Table 2. How antihypertensive agents may be combined in diabetes -Blockers Yes (diuretics often required) ACE inhibition Yes (diuretics Yes Yes (theoretically interesting or angiotensin often required) combination, results promising) receptor blockers Ca blockers 1 Yes (diuretics Yes (rarely used) Yes (rarely used) Yes (often used; often required) also with diuretics) Diuretics -Blockers -Blockers + diretics ACE inhibition Careful clinical metabolic and BP monitoring always required, including control of serum electrolytes and serum creatinine of GFR index (combination therapy used in more than 50% of patients). 1 Some results suggest cardiovascular long-term effect less favorable than with ACE inhibition in type 2 diabetes. ever, since these phenomena may not point clearly to specific modalities of treatment, they will not be further discussed. Treatment of BP Elevation Mechanisms of BP Elevation and Choice of Therapy in Nephropathy Based upon the known mechanisms operating in the genesis of hyperten- sion, some interesting concepts regarding selection of antihypertensive treat- ment are evolving in diabetes. The abnormalities in renal function, where hyperfusion, hyperfiltration and increased glomerular pressure may be impor- tant mediators, favor the use of ACE inhibitors, since these agents tend to reduce efferent glomerular resistance. This effect, operating by reducing glomerular pressure, may even to some extent be independent of systemic hypertension or systemic BP level. The sodium retention evident in both type 2 and type 1 diabetes supports the use of diuretics and sodium restriction in antihypertensive programs in diabetes. The early cardiac hyperfunction in microalbuminuric patients may suggest the use of cardioselective -blockers to reduce this hyperfunction. Obviously, the generalized BP reduction seen with all these agents may be of prime importance, but these mechanisms could also favor the use of combined treatment: ACE inhibitors, diuretics and possibly  1 -blockers (or other agents) in diabetic patients (table 2). Calcium blockers reduce BP, and may be important in therapy although some, but decreasing, controversy exists. 162Mogensen Table 3. Diabetes-related side effects and favorable effects related to antihypertensive treatment in diabetics (mainly type 1 diabetes) Diuretics (thiazide Noncardio- Cardioselective ACE inhibitors Triple treatment: Calcium blockers Angiotensin or loop) selective -blockers diuretic  1 -blockers/ receptor -blockers ACE inhibitors blockers Glucose intolerance Yes, type 2, but No problem No problem No side effects Limited or no change No No related strongly Insulin sensitivity (with small dosages) to hypokalemia) not changed clinically Hypoglycemic No Yes, mainly A problem, but Not seen Limited or no change No No masking in type 1 limited, seen in (with small dosages) diabetes few patients Unfavorable lipid Yes, but not with Likely Limited or No side effects ? No No profits small doses nonexisting Other unfavorable May cause Less physical Less physical Coughing and Limited (with Foot edema seen No effects sodium depletion exercise exercise capacity drug-related side small dosages) in few patients capacity effects (uncommon) Favorable effects Elimination of Reduction of Reduction of Elimination Probably also No potentiation Under (apart from BP edema cardiovascular cardiovascular sodium excess combination of of peripheral investigation reduction) morbidity/ morbidity/ and possibly favorable effects ischemia? mortality mortality restoration of (stable GFR?) Normalization Normalization glomerular of cardiac of cardiac pressure gradients arrhythmias? arrhythmias? Effect on Not well Not well Yes, but relatively Very consistent Addition of ACE Related to BP Yes abnormal documented documented few studies exist finding inhibition reduces reduction albuminuria abnormal albuminuria Reducing fall rate Not documented Not Yes Yes GFR stable on Not documented Ungoing of GFR documented this program studies Obviously, from a theoretical point of view, potential additional beneficial effect should be considered (table 3). For example, ACE inhibitors may as suggested specifically reduce the localized increased pressures seen in these patients, as originally observed in animal studies. The presence of edema of course favors the use of diuretics. It is suggested that arrhythmias may play a role in the early mortality, especially in type 2 diabetic patients, and the observation that in trials in patients at risk -blockers are especially effective in diabetic patients points to additional beneficial effects of -blockers in the management of hypertension in diabetics where cardial disease and silent myocardial infarctions are not uncommon. Importantly, in heart failure - blockers are increasingly being used according to new trials, e.g. the Merit HF Study. Clearly, side effects are important and these are usually dose related. For example, the well-known diabetogenic effect of diuretics may be dose dependent with sufficient BP reduction with small doses that are not diabetogenic. Potas- sium loss is important but can readily be restored by potassium supplemen- tation or by the use of ACE inhibition. Also small doses of diuretics may 163Nephropathy and Hypertension in Diabetic Patients not impair lipid parameters. A side effect that has caused some concern is hypoglycemic unawareness. This was previously reported with unselective - blockers but is only of minor importance with cardioselective -blockers and the phenomenon is not important in type 2 diabetics that may especially benefit from cardioprotection by -blockers. Most ACE inhibitors do certainly not possess any diabetogenic effects, rather they are neutral. Thus there is no negative effect on glucose metabolism or lipid homeostasis; a positive effect has in fact been observed in some studies. This positive or rather neutral pattern may therefore favor the use of ACE inhibitors in diabetic patients. Importantly, no increased frequency of hypoglycemia is seen inclinical practice. Coughing as a side effect is surprisingly rare in diabetic patients, possibly due to diabetic neuropathic changes. The new angiotensin II receptor antagonists could be considered in this situation, also with other side effects caused by ACE inhibitors. Problems of Optimized Glycemic Control During Antihypertensive Treatment In recent years it has become increasingly clear that good glycemic control is of clear importance in the prevention and postponement of diabetic renal disease. As documented in the DCCT, good glycemic control can reduce the number of patients that develop advancing renal disease. Improved metabolic control seems also to protect against deterioration in renal function in patients with microalbuminuria. However, it is important to stress that it is quite often difficult to obtain good metabolic control, especially in patients with incipient or overt renal disease. There are no formalized long-term trials with a sufficient number of patients on the effect of optimized diabetes care in patients with overt renal disease. However, new studies strongly suggesta correlation between progression in renal disease, as measured by fall rate of GFR and level of HbA 1c .IfHbA 1c is satisfactory, with values around 7–8% (reference value 5.5%), progression is slow. This observation was recently confirmed. In patients with type 2 diabetes, progression can be reduced by early intervention. With overt nephropathy there is no correlation between progression and HbA 1c . The UKPDS clearly documented the role of good glycemic control in preventing microvascular complications. Intervention Trials in Normoalbuminuria Even in type 1 diabetic patients with normal BP and normal albumin excretion, renal hemodynamics may be beneficially influenced by ACE inhibi- tion. This study was of experimental nature and treatment of such individuals cannot be recommended, although a trial should be conducted in high-risk normoalbuminuric patients (high normal UAE (?12 g/min), high HbA 1c 164Mogensen (?9–10%)). However, the Euclid Study did not document any clear effect in normoalbuminuria in a 2-year trial, but longer intervention is likely to be positive, according to unpublished studies from Denmark. Microalbuminuria and Antihypertensive Treatment Several intervention studies have been published, some with self-controlled or crossover design, some double-blinded without being long term and some long term and randomized without being blinded. All these trials generally showed a reduction or a stabilization in microalbuminuria. In a recent random- ized double-blind large-scale placebo-controlled study, the effect of an ACE inhibitor was investigated with respect to progression to clinical nephropathy in normotensive type 1 diabetic patients with microalbuminuria. The major endpoint was the progression to persistent proteinuria (UAER ?200 g/min). In this large study, treatment delayed the progression to overt renal disease in normotensive, type 1 diabetic patients with microalbuminuria. Interestingly, in all these studies confirmed from 1985 to 1999, patients were included purely on the basis of microalbuminuria and indeed in most studies patients should not be hypertensive (often an exclusion criterion for participation). Therefore, in most studies BP was close to normal, and in some of the patients BP was in the middle of the range as seen in healthy young individuals (mean arterial pressure 90 mm Hg). There seems to be a tendency towards a