Journal of Clinical Pharmacy and Therapeutics, 2016

doi: 10.1111/jcpt.12361

Commentary

Antihypertensive therapy for the prevention of nephropathy in diabetic

hypertensive patients
A. N. Isaacs* PharmD BCPS and A. Vincent* PharmD BCACP BCPS
*Purdue University College of Pharmacy, Department of Pharmacy Practice, West Lafayette, IN, USA, Eskenazi Health, Department of Pharmacy Services,
Indianapolis, IN, USA and Indiana University Health Methodist Hospital, Department of Pharmacy, Indianapolis, IN, USA

Received 12 August 2015, Accepted 12 January 2016

Keywords: ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diabetes, hypertension, nephropathy

outcomes.3,4 While many diabetic patients require multiple antihypertensives to achieve recommended therapeutic goals, 2540% are
able to attain blood pressure goals with monotherapy.5,6
A primary goal in managing hypertension in diabetic patients is to
prevent or delay the progression of not only macrovascular, but also
microvascular complications, such as nephropathy, retinopathy and
neuropathy. Hyperglycaemia and hypertension increase the risk for
glomerular damage through increased intraglomerular pressure.7
Studies have demonstrated intensive glycaemic and blood pressure
control in limiting microvascular diabetic complications5,810
Diabetic nephropathy is dened based on the presence of
protein in the urine.2,7,11,12 In the 2015 ADA guideline, albuminuria is dened as a urinary albumin excretion (UAE) rate of
30 mg/day or greater or spot protein urine concentration of
30 mg/g or higher, with no distinguishing between types of
albuminuria.2 Patients are considered to lack albuminuria, or have
normoalbuminuria, with a UAE of less than 30 mg/day or a spot
protein urine concentration of less than 30 mg/g.2,7,11,12 While not
all patients with albuminuria will develop overt nephropathy,
albuminuria increases the risk for advancing nephropathy and
chronic kidney disease (CKD).13,14
Another component of diabetic kidney disease that must be
considered is the development of decreased glomerular ltration
rate (GFR) without the development of albuminuria. The Third
National Health And Nutrition Examination Survey estimates that
1
1 million adults with type 2 diabetes have chronic renal
insufciency and of those, one-third are normoalbuminuric.15 It
has also been shown that a reduced GFR, even without the
presence of albuminuria, can increase the risk of developing
diabetes-related renal and cardiovascular complications.16,17 The
exact mechanism that causes this decline in renal function is
unclear. A commonly accepted explanation is that the decline in
GFR is associated with inammation and tubular injury, rather
than glomerular damage that occurs leading to albuminuria.18
While there is a growing body of evidence that shows renal
insufciency in patients with diabetes develops prior to the onset
of albuminuria, there is a lack of evidence aimed at optimal
treatment of this group of patients that may possess some level of
renal impairment based on their GFR, but with normoalbuminuria, as they are often excluded from clinical trials.1519 Therefore,
studies evaluating the impact of albuminuria have to be utilized to
evaluate nephropathy instead of GFR until future studies evaluate
this clinical endpoint for the development of diabetic nephropathy.
There is substantial literature demonstrating the benet of select
antihypertensive medications in patients with diabetic nephropathy.

SUMMARY
What is known and objective: Although antihypertensive recommendations exist for diabetic nephropathy, there is less
guidance for diabetics with normoalbuminuria. Therefore, this
review evaluates antihypertensives in preventing nephropathy
in diabetic hypertensive patients.
Comment: A literature search was performed using PubMed and
Medline for primary literature from 1978 through August 2015.
Search terms included diabetes mellitus, normoalbuminuria,
hypertension, ACE inhibitor, ARB and calcium channel blocker.
There was no literature evaluating antihypertensive therapies in
preventing nephropathy in type 1 hypertensive diabetics. However,
in patients with type 2 diabetes and hypertension, multiple studies
demonstrate the benet of an ACEI or ARB in preventing or
delaying the onset of nephropathy, while no study demonstrated
the benet of a CCB over an ACEI or ARB.
What is new and conclusion: Due to the lack of literature,
hypertension management in type 1 diabetics with normoalbuminuria should be guided by the treatment of comorbidities. To
prevent diabetic nephropathy, an ACEI or ARB should be rstline monotherapy over a CCB for the management of hypertension in patients with type 2 diabetes mellitus, hypertension and
normoalbuminuria.
WHAT IS KNOWN AND OBJECTIVE
The American Diabetes Association (ADA) estimates there are
approximately 29 million Americans living with diabetes mellitus
and over 70% of these patients have hypertension.1 The ADA
Standards of Medical Care guideline recommends the use of an
angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin
receptor blocker (ARB) as rst-line hypertensive therapy in patients
with diabetes.2 Contrary to the ADA guideline, the Joint National
Committee (JNC) 8 guideline for the management of hypertension
recommends an ACEI, ARB, calcium channel blocker (CCB), or a
thiazide diuretic as rst-line treatment of hypertension in non-Black
patients with diabetes.3 For the Black patient population, including
those with diabetes, JNC 8 suggests the use of a CCB or thiazide
diuretic due to their observed benets in preventing cardiovascular
Correspondence: Alex N. Isaacs, PharmD, BCPS, Clinical Assistant
Professor of Pharmacy Practice, Purdue University College of Pharmacy,
640 Esekanzi Avenue, Indianapolis, IN 46202, USA. Tel.: 317 880 5423;
fax: 317 880 0568; e-mail: isaacs5@purdue.edu

