascular outcomes will be additive.

4

UKPDS and DCCT re glucose control benefits. what is still not known re sub-groups?

The UKPDS and the DCCT have answered the question of whether blood glucose control is beneficial for people with type 1 and type 2 diabetes. It definitely is.

However, both trials enrolled patients before serious microvascular complications had developed.

The benefits of achieving normal blood glucose levels are not known in those who already have more advanced complications

Neither study gave a definitive answer to the question of whether glucose control reduces the risk of cardiovascular disease.

5

UKPDS metformin

Despite there being no significant difference in HbA1c levels between subjects treated with metformin or conventionally treated subjects, the use of metformin was associated with a 39% relative reduction in the risk for myocardial infarction (p = 0.01) and a 36% relative reduction in all-cause mortality (p = 0.01) without any effect on microvascular complications.


These results have been widely interpreted to mean that metformin has beneficial effects on reducing CV events that are to some extent independent of glucose control.

6

UKPDS follow-up in 2007 (after 10 year)

just over one third of subjects who completed the trial in 1997 were followed up.

there was significant 13% reduction in all cause mortality, also in MI, although no difference in HbA1c.

7

Legacy effect

lowering glucose levels clearly reduces microvascular outcomes and that in the setting of newly diagnosed type 2 diabetes, aggressive glucose control almost certainly has a benefit on CV outcomes. However, early strict glycaemic control may also generate a legacy effect that takes many years before being eventually translated into protection from CV events. For subjects with established type 2 diabetes, strict glucose control most likely has an attenuated benefit on CV events that is mainly confined to CHD outcomes, when compared to subjects with newly diagnosed diabetes.

8

glycaemic control and CVS events - recent analyses

Recent meta-analyses of the above randomised trails have also shown that intensive glucose control is associated with a reduced risk of MI, without a clear benefit on other CV diseases such as stroke. 

9

WHAT ABOUT LIPIDS AND MICROVASCULAR COMPLICATIONS?

• Mixed associations between lipids/lipoproteins and microvascular complications
• Mixed results for the role of statins in reducing risk or preventing microvascular complications
• Above uncertainty due to:
- Correlation between risk factors
- Quality of studies (size, follow-up)

- Majority of people with type 2 diabetes now on statins

10

what are the main processes tha lead to CVD ?

atherosclerosis and hypertension.

Atherosclerosis
• increased risk in diabetics
• process is accelerated, more severe and more widespread with diabetes
• atherosclerosis leads to damage of medium and large blood vessels (=macroangiopathy)
• atherosclerosis in diabetes results from a complex interplay between a number of risk factors.
Hypertension
• twice as common in diabetics
• Independent risk factor of CVD

11

Other CVD processes caused or accelerated by diabetes:

Microangiopathy
Autonomic neuropathy
Microangiopathy and autonomic neuropathy worsen the consequences of atherosclerosis/macroangiopathy and hypertension
• May lead to nephropathy and impotence.


Damage to small blood vessels and capillary circulation
Clinical consequences:
• Retinopathy
• Nephropathy
• Neuropathy
• Diabetic foot

12

Damage to the nerve supply of the internal organs of the body
Clinical consequences of AUTONOMIC NEUROPATHY:

• Problems with the pulse rate
• Postural fall in blood pressure
• Foot ulcers
• Impotence
• Gastro-intestinal dysfunction
Type of neuropathy affecting the nerves that carry information from the brain and spinal cord to the heart, bladder, intestines, sweat glands, pupils, and blood vessels
Damage to the nerves of the autonomic system is often not reversible, and comprehensive disease management is essential to improving patient quality of life

13

epidemiological prognosis re DM? and CVD?

Number of people with DM worldwide set to double between 2000 & 2030 – 70% of these will be in developing world
Due to increasing obesity, and an ageing population.
DM increases risk of CVD due to associated risk factors (BP, lipids etc) as a consequence of insulin resistance. These changes pre-date diabetes diagnosis
Increasing burden of DM likely to reverse favourable downward trends in CVD

14

Levels of established risk factors for CHD in type 2 diabetics compared with non-diabetics:

are increased across all categories, which include: BMI, Systolic BP, high total cholesterol, low HDL, markedly high triglycerides.