Slide 1

Professor Basile, Ladies and Gentlemen. First of all, I would like to express my thanks to Professor Norbert Lameire the editor-in-chief of NDT and the chairman of the scientific committee. When I accepted his invitation, I didn’t realise that it’s almost impossible to review this very complex topic within 18 minutes. Nevertheless, I will try to do my best.

Slide 2

So diabetic dialysis patients are at a very high risk for vascular complications. More than 23% of incident diabetic dialysis patients in the US are dieing due to cardiovascular and infectious complications during the first year of renal replacement therapy and less than 1/3 survive for 5 years. Survival in patients on hemodialysis seems to be related to glycemic control and moreover, even mild degrees of hyperglycemia in non-diabetic dialysis populations have been associated with reduced survival.

Slide 3

The first report came from the university clinic of Osaka by Oomichi. This is a 7-year observational study. You see here the survival is very similar in patients with good glycemic control and in the fair group, however the poor glycemic control patients had a significantly decreased survival. So in the diabetic patients on hemodialysis with poor glycemic control the survival rate after 33 months was only 50%. These findings indicate that careful glycemic control after initiation of hemodialysis seems to be very important.

Slide 4

Then a report, a period from the UCLA in Los Angeles by Kalantar-Zadeh informing us that unadjusted survival analyses in 23.000 diabetic hemodialysis patients indicated paradoxically lower death hazard ratios with higher A1C levels. However, after adjusting for important confounders namely malnutrition and anaemia higher HbA1C values were incrementally associated with higher death risk. Here you see the increase of all cause mortality and cardiovascular death in patients with an HbA1C of 3 of 10% versus 6% and the authors concluded that lower HbA1C levels not related to malnutrition or anaemia appeared to be associated with improved survival in diabetic hemodialysis patients. Here you have the data. This is the unadjusted situation, here the adjusted data and you can see there’s a clear relationship between HbA1C in the 19.000 patients with a haemoglobin value above 11 mg/dL.

Slide 5

What is the situation in anaemic patients? In anaemic patients the situation is different, you see also an increase in mortality by about 40% in the high range patients with an HbA1C of 10% but overall the relationship is not seen.

Slide 6

So 2 messages can be taken from this very important study; one is anaemia is a very important predictor of mortality and secondly, probably HbA1C is not a reliable index in diabetic patients with anaemia and ESRD.

Slide 7

Already in 1979, 30 years ago we made a small but early contribution ---, as you can see as we measured total glycosylated haemoglobin in different stages of renal disease and in this report we concluded that in Chronic renal failure a shortened life span of the erythrocytes is well known and low HbA1C levels might be expected.
Thus, glycosylated haemoglobin as an indicator of diabetic long-term control should be used with caution in patients with serum creatinine above 2.5 mg/dL. This was in 1979.

Slide 8

Almost 30 years later investigators from the University Clinic of Osaka made an important new contribution. They measured plasma glucose, glycated albumin and HbA1C levels in hemodialysis patients with and without diabetes. Here you see the data without diabetes and here the data with diabetes and as you can see, HbA1C was only increased by 70% whereas glycated albumin was increased by 23% and glucose by 51%.

Slide 9

Very recently in the last issue of KI investigators from the United States confirmed the Japanese observation when they measured HbA1C and glycated haemoglobin in diabetic patients on hemodialysis. So what they found is that HbA1C was positively associated with haemoglobin and negatively associated with erythropoietin dose, whereas there was no relationship with glycated albumin. The authors concluded that in diabetic hemodialysis patients HbA1C levels significantly underestimate glycemic control, while doses of glycated albumin more accurately reflect diabetes control. If you’re looking at the poster session, you can see a poster from Spain confirming what the Japanese and the American authors described very nicely.

Slide 10

Now we are coming to the topic of my lecture after this introduction. The goals of anti-diabetic treatment are of course, optimal and persistent blood glucose lowering, prevention of progression of β-cell failure, this is a key problem of type 2 diabetic patients. The patients should have treatment with a low rate of side effects, hypoglycaemia, gastrointestinal side effects, weight gain, oedema, heart failure and bone fractures. Primary prevention and in particular, secondary prevention of vascular complications is mandatory.

