Blood pressure, blood glucose, and diabetic renal disease

C. E. Mogensen,Denmark

Medical Department M
Aarhus University Hospital
Aarhus Sygehus
Nørrebrogade, DENMARK

The main focuses of this paper are the crucial role of blood glucose control as well as, and maybe even more importantly, the role of good blood pressure (BP) control. This concept was reviewed in an editorial of the British Medical Journal after publication of the main results of the United Kingdom Prospective Diabetes Study (UKPDS) in 1998. UKPDS, which studied patients with newly diagnosed type 2 diabetes, was a landmark study in the field of type 2 diabetes treatment, shifting the treatment strategy toward better recording of blood pressure and HbA1c as well as toward more intensive treatment. It is clear from new studies that overly intensive glycemic control in type 2 diabetes—at least in certain populations—results in detrimental effects, namely increased mortality (as seen in the Action to Control CardiOvascular Risk in Diabetes [ACCORD] study). Nevertheless, it is clear that multifactorial intervention is important, as documented in the 13-year Steno 2 study follow-up. Obviously, it is important to start at the point of type 2 diabetes diagnosis, but, on the other hand, many complications occur later on. In light of this fact, the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study is especially interesting. In fact, ADVANCE continued where UKPDS left off (ie, after approximately 8 years of type 2 diabetes). This study also focused on the relation between renal aspects of diabetes and blood pressure–lowering treatment as well as the treatment of hyperglycemia. Several earlier studies from our group focused specifically on these aspects of type 2 diabetes and on the reduction of albuminuria. We examined the blood pressure reductions in ADVANCE compared with those in UKPDS. In ADVANCE, BP was lowered more, including BP in nonhypertensive diabetics, and glycemic control was also documented to reduce complications. In both studies, it was found that complications were reduced by better BP treatment.

Medicographia. 2009;31:299-306 (see French abstract on page 306)

Diabetes research, with special reference to renal disease, hypertension, and glycemic control, has been previously discussed by me in papers in Medicographia.1-5 The main focuses of these papers were the crucial role of good blood glucose control as well as, and maybe even more importantly, the role of good blood pressure control. This concept was reviewed in an editorial of the BMJ after publication of the main results of The United Kingdom Prospective Diabetes Study (UKPDS) 1998.6 UKPDS is a landmark study in the field of type 2 diabetes treatment and has shifted the treatment strategy toward better recording of blood pressure and HbA1c as well as toward more intensive treatment, while carefully avoiding overtreatment. It is clear from new studies that overly intensive glycemic control in type 2 diabetes—at least in certain populations—results in detrimental effects, namely, increased mortality, as seen in the Action to Control CardiOvascular Risk in Diabetes (ACCORD) study (recently discussed by Home)7 and in the recently published VADT (Veterans Affairs Diabetes Trial),8 without positive results in any of the clinical end points and with only borderline significance in the change in albuminuria. Nevertheless, it is clear that multifactorial intervention is important, as documented in the 13-year follow-up of the Steno 2 study that comprised not only glycemic control and blood pressure control, but also treatment with statins to reduce cholesterol values. This study showed that microalbuminuria and type 2 diabetes can have dramatic effects on cardiovascular implications and mortality in patients.9

UKPDS studied patients with newly diagnosed type 2 diabetes (not necessarily newly established type 2 diabetes, since there may be a time lag between development of diabetes and diagnosis). Obviously, it is important to start from the diagnosis of type 2 diabetes, but, on the other hand, many complications occur later. In light of this, the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study10,11 is of special interest. In fact, this study continued where UKPDS stopped (after approximately 8 years of type 2 diabetes) (Figure 1). This study also focused on renal aspects of diabetes in relation to blood pressure– lowering treatment as well as the treatment of hyperglycemia (Figure 2).12 Several earlier studies from our group focused specifically on these aspects of type 2 diabetes and on the reduction of albuminuria. Figure 2 shows the BP reduction in ADVANCE compared with that in UKPDS. In both studies, it was found that complications were reduced by better BP treatment.

