Retinopathy progression
- retinopathy progression and sudden lowering of HbA1c
- a typical scenario
- illustrated graphically
- prevent this rapid progression
- treatment of rapid progression
- mechanism of sudden deterioration
- Type 2 diabetes, changing to insulin, & retinopathy progression
- diabetes control has a long-term memory
- MODY diabetes
- Carotid artery occlusion
Retinopathy progression and sudden lowering of HbA1c , etc
Generally retinopathy progresses according to the parameters below. There are very few exceptions. Once background retinopathy develops, unless diabetic control is improved as below, the retinopathy will deteriorate, laser will be needed, and even with laser sight may be affected.
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glucose level/HbA1c, linear relationship with retinopathy progression
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blood pressure, linear relationship
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lipid level, probably a near linear relationship
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smoking, probable linear relationship(some work suggests 20 cigarettes a day triples retinopathy, others less so)
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pregnancy may cause a rapid deterioration
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sudden improvement (lowering to normal) of glucose levels in a person whose diabetes has been poorly controlled for sometime. Typically this includes the time when a patient with poorly controlled type 2 diabetes with early retinopathy changes over to insulin, see here and here
Certain clinical situations are recognised:
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Some people never seem to develop retinopathy: a suggestion has been made that these patients have ultra-low blood pressures, and this is what protects them. There are genes controlling retinopathy progression, and these may act through blood pressure effects. Retinopathy may run in families; there is certainly a genetic contribution All of a sudden a patient's retinopathy may start to get much worse: this may be because of a relatively sudden rise in blood pressure, which is quite common. Sometimes this seems to occur as renal function decreases. Some people's retinopathy never seems to get worse. I am not convinced this situation exists, but if it does it could be explained: a person whose diabetes was reasonably, but not well, controlled, perhaps an HbA1c of 8% with a low blood pressure, develops retinopathy, but then starts to control their diabetes and blood pressure really well, achieving an HbA1c of 7%, then the retinopathy does not progress.
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When a patient with poorly controlled type 2 diabetes with early retinopathy changes over to insulin, sugars may drop rapidly, but this may aggravate the retinopathy. This data was presented in Portugal (Y Sivas 2005) in a really excellent study, below.
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A sudden improvement (lowering to normal) of glucose levels in a person whose diabetes has been poorly controlled for sometime may cause rapid and often uncontrollable retinopathy. This is a very common problem in clinical practice. Good diabetic control is essential in the long term, but unfortunately in the short term may cause a rapid deterioration in retinopathy. A lot of laser may be needed, and usually stabilises the condition.
A typical scenario
A patient has poorly controlled diabetes (HbA1c 9%) for many years, and gradually develops retinopathy. She may have mild retinopathy, is told how important it is to control her retinopathy, and then becomes very frightened, starts to control the diabetes very well, and the retinopathy starts to get rapidly worse. She develops macular oedema that becomes diffuse and will not respond to laser. Gradually the retinopathy becomes under control but there will have been permanent macular damage and her sight is markedly reduced.
Enlarge A 3% drop in HbA1c may increase the progression rate for 1-3 years. But after 3-4 years of good control, progression rates drops significantly (lilac line). In the long term, good control causes much less progression.
If the diabetes is well controlled, retinopathy may progress, but much slower than the 'average' person with diabetes.
If blood pressure rises, as may happen if renal failure starts or a patient stops their blood pressure medication, the retinopathy starts to progress more quickly.
A sudden improvement of control, perhaps with a 3% HbA1c drops, causes an increase in retinopathy progression for 1-3 years.
After 3-4 years of very good control retinopathy usually stops progressing completely and most patients will never need laser again (our patients are discharged back to the retinopathy screening service).
Prevent this rapid progression
Ophthalmologists are aware of this scenario and it was discussed in detail at the EASDec meeting 2003. In order to prevent this scenario happening over and over again, it is important to
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never let the diabetes get out of control in the first place! (But unfortunately this does not seem possible in most clinics).
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if somebody who is poorly controlled has background retinopathy, and then starts to tighten their control, their eyes need checking every 3-4 months to see if laser is needed. (By 'control', I mean HbA1c, BP, and cholesterol.)
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there is probably no such rebound effect if someone stops smoking, only benefit. Similarly, there is only benefit if blood pressure and cholesterol are reduced.
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screening of retinopathy is important: any patient with macular oedema should be referred as it will get much worse if the control tightens.
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(My view) any retinopathy suggests poor control, so any patient with background retinopathy detected on a screening program should be considered to have poor diabetic control until proved otherwise, and appropriate action taken.