Slide 11

So which options for anti-diabetic treatments are available? We have several key organs involved in type 2 diabetes; the liver, the muscle, the endocrine pancreas not seen in this slide I don’t know why. Then you have several drugs for insulin resistance made from pioglitazone, rosiglitazone. For insulin secretion you have glucose independent mechanisms meaning that they don’t stop to work when you have hypoglycaemia like sulfonylureas, glinides or exogenous insulin.

Slide 12

On the other side you have glucose dependent drugs, they stop when patients are becoming hypoglycaemic such as DPP-4 inhibitors or GLP-1 mimetics. On the other side of the spectrum you can inhibit the glucose reabsorption by so-called α-glucosidase inhibitors which are very popular in China and Japan, less used in Europe and not used at all in the United States.

Slide 13

In this slide I have summarised for you the route of elimination and metabolism of oral anti-diabetic drugs used for many years. You can see in red many are eliminated by the kidneys, so urinary excretion is quite high for many of these drugs. Please look at metformin or at migitol, so the consequences you can only use the green ones with no dose adjustment, very few. You have to avoid some drugs and other drugs you have to reduce otherwise you will result in severe hypoglycaemia.
So which other anti-diabetic drugs can be used in diabetic patients with CKD stages 3-5? You have here a summary of the drugs and also the side effects and many anti-diabetic drugs cannot be used or should not be used such as metformin, glibenclamide, nateglinide, migitol, sitagliptin and also exenatide.

Slide 14

Some years ago German investigators reported alarming data from 93 severe hypoglycaemic comas in patients treated with glimerpiride or glibenclamide and as you can see, the patients were quite old 77 years, they had a very low HbA1C, 5.4 and even very low dosage of sulfonylureas were able to reduce the comas, namely 0.5 mg glimepiride or 0.9 mg glibenclamide. Please look at creatinine clearance so all these severe cases are many times associated with reduced kidney function.

Slide 15

So kidney function is already important in earlier stages of CKD, as you can see here in a double blinded study which we performed several years ago. When we compared the most commonly used sulfonylureas worldwide namely glimerpiride and gliclazide, amaryl and – are the official names and here you can see that diabetic patients with impaired renal function had a four-fold increased risk for hypoglycaemia when treated with glimepiride versus gliclazide MR which has a different metabolism compared to glimepiride.

Slide 16

Nowadays the stages of CKD are also more and more accepted by their pathologists. Non-diabetic patients with a GFR lower than 60 have a significantly higher risk for cardiovascular disease.

Slide 17

Nothing was known about the diabetic patients up to now, so we made analysis in the PROactive trial together with Ralph DeFronzo from the States and Ele Ferrannini, the president of the European Diabetes Association published the data recently in JASN as you can see.

Slide 18

So from these 5200 patients with macrovascular disease about 600 had CKD and the PROactive data confirmed that CKD is an independent risk factor for cardiovascular events and death among patients with diabetes and pre-existing macrovascular disease.

Slide 19

Here you see the increase in death, myocardial infarction and stroke from the right to the left side, you can see it’s almost doubling or more than doubling when you’re going from a GFR of above 90 to a GFR of 45. These are the data in the placebo treated patients they had many anti-diabetic drugs 3 had the most ACE inhibitors, --- inhibitors and so on then when we added pioglithazone, you can see up to 45 there was no increase in mortality, it was the same like in this group only at the end and overall this was statistically significant and as you can see the hazard ratio was 0.66 independent of the severity of renal impairment.

Slide 20

What do we know about insulin treatment? I would need 20 minutes to explain this to you but I have only 2 minutes for insulin. What do we know about change in insulin requirement? Is there an increased risk for severe hyperglycemia? Which insulin strategies should be preferred? Not the basal oral treatment, it’s not possible for these patients. Is there a need for insulin dosage adjustment? This is very important.

Slide 21

So what is recommended? As you know, exogenous insulin is primarily eliminated by the kidneys whereas endogenous secreted insulin is mainly degraded by the liver, this is the problem. So when the GFR decreases to a range between 10-50, then you should use the reduce the insulin dosage to 25% and to 50% when the GFR is going down to less than 10 ml/minute. Interestingly enough once patients start dialysis, they often require less insulin since peripheral insulin resistance improves with initiation of dialysis and finally interesting data were reported for peritoneal dialysis.

