Chapter Three

Practical Part

1.1 Understanding Diabetes

Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia,

resulting from defects in insulin secretion, insulin action, or both. It is a significant
public health concern worldwide, given its rising prevalence and association with
numerous long-term complications, including cardiovascular disease, neuropathy,
and nephropathy. This section will delve into the definition, types, pathophysiology,
and the broader implications of diabetes.

Definition and Types of Diabetes

Diabetes can be classified primarily into three types:

1.1.1 Type 1 Diabetes

- Definition: Type 1 diabetes (T1D) is an autoimmune condition where the body's

immune system attacks insulin-producing beta cells in the pancreas. This results in
little or no insulin production.

- Characteristics: It typically presents in childhood or early adulthood, though it can

occur at any age. T1D requires lifelong insulin therapy for management.

1.1.2 Type 2 Diabetes

- Definition: Type 2 diabetes (T2D) is characterized by insulin resistance and

eventual pancreatic beta cell dysfunction. It accounts for approximately 90-95% of
all diabetes cases.
- Characteristics: T2D often develops in adults, although it is increasingly diagnosed
in children and adolescents due to rising obesity rates. It can often be managed with
lifestyle modifications and oral medications, although some patients may eventually
require insulin.

2.2. Diabetic Nephropathy And Hypertension

[Link]

Hypertension is approximately twice as prevalent in patients with diabetes compared

to the general population . In DM1, hypertension typically occurs in patients with
microalbuminuria or overt nephropathy . Estimates of the prevalence of
hypertension in normoalbuminuric patients with DM1 are varied; older studies using
the definition of hypertension as 160/95 mmHg showed a prevalence of 19% . One
larger Danish cross sectional study including over 1700 diabetics and 10,000
controls showed that in patients with DM1 and without micro or macroalbuminuria,
the prevalence of hypertension (again defined as 160/95 mmHg) was similar to that
of the general population (3.9% vs. 4.4%) (8). Of note, subjects with DM1 in the
latter study were younger on average than those in the former, which may explain
the lower prevalence of hypertension. However, a “non-dipping” nocturnal blood
pressure pattern in normoalbuminuric DM1 patients predicts future
microalbuminuria, possibly identifying high risk patients before the onset of kidney
disease(10). In the visit before microalbuminuria occurred, elevated daytime systolic
blood pressure (either office or ambulatory) was still not present. Genetic factors
also play a role in the association of hypertension with microalbuminuria based on
blood pressure analysis of family members of diabetic patients with
microalbuminuria .
The above studies overall suggest that microalbuminuria precedes hypertension
more commonly in DM1 than DM2. In either scenario, worsening renal function
further contributes to elevated BP. The prevalence of hypertension in diabetic
nephropathy increases at each stage of CKD, approaching 90% for ESRD patients .
Individual susceptibility to renal disease and hypertension likely involves the
combination of metabolic and hemodynamic disturbances that are commonly shared
by most diabetics, as well as genetic determinants that further dictate each patient’s
vulnerability. Some genes may increase susceptibility, while others may be
renoprotective. It is not clear whether these genes determine the incidence of diabetic
nephropathy specifically or just the vulnerability of renal disease in general in the
context of an additional risk factor such as diabetes. The reader is directed to other
reviews for further details on this topic .

[Link]

Multiple factors contribute to increases in blood pressure and hypertension in

patients with diabetes and nephropathy. The major causes of hypertension in both
DM1 and DM2 include volume expansion owing to increased renal sodium
reabsorption and peripheral vasoconstriction owing to dysregulation of factors that
regulate peripheral vascular resistance (Figure 1). Activation of the RAAS,
upregulation of endothelin1 (ET-1), upregulation of reactive oxygen species, and
downregulation of nitric oxide (NO) conspire to produce hypertension in this setting.
Importantly, many of these pathogenic factors have local non-hemodynamic effects
that can accelerate kidney disease and CV disease among patients with diabetes and
kidney disease.
 Figure 1 : The mechanisms of hypertension in diabetes and kidney disease