2016 John Wiley & Sons Ltd

A. N. Isaacs and A. Vincent

Preventing diabetic nephropathy

L-type or N-type calcium channels in arteriolar smooth muscle,

leading to peripheral vasodilation and subsequently reduced
blood pressure. It is hypothesized that DHP CCBs which inhibit
N-type calcium channels may have more benet in preventing the
progression of nephropathy.32 This is based on the clinical studies
which show that traditional L-type CCBs lead to vasodilation of
afferent arterioles which can increase intraglomerular pressure
while N-type CCBs inhibit calcium channels in nerve endings in
efferent arterioles leading to reduction in intraglomerular pressure.32 However, there is limited literature to support this
hypothesis and no data in diabetic patients with hypertension
and normoalbuminuria. The non-DHPs work within the myocardium to delay depolarization resulting in direct negative chronotropic effects. The theoretical benet of CCBs in delaying diabetic
nephropathy is a result of the reduction in systemic blood pressure
rather than by some other mechanism.31
Both ACEIs and ARBs antagonize the effects of angiotensin II
within the reninangiotensinaldosterone system. Angiotensin II
increases blood pressure through vasoconstriction and also by
increased aldosterone secretion leading to enhanced sodium and
water retention. Inhibition of angiotensin II results in a reduction
of systemic and intraglomerular blood pressure which may delay
the onset of nephropathy. However, unlike CCBs, ACEIs and
ARBs have proposed mechanisms independent of blood pressure
reduction that benet diabetic patients with hypertension.
Through the decrease in renal vasoconstriction, ACEIs and ARBs
may be more benecial than CCBs in reducing the risk of renal
complications in diabetic patients with hypertension and normoalbuminuria.31 While benecial individually, some have evaluated
the utility of an ACEI and ARB combined to prevent diabetic
nephropathy. However, there is concern for dual angiotensin
inhibition in patients with diabetic nephropathy as the
combination led to increased side effects, including hyperkalaemia, with little to no benet in preventing the progression
of nephropathy.3335
Blood pressure control is vital to delay the onset of diabetic
nephropathy, but the pharmacologic targets may be of importance
as well.2025,3641 Studies have demonstrated the benets of an
ACEI or ARB over alternative therapies in delaying the progression of diabetic nephropathy, independent of blood pressure
lowering effects.2025 However, these studies were in patients with
established nephropathy. The remainder of this review will
evaluate CCBs compared to ACEIs or ARBs in preventing the
onset of albuminuria in diabetic patients with hypertension and
normoalbuminuria.