Slide 22

So this is an observational study published by Gerard Biesenbach from Austria. He showed very nicely data in patients at 80 and at10 ml/minute the insulin requirement but there you see a decline of 38% in type 1 diabetic patients

Slide 23

and a decline of 51% in similar observation of type 2 diabetic patients.

Slide 24

Ingrid Mulhauser who worked in my unit in the 70s and early 80s reported that in type 1 diabetic patients there is an increased risk for severe hypoglycaemia when kidney function is already decreased, 5 fold increased incidence of hypoglycaemic episodes.

Slide 25

Now I’m coming finally to the newer drugs. What do we know about glithazones? We do not have much information about the use of glithazones in ESRD. We have 3 publications; one came from the States, this can no longer be used with insulin the EMBA informed us by a warning but pioglitazone can be used in combination with insulin and here you have two studies from Japan telling us that you can nicely combine pioglithazone with voglibose

Slide 26

and can result to HbA1C levels lower than 6%.

Slide 27

Another study’s coming out in a clinical diabetes journal. They used pioglithazone in 20 Japanese diabetic hemodialysis patients. They observed all the well-known changes lowering of systolic-diastolic blood pressure, insulin resistance. Interestingly enough dry weight in the dialytic weight change, cardiothoracic ratio remained unchanged before and after PIO treatment. ANP did not increase and no serious adverse events were seen and the authors concluded that pioglithazone might have the potential to reduce the number of type 2 diabetic patients who ultimately require insulin injection therapy.

Slide 28

Coming to the final drug, so --- cells secrete immediately from the GI tract a number of --- hormones including GLP-1 and this GLP-1 has a very important role in reducing glucagon secretion from the alpha cells, increasing insulin from the beta cells resulting in a nice glycemic control in the non-diabetic individuals and unfortunately, type 2 diabetic patients have an impaired GLP-1 secretion after food ingestion with the consequences of diminished insulin secretion and increased glucagon secretion.

Slide 29

So we have now two totally new designed drugs. On the one side, the mimetics like liraglutide and exenatide. The positive effects are shown in green here; reduction of body weight, improvement of beta cells and alpha cell function and on the other side you have the enhancers such as sitagliptin, vlidagliptin, alogliptin and about 10 new drugs are in the state of development.

Slide 30

What do we know about the effects? One is the endocrine pancreas, one is the liver, one is the muscle. You have reduction of appetite, it’s a very nice effect in the type 2 diabetic patients. You have a decrease in gastric emptying and you might have some positive effects on the heart.

Slide 31

Unfortunately, sitagliptin is eliminated by the kidneys, so you have to adjust the dosage already in mild renal insufficiency, 2-fold and 4-fold in patients with ESRD.

Slide 32

What do we know about exenatide? Exenatide again you have a problem the mean half-life of exenatide is significantly longer in patients with mild or moderate or advanced kidney disease. The situation is not good as you see here. You have accumulation so we cannot use exenatide. On the other side liraglutide, which will be available at the end of this year in Europe, has a different situation you see no change in the plasma concentrations from normal to ESRD.

Slide 33

Now I’m at the end 18 minutes exactly. Diabetic dialysis patients are at a very high risk for severe cardiovascular complications and death. Only about 30% survive 5 years.

Slide 34

The treatment of these patients is very, very important since they represent now at least 1/3 or even half of the patients as I learned yesterday from a nephrologist from Haifa.

Slide 35

So poor glycemic control is associated with a significantly increased all-cause and cardiovascular mortality. HbA1C underestimates glycemic control in patients with ESRD. Glucose monitoring is mandatory and glycated albumin may help and more accurately reflect the diabetes control. Many of the widely used anti-diabetic drugs such as metformin, most sulfonylureas, exenatide and others cannot be used in patients with ESRD.
Dose reduction is mandatory for many drugs eliminated by the kidneys to reduce the high risk of ESRD bases for severe hyperglycemias and finally newer drugs such as pioglitazone, liraglutide and some future DPP-4 inhibitors hopefully will improve the very limited treatment options for these severely ill patients. Thank you for your attention.