DR RAJEEV CHAWLA

                    Sr. Consultant Physician Diabetologist

                 Maharaja Agrasen Hospital

                  North Delhi Diabetes Centre

                    New Delhi

 

Prevention of Diabetic Complications

Rising prevalence of Diabetes Mellitus especially Type-2 DM in Urban population is a serious concern. The countries with the largest number of people with diabetes are and will also be in the year 2025, India, China and the U.S.1 With the increasing prevalence of diabetes especially in the middle age group populations who are commonly affected in India,2 the chances of developing micro & macro vascular complications are very high & it is going to bring enormous burden on the family, society & the health care providers involved in the management of diabetes due to high morbidity & mortality. (Table 1)

In a study of 3010 diabetics by Ramachandran. A,3 the prevalence of microvascular complications was, Retinopathy 23.7%, Nephropathy 5.5%, Neuropathy – 27.5% & prevalence of CHD 11.4 % & PVD was 4%. In our own study from North Delhi Diabetes Centre.4 comprising 720 type-2 Diabetics, Retinopathy was seen in 21.2 %, microalbuminuria in 41%, Peripheral Neuropathy in 15.3 %, CAD in 7% & PVD was in 7.4% of Patients.

Table 1. Chronic Complications of Diabetes

·                     Mortality increased by 2-3 folds.

·                     Heart Disease & stroke increased by 2-3 folds.

·                     Blindness 10 times more common than in the general population.

·                     Gangrene and amputation about 20 times more common than in general population.

·                     Second leading cause of Fatal kidney disease.

·                     Other chronic disabilities (e.g. Neuropathy, Infections and sexual dysfunctions)

·                    Hospitalization increased 2-3 folds.

(WHO expert committee on Diabetes Mellitus 1980.5 )

Glycemic Control & Diabetic Complications

Hyperglycemia is a well known risk factor for vascular complications both microvalcular and macrovascular in diabetes. However unlike the clear & linear relationship of hyperglycemia with microvascular disease, relationship with macrovascular disease & mortality is clouded by many confounding risk factors like obesity, hypertension, dyslipidemia and hyperinsulinemia.6 The risk for CAD with hyperglycemia has been seen with blood sugar levels far below the cut off value for the diagnosis of diabetes.7 Unlike microangiopathy where the clock starts ticking with the onset of diabetes, in case of macroangiopathy, the clock may start ticking a decade or two earlier.

Prevention of complications

Primary Prevention is an attempt to prevent onset of complications associated with disease.

Secondary prevention aims at arresting or retarding the progression of preexisting complications, hence, preventing the occurrence of end point of  particular complications e.g. end stage renal failure due to diabetic nephropathy or blindness due to diabetic retinopathy.

Primary Prevention of Microvascular Complications

  1. Glycemic Control

The Diabetes control and complication trial (DCCT)8 was a landmark study conducted in United States from 1983 to 1993 in Type-1, diabetic patients. In the primary prevention group (726 patients with no retinopathy at baseline) internsive therapy reduced the risk for development of retinopathy by 76% as compared to conventional therapy. In patients with some eye changes (secondary prevention cohort) intensive treatment slowed the progression of the disease by 54% & reduced the development of proliferative or severe non proliferative retinopathy by 47%. Intensive therapy also reduced the occurrence of microalbuminuria by 54%.

            The United Kingdom prospective Diabetes Study (UKPDS),9 the largest perspective landmark trial has also demonstrated the increased risk of microvascular complications with deteriorating glycemic control. There was 25% risk reduction for microvascular end points, 21% risk reduction for cataract extration & 33% risk reduction for microalbuminuria.

            It was the degree of glycemic control which was important irrespective of type of therapy whether SUs, insulin or metformin which was used.

  1. Blood Pressure Control

Aggressive treatment of even mild to moderate hypertension to a mean of 144/82 mmHg goes a long way in reducing microvascular complications as evidenced in UKPDS.10 It is more relevant in primary prevention of nephropathy. In Type-2 Diabetes Mellitus,  hypertension may be part of coexisting essential hypertension but Type-1 Diabetes Mellitus it is always caused by diabetic nephropathy.

ACE inhibitors are drug of choice for all Type-I Diabetics with microalbuminuria, even if normotensive but still there is not enough evidence to suggest its usage in Type-2 Diabetics who are normotensive.