Specically, ACEIs and ARBs have been shown to delay the

progression of diabetic nephropathy.2025 From this evidence,
multiple consensus hypertension guidelines support the use of an
ACEI or ARB in patients with diabetes mellitus in the presence of
nephropathy.2,3,2630 However, in normoalbuminuric patients with
diabetes mellitus, consensus hypertension guideline recommendations differ in rst-line therapies (Table 1).2,3,2630
The objective of this review was to evaluate rst-line antihypertensive therapy in the prevention of renal complications in
patients with diabetes mellitus and hypertension without established nephropathy. Due to the lack of literature evaluating the use
of thiazide diuretics in preventing diabetic nephropathy in this
patient population, this review will not discuss thiazide diuretics.
The primary focus of this review was to evaluate the use of CCBs
compared to angiotensin II antagonists, ACEIs or ARBs, for the
prevention of nephropathy in diabetic patients with hypertension
and normoalbuminuria.
COMMENT
A literature search was performed using PubMed and Medline for
primary literature from 1978 through August 2015. Search terms
included diabetes mellitus, normoalbuminuria, hypertension, ACE
inhibitor, ARB and calcium channel blocker. References from identied articles were also utilized in the composition of this review.
Studies were included if they were prospective, randomized
controlled English-language studies in diabetic patients without
albuminuria. Additionally, the studies had to include hypertensive
patients and albuminuria status at baseline.
Pharmacology of antihypertensive therapies
The prevention of albuminuria in diabetic hypertensive patients
may be dependent upon the pharmacologic properties of the
antihypertensive therapies.31 Dihydropyridine (DHP) CCBs inhibit

Table 1. Consensus guideline recommendations for hypertensive

diabetics
Guideline (Year)

First-line treatment options

ADA (2015)2

JNC 8 (2014)3

ASH/ISH (2014)2
ESH/ESC (2013)27
AHA (2007)28
AACE (2010)29
KDOQI (2004)30

ACEI
ARB
ACEI
ARB
CCB
Thiazide diuretic
ACEI
ARB
All antihypertensive medication classes
ACEI
ARB
ACEI
ARB
ACEI
ARB

Preventing nephropathy in type 1 diabetes mellitus

There is a lack of literature evaluating therapies in preventing the
development of nephropathy in normoalbuminuric type 1 diabetic
patients with hypertension. The EUCLID study did evaluate an
ACEI compared to placebo in type 1 diabetics. However, the study
included patients with albuminuria regardless of blood pressure.36,42 Therefore, based on the lack of literature, rst-line
treatment recommendations for this patient population should
be guided by comorbid disease states or attainment of blood
pressure goals.2,3,2630
Preventing nephropathy in type 2 diabetes mellitus
The evidence is substantially different for the prevention of
albuminuria onset in type 2 diabetics (Table 2).7,3741 Chan et al.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor

blocker; CCB, calcium channel blocker.

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A. N. Isaacs and A. Vincent

Preventing diabetic nephropathy

hypertension. Over 1000 patients were randomized to verapamil,

trandolapril, the combination of verapamil plus trandolapril, or
placebo. After a median follow-up of 3
6 years, all treatment
groups had a reduction in blood pressure. New-onset albuminuria
developed in 11
9% of verapamil monotherapy patients, 6% of
trandolapril monotherapy patients, 5
7% of combination therapy
patients and 10% of patients taking placebo. Trandolapril as
monotherapy and in combination with verapamil had a statistically signicant decrease in the number of patients developing
albuminuria compared to the verapamil monotherapy and placebo
groups.41
There were no studies evaluating the impact of an ACEI vs.
an ARB for the prevention of nephropathy. Additionally, there
were no literature on dual RAS blockade in this patient
population. Based on the lack of literature, guidance can be
taken from treatment of established diabetic nephropathy, in
which an ACEI or ARB alone are suggested, but not in
combination.2,3,33
In type 2 diabetics with hypertension and normoalbuminuria,
there is evidence to guide antihypertensive selection. Earlier
trials in this patient population were less conclusive, but these
studies had shorter follow-up and included fewer patients.3739
While the studies failed to demonstrate a difference in renal
outcomes at the end of the study period, the ABCD trial and
J-MIND did demonstrate a decreased UAE at various time
points in patients treated with an ACEI compared to a CCB. The
best evidence for the use of an ACEI or ARB in this patient
population comes from the two largest randomized controlled
trials, BENEDICT and ROADMAP.40,41 While a placebocontrolled trial, ROADMAP still demonstrated the use of an
ARB in delaying the onset to diabetic nephropathy.40 BENEDICT
demonstrated the superiority of an ACEI over a CCB in
preventing the onset of albuminuria in patients with type 2
diabetes and hypertension.41

