- Email: [email protected]
creatinine ratios
G Model
DSX-377; No. of Pages 4 Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios Venkata Ranga Rao Kodali * Department of Medicine (Diabetes & Endocrinology), University Hospital of Hartlepool, Holdforth Road, Hartlepool TS24 9AH, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Keywords: Albuminuria Blood pressure Diabetes mellitus Lipids Neuropathy Prevalence Retinopathy Peripheral vascular disease
Objective: To test the hypothesis that at different urinary albumin/creatinine ratios within the normal ranges, diabetics have low but similar prevalence of metabolic and micro vascular disease. Methods: The study sample consisted of normotensive diabetics not taking any medications known to effect blood pressure and lipids. The data were collected from the Diabetes Register. The diabetics were subgrouped according to the urinary albumin/creatinine ratios. MA is defined as present if the albumin/ creatinine ratio (ACR) is more than 2 mg/mmol. Results: MA was present in 16% of the 152 diabetics. Total cholesterol, systolic BP, and triglycerides were significantly high in diabetics with ACR 1 < 2 compared with <1. The prevalence rates for retinopathy and neuropathy in the MA group were also significantly high. However, a large number of diabetics without MA had had established complications (37% retinopathy, 40% neuropathy, and 16% peripheral vascular disease). Because these results were based on single early morning urine samples, we looked at their MA in the past year. After exclusion of regressed and progressed groups, the complications rate remained the same. Conclusion: The high prevalence of metabolic and vascular complications seen even in absence of MA indicates an early intervention and those diabetics should not wait unitl CVD risk scores raise to receive preventive treatment. ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction Persistent microalbuminuria portends progression to renal failure. Microalbuminuria (MA) indicates incipient nephropathy and is a predictor of cardiovascular mortality [1,2]. The prevalence of MA varies from 9% to 54% [3,4] in various studies however all these studies have hypertensives and those taking medications that could have influenced these rates. Early detection and intervention of MA will delay the onset of renal failure as well as the associated metabolic and vascular complications [5,6]. Coronary heart disease accounts for a large number of deaths in diabetics with renal failure. Dyslipidemias are recognized in renal failure but the onset of these may be much earlier [7,8]. There is little information on metabolic and vascular complications in the early stages of the MA. Therefore, we aimed to study (a) the prevalence of MA, (b) the associated complications – lipids, retinopathy, peripheral vascular
* Correspondence to: Consultant Physician with Interest in Endocrinology and Diabetes Mellitus, Department of Medicine, Geraldton Regional Hospital, 51-85 Shenton Street, Geraldton, WA 6530, Australia. E-mail address: [email protected]
disease, neuropathy and blood pressure in a selected group of diabetics without MA. 2. Materials and methods Every registered diabetic undergoes an annual examination in the month of his or her birth at the diabetes clinic in the University Hospital of Hartlepool. Demographic details are continuously updated on the electronic Diabetes Register. The data for this study were collected by going through each patient’s case record at his/her last annual check up. Hb A1c%, albumin/creatinine ratio (ACR in mg/mmol), total cholesterol, triglycerides and HDL cholesterol were all measured and low density lipoprotein (LDL) cholesterol is calculated using the Friedwald’s formula. Using strict criteria, diabetics with the following conditions were excluded – overt proteinuria, urinary infection, known hypertensives or those antihypertensives, diuretics, on lipid lowering therapy, thyroid disorder, pregnancy, hormone treatment; includes steroids, malignancy, connective tissue disorder, bowel disorder e.g. coeliac disease, ulcerative colitis, abnormal liver function tests and above normal serum creatinine values. The data were grouped based on ACR: <1; 1 < 2 and 2 but no overt proteinuria. Complications were summed and Chi-Square
1871-4021/$ – see front matter ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dsx.2013.10.025
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
G Model
DSX-377; No. of Pages 4 V.R.R. Kodali / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
2
60
Table 1 General characteristics of the study population. Parameter
ACR < 1
ACR 1 < 2
ACR 2
Number of diabetics Age (years) Gender Men Women Duration (years) BMI Type 1 2 Previous high BP
104 51.5 1.59
24 62.4 2.91*
24 55.8 3.36
63% (66) 37% (38) 12.5 1.36 28.4 0.54
77% (17) 29% (7) 11 1.68 27.4 0.85
62% (15) 38% (9) 14.6 2.56 28.8 1.6
50% (52) 50% (52) 70% (73)@
17% (4) 83% (20) 88% (21)
29% (7) 71% (17) 67% (16)
* @
50 40 30 20 10 0
Retinopathy
P < 0.07 compared with ACR < 1. P < 0.001 compared with ACR 2.