  1. Antioxidants

In diabetic rodents, deficiency of gamma – Linolenic acid has been demonstrated. This leads to an imbalance between the lipo-oxygenase and cyclo-oxygenase system and consequent deficient production of vasodilatory prostaglandins. However, use of GLA supplements in diabetic neuropathy in humans has only been partially successful.11

A series of new Aldose reductase inhibitors are now under long term clinical trials. In animal studies, alpha tocopherol has proved beneficial, but there is no convincing human data. Alpha Lipoic acid is another antioxidant used in diabetic neuropathy with fair results as confirmed in ALADIN Study.12

Primary Prevention of Macrovascular Complications

Role of hyperglycemia per se in propagation of macrovascular complications is less clear, Infact, risk for CAD with hyperglycemia has been seen with blood sugar levels far below the cut off values even for the diagnosis of diabetes.

            The Whitehall Study13 clearly demonstrated a two-fold increase in CHD mortality after 10 yrs. in men whose post load capillary glucose was as low as 98 mg%.

            The Hoorn Study14. is a prospective follow up study of 2363 oldermen from Netherlands & has demonstrated that 2 hour plasma glucose and HBAic levels even in non-diabetic range are associated with risk of cardiovascular mortality.

            UKPDS although revealed 16% reduction in CAD risk by control of hyperglycemia but it failed to be statistically significant. An impressive CAD risk reduction in a diabetic comes from reduction in blood pressure, life style modification & most importantly by lipids lowering drugs like statins as demonstrated in 4S study where upto 30% CAD risk reduction was achieved. 15

Secondary Prevention of Complications.

Unfortunately many Type-2 diabetics present with various micro & macrovascular complications right at the time of diagnosis. About 10% of patients might have evidence of retinopathy at the time of diagnosis, obviously because of undetected Type-2 diabetes for several years. This deprives these patients from primary prevention of microvascular complications.

Hence, any strategy is likely to be more effective in primary than in secondary prevention. Secondary prevention can only yield good results if emphasis is on picking up complications early by regular screening for complications in all diabetics periodically as suggested by ADA also e.g. Fundoscopy for DR Microalbuminuria for D.Nephropathy, Monofilament & Biothesiometry for Peripheral Neuorpathy, ABI measurement for PVD & Lipids estimation for CAD.

Future Modalities for Prevention

Future research has led to the discovery of many interlinking mechanisms, which lead to manifestations of diabetic complications.

            The discovery of RAGE receptors (Receptors for Advanced Glycation End Products) & the macrophage receptors explains how glucotoxicity occurs. Moreover, better understanding of oxidative and carbonyl stress in diabetes, voasoactive and haemodynamic factors along with genetic predisposition have opened doors for therapeutic interventions in prevention of complications in diabetes.16-17

RAGE blockers, AGE lytics & development of Nerve growth factors (NGF) are the possible therapeutic agents of the future.

Protein kinase C (PKC) beta fraction is an enzyme, which is elevated in diabetics and has already been linked to both diabetic retinopathy and nephropathy.

An inhibitor of PKC beta has been developed and is being used in prevention & treatment of diabetic retinopathy & prevention of Cardiomyopathy in rats.

Histamine is thought to inhibit occludin, a key pretein that regulates “ tight junctions”, permeability. As occludin is greatly reduced in retinas of diabetic, hence, leakage from these junctions results in macular odema, the type of retinopathy more commonly seen in Type – 2  diabetics. An antihistamine”  “Hismanal” is being tried to increase the levels of occludin in diabetic retinas so offers hope to salvage eye sight in diabetics.18

Similarly a new neurotropin, Nerve growth factor–1 (NGF-1) has shown exceptional promise in Laboratory in protecting both neurons and the schwann cells even in presence of hyperglycemia. Although results with some aldose reductase inhibitors were expected theoratically but Sorbinil has been quite disappointing. Hence, a series of new aldose reductase inhibitors are now under long term clinical trials.

Microalbuminuria is now considered an indicator of generalized endothelial dysfunction, hence, correlates well with many macrovascular complications like CAD, PVD and Stroke.19

Control of hypertension gains precedence over metabolic control, once microalbuminuria has set in. Dual blockade of Renin Angiotensin system by ACE inhibitors and ARBs have shown good results.20

Epidemiological data from US Renal Data System (USRDS) has revealed a strong relationship between oestrogen deficiency and increased risk of diabetic nephropathy as oestrogens increase matrix metalloproteinases in the measangial cells thus promoting removal of measangial tissues. Hence, the role of oestrogens in females with  diabetic nephropathy is being explored.21

References:

1.                  King H, Aubert ER, Herman WH

Global burden of Diabetes 1995– 2025.-Prevalence, numerical estimates and projections.