[Link]-Angiotensin-Aldosterone System

Angiotensin II (Ang II) is responsible for many of the actions of the RAAS. Ang II
binds to angiotensin type 1 (AT1) receptors in many tissues causing vasoconstriction
in vascular smooth muscle cells (VSMC), increased sodium reabsorption at the renal
proximal tubule, and stimulation of aldosterone release from the adrenal cortex.
These actions of Ang II in addition to aldosterone-stimulated sodium reabsorption
in the collecting duct serve to increase vasoconstriction, sodium reabsorption, and
hence blood pressure. In addition to these effects, Ang II also increases production
of superoxide by activation of NADPH oxidase in the systemic vasculature, heart
and kidney.
2.2.4. Oxidative Stress

Hyperglycemia is believed to be one of the causes of increased oxidative stress in

diabetes . CKD itself is also a state of high oxidative stress associated with increased
oxidative species and decreased antioxidant defenses . Partial nephrectomy in
animals results in increased levels of oxidative stress markers and decreased
excretion of NO, but reductions in blood pressure occur after administration of
antioxidants . In experimental animal models of DM2 with histologic evidence of
early nephropathy, urinary markers of oxidative stress were seen along with
increased peroxynitrite . Oxidative stress is influenced by and affects the mediators
of both RAAS and ECD to further contribute to hypertension enhanced
vasoconstriction (Figure 2).

Figure 2 : NO is produced by eNOS on endothelial cells using L-arginine as a

substrate and tetrahydrobiopterin (BH4) as a cofactor.
[Link] Of Hypertension In Diabetic Nephropathy

The essential goals of therapy in the management of diabetic nephropathy are

treatment of hypertension and reduction of albuminuria. The presence of
microalbuminuria is the first clinical manifestation of renal disease in patients with
diabetes. In DM1, once microalbuminuria is established as a persistent feature, it is
expected that without treatment 80% of these patients will progress to develop overt
nephropathy with macroalbuminuria. Of this group, 50-75% will progress to ESRD
at variable rates in the next 10-20 years (left untreated) [59]. Conversely, for
untreated DM2 with microalbuminuria, 40% are expected to progress to overt
nephropathy, of which 20% will progress to ESRD within the following 20 years.

Figure 3: Diabetic Proteinuria Revisited: Updated Physiologic Perspectives

Hypertension leads to progression of kidney disease and increases CV risk in these

patients. In spite of the high incidence of overt nephropathy and ESRD without
treatment, pharmacologic lowering of blood pressure was shown to slow progression
of kidney failure in patients with DM1 more than 20 years ago (60-62). In these
studies the addition of antihypertensives decreased the rate of decline in GFR from
an average of 1.23 (in 5 out of 6 subjects), 0.94, and 0.91 ml/min/month to 0.49, 0.1-
0.29, and 0.39 ml/min/month respectively. More recently, several studies
demonstrated the critical role of using drugs that block the RAAS in further slowing
progression of diabetic nephropathy (63-66). Using stricter BP goals than in earlier
studies, DM1 patients on placebo had an average decline in creatinine clearance of
17 mL/min/yr compared to 11 mL/min/yr for patients on captopril (63). For DM2
patients, irbesartan use resulted in an average decline in Cr clearance of −5.5
mL/min/yr compared to −6.5 and −6.8 mL/min/yr in placebo and amlodipine_groups
(65). These studies demonstrated that the benefit of such therapy could not be
explained solely on the basis of blood pressure lowering. Hence, angiotensin
converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) have
become standard of care in patients with diabetic nephropathy. We will first review
the evidence supporting the effects of these classes of agents on renal outcomes and
then discuss the appropriate target blood pressure for patients with diabetic
nephropathy.