Neuropathy
PVD
Fig. 2. Retinopathy, neuropathy and peripheral vascular disease.
test was applied for the numbers. t-Tests were used to compare continuous variables in the groups. Data are expressed as mean standard error. A statistical value of P < 0.05 is considered significant. In view of the sample sizes, the results were not shown separately for Type 1 and Type 2 diabetics. 3. Results Fourteen percent (152) of the 1066 diabetics screened at annual check up qualified for the study. This is a small fraction and is not unexpected in view of the wider exclusion criteria set for the study. Diabetics with ACR 2 are being followed for intervention. We preferred the cut off of 2 as this had been widely accepted and used before [9]. About 52% of Type 2 diabetics were on insulin. A large number (110 of the 152) of diabetics had at least one high blood pressure reading (systolic BP > 129 mm Hg and or diastolic BP > 89 mm Hg) recorded in the past year. (Table 1)
The prevalence of MA is 16% in our study. In the 135 diabetics who had a normal ACR < 2 last year, 9 patients had a normal reading at last year but progressed to an ACR > 2 giving an incidence of 6.6%. These are subject to further investigation and intervention and for now are grouped in ACR > 2 for the purpose of the current discussion. Subgroups became small by classifying diabetes, however the trends in the results remained unchanged. The number of diabetics who progressed or regressed is very small to make comparisons between then, however excluding them from the analysis did not affect the significance or the trends. The prevalence of MA fell to 13% from 16% when the cut off was 2.5. Figs. 1 and 2 show the lipids and vascular complications. Hb A1c% was significantly high in the microalbuminuria group. Systolic BP, total cholesterol and triglycerides were high in the middle group. Total cholesterol readings were much higher in the MA group. The number of diabetics with retinopathy and neuropathy in the MA group is also significantly higher (Table 2).
Total Cholesterol
HDL Cholesterol
5.6 5.5 5.4 5.3 5.2 5.1 5 4.9 4.8 4.7
1.45 1.44 1.43 1.42 1.41 1.4 1.39 1.38 >=1<2
<1
<1
>=2
LDL Cholesterol 3.15
>=1<2
>=2
Triglycerides 2.5
3.1 3.05
2
3
1.5
2.95
1
2.9
0.5
2.85 2.8
0
<1
>=1<2
>=2
<1
>=1<2
>=2
Fig. 1. Lipids in diabetics at different ACR levels.
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
G Model
DSX-377; No. of Pages 4 V.R.R. Kodali / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx Table 2 HbA1c%, lipids, micro and macro vascular disease and neuropathy at different albumin/creatinine Ratios. Parameter
ACR < 1
ACR 1 < 2
ACR 2
Number of diabetics ACR Creatinine Hb A1c% Systolic BP (mm Hg) Diastolic BP (mm Hg) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) LDL cholesterol (mmol/L) Retinopathy Neuropathy PVD
104 0.4 0.02 81.1 1.45 7.9 0.1* £ 134.2 1.5 78.3 0.75 5.0 0.08$,& 1.42 0.03 1.62 0.11# 2.92 0.07 30.8% (32) 38.4% (40)@ 15.4% (16)
24 1.25 0.52 81.8 3.06 8.3 0.3 £ 139.6 3.7 78 2.03 5.3 0.19$ 1.44 0.08 2.05 0.22# 2.97 0.18 37.5% (9) 45.8% (11) 20.8% (5)
24 5.5 1.0 79.3 4.9 8.7 0.37* 136.8 4.6 79.5 1.48 5.5 0.19& 1.4 0.09 2.0 0.31 3.1 0.18 54.2% (13) 54.2% (16)@ 20.8% (5)
*
£ $ # & @
P < 0.02. P < 0.09. P < 0.05. P < 0.02. P < 0.04. P < 0.02. P < 0.02.