Figure 1
Figure 1. Recent improvements in macro- and microvascular
protection. An illustration of how different types of measures and drugs have helped improve vascular outcomes over the last 30 years.
Abbreviations: ACE, angiotensin-converting enzyme; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; ARB, angiotensin receptor blocker; BP, blood pressure; MR, modified release; RAAS, renin-angiotensin-aldosterone system.

Recent papers have documented a close association between high blood pressure and type 2 diabetes (as reviewed by Nilsson).13 Elevated blood glucose is quite often found in patients suffering from hypertension in diabetic clinics. Both elevated blood pressure and hyperglycemia are part of the so-called metabolic syndrome, and, along with hyperlipidemia, coexistence of these abnormalities is quite important and prevalent. Discovery of one abnormality should focus the attention of the physician on looking for and treating the other two abnormalities. The common denominator of these abnormalities may be typical Western lifestyle, which accelerates the development of these abnormalities. The basic mechanisms, in relation to molecular biology, are, however, unclear. Formerly, it was believed that glycemic control was not very important in the treatment of patients with diabetes, but this view radically changed after the publication of the Diabetes Control and Complications Trial (DCCT) and UKPDS. The effect of better glycemic control on complications is very likely related to less oxidative stress and to effects on advanced glycation end products (AGEs).

Genetic factors used to be considered important too, and, before these publications, there was not much emphasis on these treatment modalities in many clinics in the US. Deckert14 focused on the fact that some diabetic patients escape long-term diabetic complications, in spite of poor glycemic control, an observation that is quite common in diabetes clinics. One important, possible explanation may be that patients who escape complications have low blood pressure as a consequence of the nature of their disease or as a result of their treatment program. Clearly, treatments for elevated blood pressure are used in most diabetic patients as well as antihyperglycemic treatments, but one of the problems is that, in some cases, it is difficult to normalize or near-normalize glycemia. Over the years, several questions have emerged in the medical community, and we can now answer most of these.

Microalbuminuria or abnormal albuminuria in essential hypertension

After the introduction of radioimmunoassays for albumin in urine in the 1970s, several studies showed that microalbuminuria was not uncommon in poorly treated hypertensive patients. Abnormal albuminuria may be normalized by efficient antihypertensive treatment.15-17 New papers, such as the Heart Outcomes Prevention Evaluation (HOPE),18 the Reduction of End points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL),19 and other studies, show that albuminuria is a continuum,18,20-24 just as it is with most risk factors, such as blood pressure, glycemia, and lipid levels.

Thus, it is clear that borderline and abnormal albuminuria can be found in many patients with hypertension, especially if they have other complications. In fact, in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study and in other studies, it was shown that the higher the level of albuminuria, the poorer the prognosis.25,26 In contrast with those who had high and higher values, before and after treatment, reduced albuminuria indicated a better prognosis.27 ADVANCE confirmed this in diabetic patients.10,11

Figure 2
Figure 2. ADVANCE blood pressure reduction in relation to that of UKPDS.
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study. Modified from reference 12: Adler AI, Stratton IM, Neil HA, et al. BMJ. 000;321:412-419. Copyright © 2000, BMJ Publishing Group Ltd.

High GFR and prognosis

Recent guidelines28 from the National Kidney Foundation and the American Society of Nephrology classify patients according to their level of estimated glomerular filtration rate (GFR): the lower, the worse; the higher, the better. Reduced renal function indicates a poor prognosis, but, so far, there are no clear-cut intervention strategies based on clinical trials for this parameter, only epidemiology. This classification does not take the phenomenon of hyperfiltration into consideration. This phenomenon, documented over the past few decades, has mainly been seen in diabetes29 and is mainly based on original experimental studies by Brenner and coworkers.30

The paradigm, therefore, no longer seems correct because, in patients with type 1 diabetes, hyperfiltration, defined as a GFR higher than 140 mL/min (corrected for 1.73 m2 body surface area), indicates a poor prognosis.29,31 GFR is usually well preserved in microalbuminuria with type 1 diabetes, with no tendency to decline with higher degrees of microalbuminuria. 32 In type 2 diabetes, hyperfiltration is seen quite often in young patients (eg, the Pima Indians), and also, to a limited extent, in elderly patients.32,33 In population-based studies from the Netherlands, it has been suggested that increased GFR might be related to increased risk.30 Hyperfiltration (partly related to poor glycemic control), thus, is associated with a poor prognosis, especially in documented type 1 diabetes.29