2.4. Inhibitors Of The Renin Angiotensin Aldosterone System

[Link] Inhibitors

In addition to lowering blood pressure, current recommendations include using

either an ACEi or ARB as first line treatment of hypertension in patients with
diabetic nephropathy. ACEi slow the decline in GFR and prevent increases in
albuminuria in DM1 patients with diabetic nephropathy . The Irbesartan in Diabetic
Nephropathy Trial (IDNT) and Reduction in Endpoints in NIDDM with the
Angiotensin Antagonist Losartan (RENAAL) studies were seminal studies
establishing the efficacy of ARBs in patients with DM2 and nephropathy . These
studies specified the composite of doubling serum creatinine (Cr), ESRD, and death
as their primary outcome, but most benefit came from renal outcomes. IDNT
randomized 1715 patients with nephropathy to either irbesartan 300 mg or
amlodipine 10 mg, or placebo once daily. The number of composite outcome events
was significantly lower in irbesartan compared to amlodipine and placebo. There
were significantly less subjects with doubled serum Cr and significantly slower
increases in serum Cr in the irbesartan group compared to both amlodipine and
placebo, but unadjusted rates of ESRD or death were not different. The final
achieved blood pressures in this study were 140/77 mmHg, 141/77 mmHg, and
144/80 mmHg for irbesartan, amlodipine, and placebo. The RENAAL trial studied
1513 patients with DM2 and nephropathy with the same primary composite outcome
as IDNT. Subjects were randomized to either losartan (50-100 mg daily) or placebo,
and losartan was associated with a lower occurrence of the primary outcome in both
the unadjusted and adjusted analyses. Similar to IDNT, there was a significant
reduction in the individual end point of doubling of serum Cr, but not death. Contrary
to IDNT, the risk for ESRD was significantly lower during treatment with losartan;
and in a prespecified secondary outcome hospitalization for heart failure was also
reduced by losartan. There was no benefit from losartan regarding composite CV
events (detailed analysis included below). The mean arterial pressures (MAP) were
not different between groups at baseline or the end of the study, although it was
lower in the losartan following a 1-year interim analysis. The final blood pressures
in RENAAL were 140/74 and 142/74 mmHg for losartan and placebo.

Integrating all of these results has promoted ACEi and ARB to first line therapy
options for hypertension in patients with diabetic nephropathy without any evidence
suggesting superior efficacy of active drugs to one another. The mean systolic blood
pressure in many groups in these trials was >140 mmHg (Table 1), indicating that,
 even in the research setting, further blood pressure reduction is possible. A separate
discussion of specific blood pressure targets .

Table 1 : Characteristics and Achieved Blood Pressure of Trials Using Single

Agent RAAS Blockade in Diabetes (ACE Inhibitor or ARB)
Author Population/P Treatment Achieved BP (mmHg)
roteinuria
Lewis 1993 DM1 Captopril 96+/− 8 (MAP)

(63) 500mg/24h Placebo 100 +/− 8 (MAP)

p=.16 if prior HTN;
p<.001 if no prior HTN
Parving DM1 Captopril 129/77
2001 300mg/24h Standard Therapy 137/84 p<0.02
Lewis 2001 DM2 Irbesartan 140/77

IDNT 900 mg/24h Amlodipine 141/77 144/80

Placebo p<.001 for MAP in
placebo vs other 2
groups
Brenner DM2 Losartan 140/74, MAP 95.9

2001 500 mg/24h Placebo 142/74, MAP 96.8

(p=.59)
RENAAL
Parving DM2 Irbesartan 300 141/83, MAP 102
2001 20-200 mg Irbesartan 143/83, MAP 103
IRMA II μg/min 150 mg Placebo 144/83, MAP 103
SBP: p=.004 vs combined ARB groups
Barnett DM2 Telmisartan 6.9 mmHg reduction in
2004 11-999 SBP
DETAIL μg/min Enalapril 2.9 mmHg reduction in
SBP CI (−8.5, 0.5)
Ruggennenti DM2 Placebo 142/83
2004 139/81 (p<.002 v.
BENEDICT <20 μg/min Trandolapril placebo)
141/82 (NS vs placebo)
Verapamil 139/80 (p<.002 v.
T+ V placebo)
2.4.2. ACE Inhibitors and Angiotensin Receptor Blockers as Dual Therapy

Since ACEi and ARBs individually are renoprotective, questions arose regarding the
utility of combination therapy with both an ACE inhibitor and ARB. The principle
behind this strategy was more complete inhibition of Ang II, which can be produced
through non-ACE pathways. Most older trials studying combination ACE inhibitor
+ ARB in diabetic nephropathy have had small sample sizes and treatment durations,
although the effects were promising. Combination therapy in patients with DM1 and
DM2 with nephropathy yielded significant reductions in albuminuria and/or blood
[Link] was generally well [Link] Candesartan and Lisinoril
Microalbuminuria (CALM II) study was a slightly larger and longer study
comparing the effects of adding candesartan vs. additional lisinopril 20 mg onto a
regimen already including lisinopril 20 mg [Link] therapy was not
different than maximization therapy regarding ambulatory blood pressure, clinic
blood pressure, or albuminuria after 12 months (Table 2). Of note, not all patients
had albuminuria at baseline, and renal function preservation was not different in the
2 groups.