4. Discussion There are limited data on vascular complications and lipid profile in the normotensive diabetics especially of long duration diabetes and similar extensive exclusion criteria. The prevalence of MA in absence of reno-protective medication is 16% (24 of 152 with duration of diabetes of 14 years. This rate is much lower than the true prevalence because of the exclusion criteria. In the diabetes control and complications trial in Type 1 diabetics, lipids were measured. The results in the end-study cohort with reference to albuminuria were published [10]. Systolic and diastolic blood pressure readings were going up when normoalbuminuria progressed to MA. The quantity and distribution of lipids worsened with progression of persistent albuminuria. HDL cholesterol was identical in control and normoalbuminuria groups. Total cholesterol was high in MA. In the Pittsburgh epidemiology of diabetes complications (EDC) study, lipids changed in a detrimental fashion when microalbuminuira developed [11]. We showed that total cholesterol and triglycerides were in high when the ACR 1 < 2 than when the ACR < 1, and HDL cholesterol concentrations were reversed. We noted high prevalence rates of microvascular and macrovascular disease in diabetics with the incipient nephropathy > high normal ACR > low normal ACR. A large number (73%) of diabetics without MA had recorded at least one high BP reading (SBP 130 mm Hg and/or DBP 90 mm Hg). Thus diabetics have complications much early in the course of the disease in absence of MA. Land mark studies established that slightly increased albumin excretion progresses to clinical proteinuria and diabetic nephropathy in both Type 1 and Type 2 diabetics [1,12,13]. In the MICROHOPE substudy [5], ACE inhibition lowered the risk of overt nephropathy in diabetics even without baseline MA. The geometric mean values suggest that there is a benefit in treating diabetics even without elevated ACR. The American Diabetes Association’s (ADA) Clinical Practice Guidelines in 2003 [14] recommended intervention even in absence of high blood pressure. These have been changed and the 2013 guidelines recommend a BP > 140/80 when treatment can be commenced in absence of other risk factors [15]. The Joint National Committee in their sixth report recommended a target of <135/85 mm Hg in diabetics and >140/90 mm Hg in non
3
diabetics [16]. The Hypertension Optimal Treatment and the UKPD Studies [17,6] confirmed the benefits of reducing blood pressure on cardiovascular events in Type 2 diabetics. In Type 1 diabetics, MA regresses only in presence of SBP < 115 mm Hg, Hb A1c < 8% and both low total cholesterol <5.12 mmol/L and triglyceride concentrations <1.64 mmol/L [18]. Therefore, lipid control is also mandatory to achieve active regression of the MA. In line with this are our findings indicating prudent intervention before albumin excretion increases. The current guidelines in the UK suggest treatment based on risk calculations [19]. For example, diabetics with blood pressure readings <140/90 with low CVD risk are not offered medical treatment. As seen in our data, diabetics have multiple complications even in absence of established MA. This study is not caveat free. It is a snap shot of the picture. Age groups varied though other characteristics were similar. Stage 1 or 2 of diabetic nephropathy are equivalent to expanded mesangium and thickened basement membrane. The presence of multiple unidentified risk factors from our findings tempt us conclude that intervention with ACE inhibitors and or angiotensin II receptor antagonists at these early stages should be introduced in addition to aiming a good glycemic and blood pressure control and treating dyslipidemia. Although the momentum seems to swing towards treating all diabetics, clinical judgments in this field are hampered by controversial data recently. In summary, diabetics with long term diabetes even in absence of microalbuminuria display multiple risk factors. An early intervention to prevent the metabolic and vascular complications is essential than recommending treatment after the morbid events. Acknowledgments This work is part of the MSc (Diabetes & Endocrinology) thesis submitted to the Guy’s, Kings & St. Thomas Registry, University of London. I thank Mrs Joanna Clayton, Diabetes Liaison Officer for help with the Diabetes Register. I would like to acknowledge Dr. John Frater, Consultant Chemical Pathologist for the useful discussions during the study. Conflicts of interest None. References [1] Mogensen CE. Miroalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984;310:353–60. [2] MacLeod JM, Lutale J, Marshall SM. Albumin excretion and vascular deaths in NIDDM. Diabetologia 1995;38:610–6. [3] Haffner SM, Morales PA, Gruber MK, Hazuda HP, Stern MP. Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria. Arterioscler Thromb 1993;13:205–10. [4] Mogensen CE. A complete screening of urinary albumin concentration in an unselected diabetic outpatient clinic population. Diabet Nephropathy 1983; 2:11–8. [5] Heart Outcomes Prevention Evaluation Study investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the Hope study and Micro-Hope substudy. Lancet 2000;355: 253–353. [6] U.K. Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes: UKPDS 38. BMJ 1998;317:703–13. [7] Mattock MB, Cronin N, Cavallo-Perin P, Idzior-Walus B, Penno G, Bandinelli S, et al. EURODIAB IDDM complications study. Plasma lipids and urinary excretion rate in type 1 diabetes mellitus. Diabet Med 2001;18:59–67. [8] Anonymous. Renal involvement in type 1 (IDDM) diabetes in Spain: ESTUDIO DIAMANTE. Diabet Res Clin Pract 1997;38:129–37. [9] Gerstein HC, Mann JFE, Pogue J, Dinneen SF, Halle JP, Hoogwerf B, et al. Prevalence and determinants of mciroalbuminuria in high-risk diabetic and nondiabetic patients in the heart outcomes prevention evaluation study. Diabet Care 2000;23(Suppl. 2):B35–9. [10] Sibley SD, Hokanson JE, Steffes MW, Purnell JQ, Marcovina SM, Cleary PA, et al. Increased small dense LDL and intermediate-density lipoprotein with albuminuria in Type 1 diabetes. Diabet Care 1999;22:1165–70.
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
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V.R.R. Kodali / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
[11] Coonrod BA, Ellis D, Becker DJ, Bunker CH, Kelsey SF, Lloyd CE, et al. Predictors of microalbuminuria in individuals with IDDM: Pittsburgh epidemiology of diabetes complications study. Diabet Care 1993;16:1376–83. [12] Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982;2:1430–2. [13] Gall MA, Hougaard P, Borch-Johnsen K, Parving HH. Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study. BMJ 1997;314:783–8. [14] American Diabetes Association. Clinical practice recommendations. Diabet Care 2003;26(Suppl. 1):S80–2. [15] American Diabetes Association. Clinical practice recommendations. Diabet Care 2013;36(Suppl. 1):S11–66.
[16] Anonymous. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Int Med 1997;157:2413–46. [17] Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial: HOT study group. Lancet 1998;351:1755–62. [18] Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in Type 1 diabetes. New Engl J Med 2003;348:2285–93. [19] http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf. [accessed 20.02.13].
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
DSX-377; No. of Pages 4 Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios Venkata Ranga Rao Kodali * Department of Medicine (Diabetes & Endocrinology), University Hospital of Hartlepool, Holdforth Road, Hartlepool TS24 9AH, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Keywords: Albuminuria Blood pressure Diabetes mellitus Lipids Neuropathy Prevalence Retinopathy Peripheral vascular disease
Objective: To test the hypothesis that at different urinary albumin/creatinine ratios within the normal ranges, diabetics have low but similar prevalence of metabolic and micro vascular disease. Methods: The study sample consisted of normotensive diabetics not taking any medications known to effect blood pressure and lipids. The data were collected from the Diabetes Register. The diabetics were subgrouped according to the urinary albumin/creatinine ratios. MA is defined as present if the albumin/ creatinine ratio (ACR) is more than 2 mg/mmol. Results: MA was present in 16% of the 152 diabetics. Total cholesterol, systolic BP, and triglycerides were significantly high in diabetics with ACR 1 < 2 compared with <1. The prevalence rates for retinopathy and neuropathy in the MA group were also significantly high. However, a large number of diabetics without MA had had established complications (37% retinopathy, 40% neuropathy, and 16% peripheral vascular disease). Because these results were based on single early morning urine samples, we looked at their MA in the past year. After exclusion of regressed and progressed groups, the complications rate remained the same. Conclusion: The high prevalence of metabolic and vascular complications seen even in absence of MA indicates an early intervention and those diabetics should not wait unitl CVD risk scores raise to receive preventive treatment. ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction Persistent microalbuminuria portends progression to renal failure. Microalbuminuria (MA) indicates incipient nephropathy and is a predictor of cardiovascular mortality [1,2]. The prevalence of MA varies from 9% to 54% [3,4] in various studies however all these studies have hypertensives and those taking medications that could have influenced these rates. Early detection and intervention of MA will delay the onset of renal failure as well as the associated metabolic and vascular complications [5,6]. Coronary heart disease accounts for a large number of deaths in diabetics with renal failure. Dyslipidemias are recognized in renal failure but the onset of these may be much earlier [7,8]. There is little information on metabolic and vascular complications in the early stages of the MA. Therefore, we aimed to study (a) the prevalence of MA, (b) the associated complications – lipids, retinopathy, peripheral vascular