correlation between reduction in BP and reduction in albuminuria. The clinical consequence is that the indication for antihypertensive treat- ment should be microalbuminuria (as in the clinical trials) rather than some elevation of BP (fig. 2). Obviously any elevation of BP or any increasing BP would further strengthen the indication, because there is a correlation between rate of progression of microalbuminuria and BP; still the conclusion from these studies would mean that antihypertensive treatment should be initiated whenever microalbuminuria is consistently found. A more cautious view would be to start antihypertensive treatment if microalbuminuria is clearly increasing (5–10% per year), but the variability in UAE makes this approach somewhat difficult in the practical clinical setting. All studies document a reduction or stabilization in microalbuminuria, irrespective of the treatment used; however, most studies were conducted with ACE inhibitors as the principal agent with few or no side effects. Diuretics were systematically added in one important study. Thus the scenario for the use of antihypertensive treatment, in particular ACE inhibitors, is moving from the indication of elevated BP to the indication of increased or increasing UAE as proposed in recently published guidelines. Combination therapy is also very useful in such patients. 165Nephropathy and Hypertension in Diabetic Patients Fig. 2. Microalbuminuria (MA) in type 1 diabetic patients below 60 years of age. New studies suggest similar effects in the relative young and lean type 2 diabetic patients. A/C>Albumin/creatinine ratio. Modified from Mogensen et al. In type 2 diabetic patients, microalbuminuria can be reduced by ACE inhibition and two long-term studies suggest a beneficial effect on GFR. The fall rate of GFR correlates to BP. This important topic has recently been reviewed by Cooper and McNally, and ACE inhibition as early treatment seems equally important in type 1 and type 2 diabetes. 166Mogensen Table 4. ACE inhibitors in type 1 diabetic patients: ob- served effects in clinical trials (stages as described in table 1) 1 No trials in newly diagnosed patients 2 Normoalbuminuria reduced BP not significantly changed Filtration fraction reduced (in normoalbuminuria) 3 Microalbuminuria reduced BP reduced (diastolic and systolic) Fall in GFR prevented or postponed 4 Proteinuria reduced BP reduced (diastolic and systolic) Fall rate of GFR reduced 5 End-stage renal disease and mortality postponed Trials in Patients with Proteinuria or Overt Diabetic Nephropathy In the untreated situation there is a correlation between the fall rate of GFR and BP, but interestingly the correlation between the fall rate of GFR and albuminuria is equally strong. It has been suggested that a pronounced fall in proteinuria after start of antihypertensive treatment predicts a more benign course of renal disease in type 1 diabetic patients, compatible with an important role for the level of albuminuria in the rate of progression in renal disease. Several studies have documented that antihypertensive treatment un- equivocally reduces the fall rate of GFR. This is invariably accompanied by reduction of albuminuria. Therefore, antihypertensive treatment is the major therapeutic option for these patients. The use of ACE inhibitors often with diuretics is popular, though antihypertensive programs, e.g. with  1 -blocker, have been reported equally effective, but possibly with more side effects. The recent important study by Lewis et al. showed that the number of patients with doubling of S-creatinine could be reduced by ACE inhibition, thus confirming earlier studies. However, BP was 3–4 mm Hg lower in the ACE-I group. A beneficial effect of ACE inhibition when combining ESRF and mortality was noted however. Thus, ACE inhibitors work in all stages of diabetic renal disease (table 4). Pregnant diabetic patients require special attention and ACE inhibitors are contraindicated here. In proteinuric type 2 diabetic patients it has also been shown that during treatment there is a correlation between BP elevation and the rate of decline in GFR, suggesting that elevated BP in type 2diabetic patients isalso important for the rate of progression in renal disease. When these patients exhibit overt 167Nephropathy and Hypertension in Diabetic Patients proteinuria, they generally have a poor prognosis. No very long-term interven- tion trials over several years with the fall rate of GFR as endpoint have been conducted recently in type 2 diabetes. Fall rate is generally high, and in some patients even dramatic, and ACE inhibition and -blockers seem to have a similar effect on outcome. Important large-scale studies are now ongoing using angiotensin II receptor antagonists