Diabetes care, 1998; 21 : 1414-1431

2.                  Ramachandran A,Sneh Lata C,Vijay V.

Rising Prevalence of NIDDM in Urban Population in India.Diabetologia 1997; 40: 232-7

3.                  Ramachandran A, Diabetes Research  Centre,  Chennai – Personal Communication.

4.                  Chawla R, Rathore P.- North Delhi Diabets centre.

To study the prevalence of Diabetic Peripheral Neuropathy by Biothesiometric  Evaluation & its co association with other complications Novonordisk Diabetes update 2004 proceedings.

5.                  WHO expert committee on Diabetes Mellitus 1980; - Technical Report Series 646.

6.                  Barrett-Connor E. – Does hyperlipidaemia really cause coronary heart disease?

Diabetes care, 1997; 20: 152-6

7.                  Balkau B, Bertrais S – Is there a glycemic thereshold for mortality risk?

Diabetes Care, 1999; 22:696-9

8.                  The Diabetes control and complications trial  Research group; the effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus.

N Engl J Med 1993; 329 : 986 - 997

9.                  UK prospective Diabetes Study Group.

Intensive blood glucose control with sulphonyl ureas or insulin compared with conventional treatment and risk of complications in pts with Type-2 diabetes (UKPDS, 33) Lancet 1998; 352:837-853.

10.               UK prospective Diabetes control study group. Tight blood pressure control and risk of macrovascular & microvascular complications in Type-2 diabetes.

BMJ 1998; 317: 703-713

11.               Ward J. D. _ improving prognosis in Type-2 diabetes.

Diabetes Care1999; 22 (Suppl.2) : B 84-B 88

12.               Ziegler D, Hanefeld M, - The ALADIN III Study group : treatment of symptomatic diabetic polyneuropathy with alpha lipoic acid Diabetes  Care 1999; 22:1296-1301

13.               Fuller J.H., Shipley M.J. Rose G. et al

Coronary heart disease risk and impaired glucose tolerance : the Whitehall study.

Lancet, 1980 ; 8183 : 1373 – 6

14.               Vegrde F., Dekker J. M., Ruke N. G. et al

Hyperglycemia is associated with all cause and cardiovascular mortality in the Hoorn population : the Hoorn Study, Diabetologia, 1999 : 42 : 926-31

15.               Pyorala K. Pedersen T. R; Olisson A.G et al

Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian simvastatin survival study (4 S) - Diabetes Care, 1997; 20 : 614-20

16.               Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications. A new prospective on an old paradigm. Diabetes 1999; 48 : 1-9

17.               Oturai PS, Christensen M, Robin B et al. Effects of advanced glycation end products inhibition and protein cross linked breaking in diabetic rats. Diabetes 1999 ; 48 (Suppl-1) Abs, 151, A 35.

18.               Antonetti DA, Alistair JB, Khin S et al.

-          Penn State Retine Research gropu : vascular permeability in experimental diabetes is associated with reduced endothelial occludin content. Diabetes 1998 ; 47: 1953 – 1959

19.               Castellino P, Shohat J, DeFronzo RA.

Hyperfiltration and diabetic nephropathy ; is it the beginning ? or is it the end : Semin Nephrol 1990 ; 10:228-241

20.               Rossing K, Christensen PK, Jensen BR, Parving HH. ; Dual blockade of the renin Angiotensin system in diabetic nephropathy. –

Diabetes Care 2002, 25; 95-100

21.               Striker G, Poter M, Elliot SJ et al

Pathophysiology of diabetic nephropathy : role of oestrogens. In : Di Mario U, Leonetti F, Signo A (Eds), Diabetes in New Millennium. John Wiley & Sons Ltd. West Sussex UK 2000 ; 297 – 310

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Date : 22nd June 2004

 

 

To,

 

            Dr. Nitya Nand

            Prof. Of Medicine, PGIMS, Rohtak

            President Elect., IACM

            Chairman Scientific Committee

 

Respected Sir,

 

            I am sorry to have got late in sending my article. Please find enclosed herewith the copy & CD of my topic “ Prevention of Diabetic Complications” to be presented in IACMCON – 2004 at Agra.

 

I again request you to please accommodate my session on 24th morning so as to enable me to proceed to chennai in the evening.

 

Thanking you,

 

With warm regards,

 

Yours Sincerely

 

 

Dr. Rajeev Chawla