* Correspondence to: Consultant Physician with Interest in Endocrinology and Diabetes Mellitus, Department of Medicine, Geraldton Regional Hospital, 51-85 Shenton Street, Geraldton, WA 6530, Australia. E-mail address: [email protected]
disease, neuropathy and blood pressure in a selected group of diabetics without MA. 2. Materials and methods Every registered diabetic undergoes an annual examination in the month of his or her birth at the diabetes clinic in the University Hospital of Hartlepool. Demographic details are continuously updated on the electronic Diabetes Register. The data for this study were collected by going through each patient’s case record at his/her last annual check up. Hb A1c%, albumin/creatinine ratio (ACR in mg/mmol), total cholesterol, triglycerides and HDL cholesterol were all measured and low density lipoprotein (LDL) cholesterol is calculated using the Friedwald’s formula. Using strict criteria, diabetics with the following conditions were excluded – overt proteinuria, urinary infection, known hypertensives or those antihypertensives, diuretics, on lipid lowering therapy, thyroid disorder, pregnancy, hormone treatment; includes steroids, malignancy, connective tissue disorder, bowel disorder e.g. coeliac disease, ulcerative colitis, abnormal liver function tests and above normal serum creatinine values. The data were grouped based on ACR: <1; 1 < 2 and 2 but no overt proteinuria. Complications were summed and Chi-Square
1871-4021/$ – see front matter ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dsx.2013.10.025
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
G Model
DSX-377; No. of Pages 4 V.R.R. Kodali / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
2
60
Table 1 General characteristics of the study population. Parameter
ACR < 1
ACR 1 < 2
ACR 2
Number of diabetics Age (years) Gender Men Women Duration (years) BMI Type 1 2 Previous high BP
104 51.5 1.59
24 62.4 2.91*
24 55.8 3.36
63% (66) 37% (38) 12.5 1.36 28.4 0.54
77% (17) 29% (7) 11 1.68 27.4 0.85
62% (15) 38% (9) 14.6 2.56 28.8 1.6
50% (52) 50% (52) 70% (73)@
17% (4) 83% (20) 88% (21)
29% (7) 71% (17) 67% (16)
* @
50 40 30 20 10 0
Retinopathy
P < 0.07 compared with ACR < 1. P < 0.001 compared with ACR 2.
Neuropathy
PVD
Fig. 2. Retinopathy, neuropathy and peripheral vascular disease.
test was applied for the numbers. t-Tests were used to compare continuous variables in the groups. Data are expressed as mean standard error. A statistical value of P < 0.05 is considered significant. In view of the sample sizes, the results were not shown separately for Type 1 and Type 2 diabetics. 3. Results Fourteen percent (152) of the 1066 diabetics screened at annual check up qualified for the study. This is a small fraction and is not unexpected in view of the wider exclusion criteria set for the study. Diabetics with ACR 2 are being followed for intervention. We preferred the cut off of 2 as this had been widely accepted and used before [9]. About 52% of Type 2 diabetics were on insulin. A large number (110 of the 152) of diabetics had at least one high blood pressure reading (systolic BP > 129 mm Hg and or diastolic BP > 89 mm Hg) recorded in the past year. (Table 1)
The prevalence of MA is 16% in our study. In the 135 diabetics who had a normal ACR < 2 last year, 9 patients had a normal reading at last year but progressed to an ACR > 2 giving an incidence of 6.6%. These are subject to further investigation and intervention and for now are grouped in ACR > 2 for the purpose of the current discussion. Subgroups became small by classifying diabetes, however the trends in the results remained unchanged. The number of diabetics who progressed or regressed is very small to make comparisons between then, however excluding them from the analysis did not affect the significance or the trends. The prevalence of MA fell to 13% from 16% when the cut off was 2.5. Figs. 1 and 2 show the lipids and vascular complications. Hb A1c% was significantly high in the microalbuminuria group. Systolic BP, total cholesterol and triglycerides were high in the middle group. Total cholesterol readings were much higher in the MA group. The number of diabetics with retinopathy and neuropathy in the MA group is also significantly higher (Table 2).