and results are keenly awaited in this high- risk population. Protein-Reduced Diet In normoalbuminuric type 1 diabetic patients, hyperfiltration can be re- duced by normalizing dietary protein intake, a potential beneficial effect. Studies suggest that microalbuminuria can be reduced on a 2-year intervention basis by a low protein diet, but so far, no long-term results are available, and compliance may pose a problem. In diabetic nephropathy, new data have recently been published indicating that the rate of decline of GFR can be reduced by a low protein diet. Patients were monitored on their usual dietary intake of proteins and thereafter patients were put on a low protein diet. A remarkable reduction in the fall rate of GFR was observed, although the response varied considerably. Patients served as their own controls without a parallel nontreated group and it cannot be excluded that late or long-term action of antihypertensive treatment may explain at least part of the observed beneficial effect. In a randomized parallel study, Zeller et al. also documented beneficial effect on the fall rate of GFR in these patients. The MDRD Study was not convincingly positive but this trial only included few diabetics. Nyberg et al. did not find correlation between dietary protein intake and status of renal disease in type 1 diabetic patients. At this point, the general consensus may be to prescribe a protein intake of approximately 0.8 g/kg body weight per day (#10% of daily calories) in the patient with overt nephropathy. However, it has been suggested that once the GFR begins to fall, further restriction to 0.6 g/kg/day may prove useful in slowing the decline of GFR in selected patients. On the other hand, nutrition deficiency may occur in some individuals and may be associated with muscle weakness. Protein-restricted meal plans should be designed by a registered dietitian familiar with all components of the dietary management of diabetes. Cardiovascular and Cerebrovascular Trials Along with Renal Endpoints Cardio- and also cerebrovascular diseases are important causes of death in both type 1 and type 2 diabetes, especially when the kidney is affected. Although the concept of controlled clinical or therapeutical trial has evolved 168Mogensen Table 5. Positive effect on cardiovascular endpoints in type 2 diabetes by antihypertensive treatment Favors 1. Shep [Curb et al.] Diurectics vs. placebo 2. ABCD [Estacio et al.] ACE-I vs. CCB 3. Facet [Tatti et al.] ACE-I vs. CCB 4. HOT [Hansen et al.] Strict control (CCB-based) 5. UKPDS [Turner et al.] Strict control (ACE-I +-blocker-based) 7. CAPP [Hansson et al.] ACE-I vs. conventional 8. Syst-Eur [Toumilehto et al.] CCB vs. placebo 9. Hope-study [Yusef et al.] ACE-I vs. placebo CCB>Calcium channel blockers. over the past 50 years, only a few large trials have been conducted in diabetes, the first being the UGDP (University Group Diabetes Program) which now after the UKPDS, is mainly of historical interest. No real large-scale controlled trials were done when introducing sulfonylureas, biguanides or insulin, but this has changed now with the UKPDS. There has therefore been an increasing interest in cerebro- and cardiovascular endpoints, especially in type 2 diabetes with respect to effective modulation, mainly with antihypertensive treatment strategies, which show a beneficial effect (table 5). Most studies employ ACE inhibitors but it is noteworthy that any reduction of BP seems to be important. Certain trials show ACE inhibitors to be superior to calcium blockers and also conventional treatment. Importantly, the UKPDS showed a similar out- come using ACE inhibitors and -blockers. Fewer side effects occurred with the use of ACE inhibitors. This study also clearly showed that careful BP monitoring and effective treatment reduced cardio- and microvascular end- points very considerably (around 30%). Therefore, antihypertensive treatment should be given a great priority in the management of patients with type 2 diabetes. The UKPDS showed some effect of optimal glycemic control, but due to the nature of the trial this was not so evident. However, combined euglycemia (HbA 1c 6–7%) and normotension is highly protective when BP is around 130–135/80–85 mm Hg. Guidelines with Origin in Pathophysiological and Clinical Trials The World Health Organization-International Society of Hypertension (WHO-ISH) Liaison Committee on Hypertension was established in the mid- 169Nephropathy and Hypertension in Diabetic Patients Table 6. Suggested target BPs during antihypertensive treatment (systolic and diastolic should be attained, e.g. =140/85 mm Hg means =140 systolic and =85 diastolic) Clinic BP ABPM or home BP no diabetes 1 diabetes no diabetes 1 diabetes Titrate to diastolic BP O85 O80 O80 O75 Optimal BP =140/85 =130/80 =130/80 =125/75 Suboptimal BP O150/90 O140/85 O140/85 O130/80 ABM>Ambulatory blood pressure monitoring. 