Table 2 : Characteristics and Achieved Blood Pressure in Trials Using

Combination of ACE Inhibitor and ARB in Diabetes
Author Population/Proteinuria Treatment Achieved BP
(mmHg)
Andersen DM1 or 2 L 20 mg + L 20 mg 128/74
2005 CALM II 123/73
L 20 mg + C 16 mg p=.16 for ASBP
ON DM 1 or 2; or Vascular Ramipril (R) −0.9/0.6 from
TARGET Disease baseline
Telmisartan (T) − 2.4/1.4
R+T mmHg from
baseline
VA- DM2 Losartan+Lisinopril
NEPHRON 300 mg/g Losartan+Placebo
Concerns about this strategy arose with The Ongoing Telmisartan Alone and in
Combination with Ramipril Global Endpoint Trial (ONTARGET) .This study tested
the hypothesis that among patients at high risk for a CV event, the combination of
an ACEi and an ARB would be superior to either agent alone. Importantly 38% of
study subjects had DM2, and 13% had microalbuminuria. Overall, there were no
differences in the primary end point consisting of stroke, myocardial infarction and
sudden cardiac death between groups. However, those randomized to combination
therapy had a higher rates of renal impairment and hyperkalemia (serum potassium
>5.5 mmol/L). Further analysis of the renal outcomes indicated a more rapid decline
in estimated GFR and a higher rate of need for dialysis for acute renal failure
episodes during the trial .

[Link] Receptor Antagonists in Diabetic Nephropathy

With both ACEi and ARBs, plasma aldosterone levels are expected to decrease. In
some patients on maintenance therapy with these drugs, aldosterone levels increase
to pre-treatment levels via the phenomenon of “aldosterone escape.” Aldosterone
escape occurs in up to 40% of patients on ACEi or ARBs and may contribute to local
renal damage, albuminuria increases, and possibly systemic hypertenson . This
occurs irrespective of which agent or dose is used . Interest in using
mineralocorticoid receptor antagonists (MRA) has been justified by their ability to
decrease proteinuria in diabetic nephropathy when used with other RAAS blockers.
A small randomized crossover study in DM1 patients with diabetic nephropathy
already taking an ACEi or ARB demonstrated a 30% reduction in albuminuria
(p<0.001) with 25 mg daily of spironolactone vs. placebo . A significant difference
in the 24-hour ambulatory blood pressure was not found, although the daytime
ambulatory blood pressure was lower with spironolactone (p<0.02). Another small
study including patients with DM1 and DM2 with nephrotic-range proteinuria
showed a similar reduction in albuminuria . In this study 24 hour and daytime
systolic and diastolic blood pressure were significantly lower with MRA, although
nocturnal blood pressure was not different. A larger randomized parallel design
study compared the effects of spironolactone vs. losartan vs. placebo as add on
therapy to patients with diabetic nephropathy already taking Lisinopril 80 mg daily
. There was a 34% decrease in albuminuria with spironolactone compared to placebo
and a 17% decrease with losartan compared to placebo. Neither ambulatory nor
clinic systolic blood pressure were significantly different between groups. In all
these studies, effects on albuminuria were determined to be blood pressure
independent. The effects on blood pressure from these trials are summarized in Table
4. An increased risk for hyperkalemia exists when combining an MRA with other
RAAS blocking agents or with combination of ACE/ARB. This risk appears to be
related to baseline potassium levels, baseline GFR, and change in GFR during study
. Prudent monitoring of patients on multiple agents is recommended to reduce the
risk of adverse events.

Table 3 : Characteristics and Achieved Blood Pressures in Diabetic Nephropathy

Studies Using Mineralocorticoid Receptor Antagonists
Population/Protein Treatment Achieved BP (mmHg) Notes
uria
Schjoedt 2005 (87) DM1; 300 mg/day Spironolactone: 24 hr SBP: p = 0.082
(already on ACEi or 136/69 24 hr DBP: p = 0.067
ARB) Placebo: 144/72
Schjoedt 2006 (88) DM1 or DM2; 2.5 Spironolactone: 24 hr SBP: p = 0.004
g/day (already on 137/77 24 hr DBP: p = 0.001
ACEi or ARB) Placebo: 143/81
Mehdi 2009 (89) DM1 or DM2; 300 Spironolactone: 132 NS between groups
mg/g Cr Losartan: 134
Placebo: 136
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