Total Cholesterol
HDL Cholesterol
5.6 5.5 5.4 5.3 5.2 5.1 5 4.9 4.8 4.7
1.45 1.44 1.43 1.42 1.41 1.4 1.39 1.38 >=1<2
<1
<1
>=2
LDL Cholesterol 3.15
>=1<2
>=2
Triglycerides 2.5
3.1 3.05
2
3
1.5
2.95
1
2.9
0.5
2.85 2.8
0
<1
>=1<2
>=2
<1
>=1<2
>=2
Fig. 1. Lipids in diabetics at different ACR levels.
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
G Model
DSX-377; No. of Pages 4 V.R.R. Kodali / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx Table 2 HbA1c%, lipids, micro and macro vascular disease and neuropathy at different albumin/creatinine Ratios. Parameter
ACR < 1
ACR 1 < 2
ACR 2
Number of diabetics ACR Creatinine Hb A1c% Systolic BP (mm Hg) Diastolic BP (mm Hg) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) LDL cholesterol (mmol/L) Retinopathy Neuropathy PVD
104 0.4 0.02 81.1 1.45 7.9 0.1* £ 134.2 1.5 78.3 0.75 5.0 0.08$,& 1.42 0.03 1.62 0.11# 2.92 0.07 30.8% (32) 38.4% (40)@ 15.4% (16)
24 1.25 0.52 81.8 3.06 8.3 0.3 £ 139.6 3.7 78 2.03 5.3 0.19$ 1.44 0.08 2.05 0.22# 2.97 0.18 37.5% (9) 45.8% (11) 20.8% (5)
24 5.5 1.0 79.3 4.9 8.7 0.37* 136.8 4.6 79.5 1.48 5.5 0.19& 1.4 0.09 2.0 0.31 3.1 0.18 54.2% (13) 54.2% (16)@ 20.8% (5)
*
£ $ # & @
P < 0.02. P < 0.09. P < 0.05. P < 0.02. P < 0.04. P < 0.02. P < 0.02.
4. Discussion There are limited data on vascular complications and lipid profile in the normotensive diabetics especially of long duration diabetes and similar extensive exclusion criteria. The prevalence of MA in absence of reno-protective medication is 16% (24 of 152 with duration of diabetes of 14 years. This rate is much lower than the true prevalence because of the exclusion criteria. In the diabetes control and complications trial in Type 1 diabetics, lipids were measured. The results in the end-study cohort with reference to albuminuria were published [10]. Systolic and diastolic blood pressure readings were going up when normoalbuminuria progressed to MA. The quantity and distribution of lipids worsened with progression of persistent albuminuria. HDL cholesterol was identical in control and normoalbuminuria groups. Total cholesterol was high in MA. In the Pittsburgh epidemiology of diabetes complications (EDC) study, lipids changed in a detrimental fashion when microalbuminuira developed [11]. We showed that total cholesterol and triglycerides were in high when the ACR 1 < 2 than when the ACR < 1, and HDL cholesterol concentrations were reversed. We noted high prevalence rates of microvascular and macrovascular disease in diabetics with the incipient nephropathy > high normal ACR > low normal ACR. A large number (73%) of diabetics without MA had recorded at least one high BP reading (SBP 130 mm Hg and/or DBP 90 mm Hg). Thus diabetics have complications much early in the course of the disease in absence of MA. Land mark studies established that slightly increased albumin excretion progresses to clinical proteinuria and diabetic nephropathy in both Type 1 and Type 2 diabetics [1,12,13]. In the MICROHOPE substudy [5], ACE inhibition lowered the risk of overt nephropathy in diabetics even without baseline MA. The geometric mean values suggest that there is a benefit in treating diabetics even without elevated ACR. The American Diabetes Association’s (ADA) Clinical Practice Guidelines in 2003 [14] recommended intervention even in absence of high blood pressure. These have been changed and the 2013 guidelines recommend a BP > 140/80 when treatment can be commenced in absence of other risk factors [15]. The Joint National Committee in their sixth report recommended a target of <135/85 mm Hg in diabetics and >140/90 mm Hg in non
3