1 In those with high cardiovascular risk and initial BP 140–159/90–99 mm Hg there could be a case for adopting the targets for diabetic patients (British Hypertension Society 1999). 1970s and has subsequently produced several guidelines, the first in 1975. New guidelines have recently appeared also related to hypertension in diabetes. Several of these new guidelines have a similar approach. There is a clear emphasis on early and effective antihypertensive treatment in patients with diabetes suggesting a lower threshold for the start of the treatment and also a lower goal during treatment. ACE inhibitors are often preferred as initial agents but combination therapy is often warranted. In view of the recent observation that different types of drugs (ACE-I, -blockers, calcium channel blockers and diuretics) reduce cardiovascular risks in type 2 diabetes, there are different treatment options. In diabetic renal disease, ACE-I is however preferred. We should aim to achieve a BP around 135/85 mm Hg during treatment, or lower. The British Hypertension Society proposes: (1) ‘The threshold for antihy- pertensive treatment in type 1 diabetes is P140/90 mm Hg. The target BP is =130/80 mm Hg, or lower (=125/75 mm Hg) when there is proteinuria P1 g/24 h’. And (2): ‘Trials support treatment of all patients with type 2 diabetes and BP P140/90 mm Hg, aiming for a target BP =130/80 mm Hg. BPs O140/85 mm Hg on treatment should be considered suboptimal.’ (3) ‘Thus there is evidence from outcome trials in hypertensive patients with diabetes for the efficacy and safety of ACE inhibitors, -blockers, dihydropyrid- ines, and low-dose thiazides. The choice among these drug classes should be made using the criteria set out for nondiabetic patients. BP control will usually require more than one antihypertensive drug, and about 30% of hypertensive patients with diabetes need three or more agents in combination.’ A similar approach is seen in table 6. 170Mogensen The problem is that it may be difficult to achieve such BP with patients with proteinuria and overt renal disease and also in others with cardiovascular problems. Therefore, it is strongly advocated to start treatment early, e.g. with development of microalbuminuria, even in patients with normal BP. It has also been proposed to start treatment even before microalbuminuria. Since complications are so closely associated with BP increase (also in the normal range) this could easily be recommended in future guidelines as we now have effective treatment modalites with rather limited side effects. Summary Notes This chapter clearly documents that excess albuminuria, often accompa- nied by increased BP, is associated with actual or subsequent organ damage, not only in the kidney but also in other organs, especially in the eyes and in the heart. In the kidney, abnormal albuminuria starting in the microalbumi- nuric range reflects more advanced glomerular structural lesions, although the exact location of the permeability defect has not been defined at an ultrastruc- tural level. BP elevation may not initiate the glomerular permeability defect but high systemic BP aggravates the course of established lesions and clinical disease. Transition from micro- to macroalbuminuria is associated with a reduction in GFR, the key parameter in evaluation of renal function. Biochemical and hemodynamic hypotheses have been put forward sup- ported by animal models, but these notions are difficult to substantiate in humans, where isolated phenomena cannot be studied, and direct measurement of e.g. glomerular wall charge and intraglomerular pressure is not feasible. A unifying concept would be attractive, comprising biochemical aberrations, such as charge defects, changes in enzymatic activities and glycation phenomena as well as hemodynamic changes such as hyperfiltration with elevated glomerular pressure, aggravated by early systemic BP rise. This may be seen along with vascular and endothelial changes, reflected by increases in von Willebrand factor, circulating prorenin as well as increased transcapillary escape rate of albumin and dyslipidemia. Antioxidant status may also play a role. A common pathway explaining all or most of these abnormalities should be pursued, with the basis in prolonged hyperglycemia and related biochemical changes, characteristic for the diabetic state. However, when diabetic complications are evolving as a consequence of hyperglycemia, increasing BP remains a decisive factor in promoting organ damage in the kidney, and antihypertensive treatment seems to be the thera- peutic cornerstone in ameliorating deterioration in organ function. A low protein diet may also reduce albuminuria and the fall rate in GFR. However, 171Nephropathy and Hypertension in Diabetic Patients [...]