Poor prognosis of proteinuric diabetic patients

It has been well established that patients with proteinuria and diabetes have a poor prognosis, as documented in follow- up studies from the Steno and Joslin centers. Prognosis has, however, improved due to efficient treatments, especially antihypertensive treatment. Nevertheless, studies in the early 80s documented that poor prognosis was not only determined by proteinuria, but also by the then so-called microalbuminuria, which increased the risks of progression toward proteinuria and of reduced renal function, with increased mortality.34

This paradigm has thus radically changed, and the concept of microalbuminuria as a major risk marker in both type 1 and type 2 diabetes and even in population-based studies is now firmly established.35,36 Microalbuminuria is defined as the excretion rate between normal albumin excretion rate and the level characterized by proteinuria. This level has been defined as an excretion rate between 20 and 200 ìg/min or 30 to 300 mg/24 hours.37 However, the level is now indicated as the albumin/creatinine ratio because collecting urine is cumbersome. In diabetes clinics, the albumin/creatinine ratio or albumin concentration is usually measured in early morning urine.37,38

Figure 3
Annual probability of death with progressive renal deterioration. Annual transition rates through the stages of nephropathy to death from any cause. The United Kingdom Prospective Diabetes Study (UKPDS) showed that the probability of death increases as renal deterioration progresses.
Modified after reference 38: Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS Group. Kidney Int. 2003;63:225-232. Copyright © 2003, International Society of Nephrology.

Microalbuminuria: does it only predict renal disease?

Originally, it was hypothesized that microalbuminuria would predict proteinuria and reduced renal function, but, surprisingly, it was shown, first in type 2 diabetes, that microalbuminuria was also a strong predictor of early mortality35 (later confirmed in UKPDS by Adler et al) (Figure 3).38 The same was found in population-based studies.36 Thus, microalbuminuria is increasingly recognized as a general risk marker for microvascular damage, such as endothelial dysfunction or inflammation in the small blood vessels.36 The abnormalities in small blood vessels are most easily detected in the urine, where the transcapillary escape rate can be measured in terms of urinary protein excretion. However, it must be mentioned that there is sizeable tubular reabsorption. Nevertheless, it is still clear that the albumin level in final urine is a very strong predictive marker. Thus, microalbuminuria not only predicts renal disease, but cardiovascular disease and mortality also and may be the strongest parameter in this respect.

BP, low kidney perfusion, and long-term effect on GFR

Once, it was widely believed that antihypertensive treatment would compromise renal circulation and, thus, be deleterious to renal function.16,23 Indeed, it was observed that treatment with antihypertensive agents acutely reduced GFR, and there was a fear that renal function would be reduced further and progressively over time. Therefore, it was suggested in several centers that physicians should not reduce blood pressure in patients with diabetes and hypertension or elevated blood pressure.16

However, this paradigm appears to have been entirely wrong. In the mid 70s, studies showed that renal disease progression, as measured by the exact rate of decline in GFR, was closely related to blood pressure level.39,40 Subsequently, it was shown that antihypertensive treatment could reduce albuminuria and, finally, that antihypertensive treatment over time reduced the rate of decline in GFR.39-44 This was a major breakthrough in the management of patients with type 1 diabetes. This treatment was the first to be based upon studies utilizing â-blockers, diuretics, and other antihypertensive agents. Later, agents blocking the renin-angiotensin system (RAS) became available and important, although it was clear that blood pressure reduction per se should also be a focus.44 Taguma et al45 were the first to define a paradigm, in this regard. Namely, that angiotensin-converting enzyme (ACE) inhibition was useful in diabetic renal disease. The recent ADVANCE study also emphasized the importance of lowering BP in type 2 diabetes, even if it was in the so-called normal range. Prevention or reduction of microalbuminuria, indicating good prognosis, was a key finding.10,11