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An extremely low blood pressure is probably helpful, as low as possible as long as the patient feels well.
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It is probably safer to lower the HbA1c gradually, over a year if necessary, as below. There is no hard evidence that this will help, but logical argument. This paper, the DCCT study here , and Sivas above describes the problems. This paper advises laser in patients with severe pre-proliferative retinopathy, and this prevented 60% of the visual loss (which will be due to macular oedema or scarring).
If such a patient with florid retinopathy caused by a rapid change in HbA1c is allowed poorer control and a higher HbA1c, the retinopathy progression slows, see. - Prof Harding recommends (2011, Manchester) dropping the HbA1c gradually at the rate of 1% a year. But this seems too gradual to me. We know from the DCCT study that good control helps in the long term, so why delay good control so long? However, by dropping he HbA1c quicker than this does result in progress on of retinopathy, and some patients do develop severe macular problems and sight is not so clear. Nevertheless I think it is preferable to accept this rather than delaying good control several more years.
So as a person tightens their control, they may develop severe
retinopathy (maculopathy or new vessels), which cannot be controlled.
This was discussed at the EASDec meeting in 2003 by Massin as
below, and also reviewed by Ellis, at the Royal College meeting
2003 here.
We are now learning to take this into account when planning laser see .
Ellis (described in detail here)
demonstrated that if florid proliferation is present, and it does
not respond to laser, even without fibrovascular traction, vitrectomy
can be very helpful. The case he showed demonstrated a complete
resolution of proliferation after surgery.
Massin presented a case (~2003): A patient (age 40y) with poorly controlled diabetes and background retinopathy underwent rapid control of her diabetes. Her retinopathy became proliferative. She was lasered, but developed macular oedema. This did not respond to grid laser. Intravitreal triamcinolone was effective at reducing the macular oedema.
Treatment of rapid progression
Rapid progression needs to be predicted and taken into account when planning laser, as a lot more laser will be needed. A low blood pressure, not smoking, with regular exercise will slow progression (see paragraphs above).
The mechanism for this rapid progression with rapid HbA1c lowering
It is well recognised that diabetes causes an increase in retinal perfusion and blood flow, and this flow is directly related to glucose levels. We know that neovascularisation is caused by ischaemic retina (which releases growth factors such as VEGF).
The hyper-perfused retina develops microvascular damage and becomes slightly ischaemic..but as soon as the glucose levels drops, perfusion drops, and the retina becomes even more ischaemic. This induces a rapid growth of new vessels.
We do not know the rate at which should be lowered in an individual patient. 32% of patients with retinopathy progressed as their HbA1c was lowered, here, whereas only 2% of those with no retinopathy progressed. May be those with higher IGF1 levels will do worse, as here. In the DCCT, some patients retinopathy deteriorated before stabilising, see here. Logically high risk patients will need careful supervision....anti-VEGF drugs may help.
At Good Hope we will now recommend gradual HbA1c control in patients with retinopathy. We hope this will allow time for the retinal vasculature to remodel and slow down the progression, but we do not know whether this will work. Have you any ideas?
Type 2 diabetes, changing to insulin, & retinopathy progression
Sivas (EASDec 2005), presented this data from about 300 patients, from her previous clinic in St Petersburg. 90% of diabetes is type 2, and 50% of type 2 patients eventually need insulin 5-10 years after becoming diabetic.
After converting to insulin, of those who developed or already had retinopathy, 60% progressed in the first year, 20 % the second, as shown. Of the 50% that progressed, half of these already had retinopathy, and half developed it.
Diabetes control has a long-term memory
However, this data does not exactly agree with the DCCT data. Even after 10 years a period of intensive control (10 years) can significantly reduce retinopathy (retinopathy has along-term memory). So after 10 years of intensive (one group) or bad control (the other group), then another 10 years of mediocre control (HbA1c 8%, both groups) there was a 56% difference in progression rates between the intensive and bad controlled groups.
Retinopathy progression
Blood pressure and dyslipidaemia also increased progression.
Progression rate was also linked to obesity.
MODY diabetes and progression
Some types of MODY diabetes have much less retinopathy. This was reviewed by Guillausseau , at the EASDec 2005 meeting. He also found that genetic variants of the angiotensin 11 gene significantly alter the retinopathy risk (x6). The VEGF gene, x2.6.
Carotid artery progression
If the retinopathy progresses despite lots of laser, and particularly if it asymmetrical, then occasionally carotid artery occlusion is responsible. Acta 11 1990