... Reading Austin MA, Edwards KL: Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes Curr Opin Lipidol 1996 ;7: 1 67 171 Coppack SW: Postprandial lipoproteins in non-insulin-dependent diabetes mellitus Diabet Med 19 97; 14(suppl 3): 67 74 De Man FH, Cabezas MC, Van Barlingen HH, Erkelens DW, de Bruin TW: Triglyceride-rich lipoproteins in non-insulin-dependent... P, Yki-Jarvinen H, Shepherd J, Taskinen MR: Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects Diabetes 1998; 47: 779 78 7 Steiner G: Clinical trial assessment of lipid-acting drugs in diabetic patients Am J Cardiol 1998;81: 58F–59F Taskinen MR: Lipoproteins and apoproteins in diabetes; in Belfiore F, Bergman RN, Molinatti GM (eds): Current Topies in Diabetes. .. 1998;82:67U 73 U, 85U–86U Laakso M: Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus Lipoproteins and coronary heart disease in non-insulin-dependent diabetes mellitus J Diabetes Complications 19 97; 11:1 37 141 Lopes-Virella MF, Virella G: Modified lipoproteins, cytokines and macrovascular disease in non-insulindependent diabetes mellitus Ann Med 1996;28:3 47 354 Malmstrom... TG-containing core The excess surface components, including UC and phospholipids, are transferred to HDL ApoC and ApoE are also transferred back to HDL Through this process, the original VLDL particle is first converted into IDL, containing ApoB-100 and ApoE (step 3 in figure 1), and then into LDL, which are mainly composed of C and ApoB-100 (step 4 in figure 1) LDL Lipid Abnormalities and Lipid Lowering... non-insulin-dependent diabetes mellitus: Post-prandial metabolism and relation to premature atherosclerosis Eur J Clin Invest 1996;26:89–108 Groop PH, Elliott T, Ekstrand A, Franssila-Kallunki A, Friedman R, Viberti GC, Taskinen MR: Multiple lipoprotein abnormalities in type I diabetic patients with renal disease Diabetes 1996;45: 974 – 979 Gylling H, Miettinen TA: Treatment of lipid disorders in non-insulin-dependent diabetes. .. microalbuminuria under long-term (8 years) ACE inhibition Nephrol Dial Transplant 1998;13:1062 Microalbuminuria Collaborative Study Group, UK: Intensive therapy and progression to clinical albuminuria in patients with insulin-dependent diabetes mellitus and microalbuminuria BMJ 1995;311: 973 – 977 Mogensen CE: Combined high BP and glucose in type 2 diabetes: Double jeopardy (editorial) BMJ 1998;3 17: 693–694 Mogensen... has been found in microalbuminuric and albuminuric type 1 diabetics Concerning apoproteins, it is noteworthy that in type 1 diabetic patients with good metabolic control, although the level of LDL is often normal, the ratio LDL-C/ApoB is elevated, suggesting changes in the composition of the LDL particles Depletion of the choline-containing phospholipids in the ApoBcontaining lipoprotein particles has... first used, and thyroid, renal, and liver function, and ApoE fenotype should be checked; if LDL-C levels remain elevated, combined fibrate-statin therapy should be advised Combined therapy (beginning with a statin) is also suggested when both LDL-C and TG are markedly elevated Finally, it is noteworthy that antiproteinuric and lipid-lowering therapy can be expected to reduce vascular damage and the progression... Department M (Diabetes and Endocrinology), ˚ ˚ Kommunehospitalet, Arhus University Hospital, DK–8000 Arhus C (Denmark) Tel +45 89492011, Fax +45 861 378 52, E-Mail cem@afdm.au.dk Nephropathy and Hypertension in Diabetic Patients 173 Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment Basel, Karger, 2000, pp 174 –185 Chapter XII Lipid Abnormalities and Lipid Lowering in Diabetes E... dietary protein harmful? J Diabetes Complications 19 87; 1: 37 40 Østerby R, Schmitz A, Nyberg G, Asplund J: Renal structural changes in insulin-dependent diabetic patients with albuminuria Comparison of cases with onset of albuminuria after short or long duration APMIS 1998;106:361– 370 Parving HH: Renoprotection in diabetes: Genetic and non-genetic risk factors and treatment Diabetologia 1998;41 :74 5 75 9 Ravid . therapy and progression to clinical albumi- nuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. BMJ 1995;311: 973 – 977 . Mogensen CE: Combined high BP and glucose in type. IDL, containing ApoB-100 and ApoE (step 3 in figure 1), and then into LDL, which are mainly composed of C and ApoB-100 (step 4 in figure 1). LDL 175 Lipid Abnormalities and Lipid Lowering in Diabetes particles. changes in lipoprotein 177 Lipid Abnormalities and Lipid Lowering in Diabetes composition. However, the use of apoprotein determination in the clinical setting is limited by the lack of standardized