Microalbuminuric patients and antihypertensive treatment

In recent years, it has become clear that microalbuminuria is a major risk factor. Initially, however, the treatment of these patients with antihypertensive agents was not advocated unless they had clearly elevated blood pressure. The definition of hypertension varied: a systolic BP higher than 140 mm Hg, or, previously, a systolic BP higher than 160 mm Hg. It was shown that the rate of progression of microalbuminuria was related to blood pressure—even below these levels. Therefore, the possibility of treating these patients with persistent microalbuminuria (even those with so-called normal or high normal BP) and incipient diabetic nephropathy with antihypertensive agents came as a major breakthrough. When these studies were initiated, it was not possible to block the renin-angiotensin system with ACE inhibitors or angiotensin receptor blockers (ARBs). At the same time, GFR was still well preserved and quite often even in the hyperfiltration range.31,35,46 Figure 4 shows renal outcomes in ADVANCE.

The paradigm shift became apparent: treatment with agents blocking the renin-angiotensin system became much more acceptable (compared with â-blockers) because of fewer side effects, and now all guidelines propose treating patients with microalbuminuria with agents that block the renin-angiotensin system. New studies from Michael Mauer’s group have not documented any structural protection afforded by RAS blockade in normoalbuminuric type 1 patients. However, these patients are known to have a low risk of progression, which explains the negative and disappointing findings.

Figure 4
Figure 4. Renal outcomes in ADVANCE.
In the ADVANCE study, the fixed combination Preterax significantly reduced all renal events and microalbuminuria in type 2 diabetic patients (presentation at the 2007 congress of the European Society of Cardiology).
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; Per-Ind, perindopril-indapamide.

The importance of reducing BP by blocking RAS in diabetes

At present, it is recommended that patients with microalbuminuria or proteinuria start treatment with agents that block the renin-angiotensin system. However, initial studies were conducted at a point in time when only â-blockers, diuretics, and a few other agents were available for antihypertensive treatment.39,40 In fact, these first studies showed that decline in renal function might be reduced, and a small and simple meta-analysis from Denmark of all the available studies at the time showed that decline in GFR was not improved by blocking ACE when compared with other antihypertensive agents.42 It is, however, now clear that treatment strategy is more easily implemented with the new agents because they cause fewer side effects. The most noticeable side effect in clinical practice with ACE inhibitors is cough, and, in this case, it is justified to switch to ARBs, although not initially. The renal effect of these two classes of drugs are not too different, but if blood pressure is not reduced by this strategy, the effect is more limited. Reduction of BP is crucial.44

“Normal” values in normoalbuminuria

Normoalbuminuria was and is defined as an albumin excretion rate below 20 ìg/min or 30 mg/24 hours. However, the excretion rate in young, normal individuals is usually around 5 ìg/min, although some normal individuals have higher values.37 The cut-off of 20 ìg/min was based upon observational studies in patients with type 1 diabetes, where an excretion rate higher than 15 to 20 ìg/min was usually associated with disease progression.35,36 However, more recent studies have shown that albuminuria in the upper normal range is also a risk factor and the exact cut-off is difficult to define. This is not surprising because albuminuria, just like other biological parameters, is a continuous variable. It is thus clear that with so-called high-normal values of albuminuria, there is a somewhat increased risk of future cardiovascular and renal disease.

ACE inhibitors and ARBs in combination

The use of either ACE inhibitors or ARBs is both useful and very feasible in practice (ACE inhibitors are substituted with ARBs in the case of cough). However, using both agents at the same time is not considered appropriate. In recent studies, it has been documented that there might be a further dual blockade effect in diabetes, in some patients. The Candesartan And Lisinopril Microalbuminuria (CALM) I study47 showed that so-called dual blockade with a combination of candesartan and lisinopril was efficient in reducing blood pressure and albuminuria. But in the next study, CALM II,48 it seemed possible to use a double dose of ACE inhibitors, with comparable results.48 The recent ONgoing Telmisartan Alone and in combination with Ramipril Global End point Trial (ONTARGET) study questions the use of dual blockade in patients with abnormal albuminuria.24 Importantly, ARBs and ACE inhibitors have shown the same results.49