diabetics [16]. The Hypertension Optimal Treatment and the UKPD Studies [17,6] confirmed the benefits of reducing blood pressure on cardiovascular events in Type 2 diabetics. In Type 1 diabetics, MA regresses only in presence of SBP < 115 mm Hg, Hb A1c < 8% and both low total cholesterol <5.12 mmol/L and triglyceride concentrations <1.64 mmol/L [18]. Therefore, lipid control is also mandatory to achieve active regression of the MA. In line with this are our findings indicating prudent intervention before albumin excretion increases. The current guidelines in the UK suggest treatment based on risk calculations [19]. For example, diabetics with blood pressure readings <140/90 with low CVD risk are not offered medical treatment. As seen in our data, diabetics have multiple complications even in absence of established MA. This study is not caveat free. It is a snap shot of the picture. Age groups varied though other characteristics were similar. Stage 1 or 2 of diabetic nephropathy are equivalent to expanded mesangium and thickened basement membrane. The presence of multiple unidentified risk factors from our findings tempt us conclude that intervention with ACE inhibitors and or angiotensin II receptor antagonists at these early stages should be introduced in addition to aiming a good glycemic and blood pressure control and treating dyslipidemia. Although the momentum seems to swing towards treating all diabetics, clinical judgments in this field are hampered by controversial data recently. In summary, diabetics with long term diabetes even in absence of microalbuminuria display multiple risk factors. An early intervention to prevent the metabolic and vascular complications is essential than recommending treatment after the morbid events. Acknowledgments This work is part of the MSc (Diabetes & Endocrinology) thesis submitted to the Guy’s, Kings & St. Thomas Registry, University of London. I thank Mrs Joanna Clayton, Diabetes Liaison Officer for help with the Diabetes Register. I would like to acknowledge Dr. John Frater, Consultant Chemical Pathologist for the useful discussions during the study. Conflicts of interest None. References [1] Mogensen CE. Miroalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984;310:353–60. [2] MacLeod JM, Lutale J, Marshall SM. Albumin excretion and vascular deaths in NIDDM. Diabetologia 1995;38:610–6. [3] Haffner SM, Morales PA, Gruber MK, Hazuda HP, Stern MP. Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria. Arterioscler Thromb 1993;13:205–10. [4] Mogensen CE. A complete screening of urinary albumin concentration in an unselected diabetic outpatient clinic population. Diabet Nephropathy 1983; 2:11–8. [5] Heart Outcomes Prevention Evaluation Study investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the Hope study and Micro-Hope substudy. Lancet 2000;355: 253–353. [6] U.K. Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes: UKPDS 38. BMJ 1998;317:703–13. [7] Mattock MB, Cronin N, Cavallo-Perin P, Idzior-Walus B, Penno G, Bandinelli S, et al. EURODIAB IDDM complications study. Plasma lipids and urinary excretion rate in type 1 diabetes mellitus. Diabet Med 2001;18:59–67. [8] Anonymous. Renal involvement in type 1 (IDDM) diabetes in Spain: ESTUDIO DIAMANTE. Diabet Res Clin Pract 1997;38:129–37. [9] Gerstein HC, Mann JFE, Pogue J, Dinneen SF, Halle JP, Hoogwerf B, et al. Prevalence and determinants of mciroalbuminuria in high-risk diabetic and nondiabetic patients in the heart outcomes prevention evaluation study. Diabet Care 2000;23(Suppl. 2):B35–9. [10] Sibley SD, Hokanson JE, Steffes MW, Purnell JQ, Marcovina SM, Cleary PA, et al. Increased small dense LDL and intermediate-density lipoprotein with albuminuria in Type 1 diabetes. Diabet Care 1999;22:1165–70.
Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025
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Please cite this article in press as: Kodali VRR. Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.025