The best parameter for recording blood pressure

Years ago, by tradition, diastolic blood pressure was considered to be the main clinical parameter. In the late 90s, the situation changed and it appeared that systolic blood pressure was a better predictor of future cardiovascular damage. Now, new studies suggest that pulse pressure may be an even better parameter.50,51 The presence of raised systolic pulse pressure seems highly predictive for the development and progression of renal disease and, maybe, also for cardiovascular morbidity and mortality in type 2 diabetic subjects (although it is difficult to determine the exact effect of systolic blood pressure). Interestingly, according to new studies, dual blockade has a pronounced effect on pulse pressure compared with high-dose monotherapy—it appears that pulse pressure may be more strongly related to central blood pressure, hence its effect on renal circulation.50,51

Figure 5
Figure 5. Abbreviation: PREMIER, PREterax in albuMInuria rEgRession. Reproduced from reference 52: Mogensen CE, Viberti G, Halimi S, et al. Hypertension. 2003;41:1063-1071. Copyright © 2003, American Heart Association, Inc.

Follow-up after screening for microalbuminuria

Screening for microalbuminuria has been proposed and accepted by many guideline committees. This is highly relevant, but new studies document that, for treatment to be effective, a reduction in microalbuminuria is of considerable importance.18,27,32 Therefore, it is now recommended that not only should microalbuminuria be screened for, but that treatment should also be followed up in order to see if microalbuminuria has declined sufficiently during treatment. Reduction in macroalbuminuria with antihypertensive treatment correlates with a subsequent reduced rate of decline in GFR.

ACE inhibition and diuretics in type 2 diabetes

New studies such as the Steno 2 study and the ADVANCE study clearly show that antihypertensive treatment, especially with drugs that block the renin-angiotensin system, is useful for patients with microalbuminuria (as seen in the Steno 2 study) and of definite benefit for many renal patients and patients with normoalbuminuria (as shown in ADVANCE). ADVANCE clearly showed the beneficial effects on mortality of antihypertensive treatment and that microalbuminuria was a major risk factor. When microalbuminuria was reduced, there was a stronger beneficial effect. It is also interesting to note that another major finding of the ADVANCE study was the protective effect of intensive glucose-lowering treatment, based on gliclazide MR, against diabetic nephropathy.11 Therefore, it seems justified that many patients with type 2 diabetes should be treated, not only with effective antihyperglycemic agents, but also with agents that reduce blood pressure, and one of the main focuses was a combination of ACE inhibitors and diuretics (as seen in ADVANCE).

The PREterax in albuMInuria rEgRession (PREMIER) study52 showed that first line treatment with a low-dose combination of perindopril/indapamide induces a greater decrease in albuminuria than enalapril (partially independent of BP reduction). A BP-independent effect of the combination may be to increase renal protection.

Significant effects on serious cardiovascular events may also be observed (Figure 5).52 In this context, it is also important to focus on the safe oral treatment of type 2 diabetes. In the GlUcose control In type 2 diabetes: Diamicron modified release versus glimEpiride (GUIDE) study,53 it was shown that gliclazide MR is at least as effective as glimepiride, either as a monotherapy or in combination. The safety of gliclazide MR was significantly better, with approximately 50% fewer confirmed hypoglycemic episodes in comparison with glimepiride. Interestingly, a recent publication retrospectively assessing the risk of developing coronary artery disease (CAD) according to initial sulfonylurea treatment in type 2 diabetic patients found less risk of CAD with gliclazide when compared with glimepiride or glipizide.54 The results showing continuous BPlowering and glycemic control effects in ADVANCE are very important.55

Figure 6
Figure 6. The paradigm circle. A schematic representation of how paradigms are formed and develop. According to this concept, new developments modify and improve our level of knowledge. It shows how paradigms are constantly being developed (from the Björn Folkow Lecture by the author at the annual meeting of the European Society of Hypertension in Milan in 2007).

Figure 6 shows the paradigm circle (modified from Thomas Kuhn). According to the paradigm circle concept, new developments modify and improve our level of knowledge. It shows how paradigms are in constant development and is taken from the Björn Folkow Lecture, given by the author at the European Society for Hypertension congress in Milan in 2007.


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