evaluated the impact of enalapril vs. nifedipine on renal outcomes

in normoalbuminuric patients. After 1 year, while there was a
signicantly larger reduction in blood pressure with nifedipine,
there was no change in the UAE from baseline in either treatment
group.37
The ABCD trial evaluated the impact of intensive blood
pressure control with enalapril vs. nisoldipine. A post hoc analysis
of this study evaluated the impact of antihypertensive therapy on
the progression of diabetic complications, including nephropathy.
For the rst 3 years of study follow-up, enalapril signicantly
lowered UAE by 20% more than nisoldipine. However, over the
entire 5-year study follow-up, there was no change in UAE from
baseline in either study group. Additionally, there was no
difference between treatment groups in the progression to
albuminuria.38
The J-MIND study randomized Japanese patients with type 2
diabetes and hypertension to enalapril or nifedipine. Normoalbuminuric patients treated with enalapril had a signicantly lower
UAE at 18 months compared to the nifedipine treatment group.
However, at the end of the 24-month study period, there was no
statistically signicant difference in UAE or progression to
albuminuria between treatment groups.39
The most recent trial to evaluate the use of an antihypertensive
in this patient population was ROADMAP, which investigated
whether treatment with olmesartan would delay or prevent
albuminuria compared to placebo. After over 4000 patients were
followed for a median of 3
2 years, albuminuria developed in
signicantly fewer patients receiving olmesartan patients compared placebo, 8
2% and 9
8%, respectively. The median time to
onset of albuminuria was signicantly delayed in the olmesartan
group compared to placebo.40
The BENEDICT trial was the rst large, multicentre study
comparing various antihypertensive regimens for preventing
albuminuria in patients with type 2 diabetes mellitus and

Table 2. Literature summary

Study (year, N)

Inclusion criteria

Treatment groups

Results/Conclusions

Chan et al.37(1992, N = 44)

Enalapril 40 mg daily
Nifedipine 60 mg daily

No difference in UAE between treatment groups

Enalapril 40 mg daily
Nisoldipine 60 mg daily
Enalapril 5 mg daily
Nifedipine 20 mg daily

Lower UAE with enalapril for the rst 3 years,* but no

difference in overall progression to albuminuria

Placebo
Olmesartan 40 mg daily

Reduction in the occurrence of albuminuria* and time

to onset of albuminuria* with olmesartan

Placebo
Trandolapril 2 mg daily
Verapamil SR 240 mg daily
Trandolapril 2 mg daily
+ verapamil SR 180 mg daily

Decreased development of albuminuria with

trandolapril* and combination therapy* compared to
placebo, but no difference with verapamil vs. placebo

ABCD post hoc analysis38

(2000, N = 470)
J-MIND39 (2001; N = 201)

ROADMAP40 (2011, N = 4407)

BENEDICT41 (2004, N = 1209)

Type 2 diabetes
Hypertension
UAE < 30 mg/day
Type 2 diabetes
Hypertension
Type 2 diabetes
(HbA1c 12%)
Hypertension
UAE < 30 mg/day
Type 2 diabetes
Hypertension
UAE < 30 mg/day
Type 2 diabetes
Hypertension
UAE < 30 mg/day

Decreased UAE in enalapril group at 18 months*;

however, no difference in UAE between treatment
groups at 24 months

*P < 0
05; UAE, urine albumin excretion; HbA1c, haemoglobin A1c; SR, sustained release.

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A. N. Isaacs and A. Vincent

Preventing diabetic nephropathy

attainment of blood pressure goals. In type 2 diabetics with

hypertension, ACEIs and ARBs have demonstrated superiority
over alternative therapies in decreasing the risk of diabetic
nephropathy.3841 Therefore, an ACEI or an ARB should be
considered rst-line for the management of hypertension to delay
the onset of nephropathy in patients with type 2 diabetes mellitus,
hypertension and normoalbuminuria.

WHAT IS NEW AND CONCLUSION

Recently published consensus hypertension guidelines differ in
rst-line treatment recommendations for patients with diabetes
mellitus and normoalbuminuria.2,3,2530 For patients with diabetes
mellitus, hypertension and normoalbuminuria, there is insufcient
evidence in the presence of type 1 diabetes mellitus to support one
specic antihypertensive class as a rst-line treatment over
alternative classes. Therefore, hypertension management in normoalbuminuric patients with type 1 diabetes mellitus should be
guided by the treatment of comorbidities in addition to the

CONFLICT OF INTERESTS
No conict of interests.

REFERENCES
1. National Diabetes Statistics Report, 2014.
CDC National Center for Chronic Disease
Prevention and Health Promotion: Division
of Diabetes Translation. June 2014. Available
at: http://www.cdc.gov/diabetes/pubs/
statsreport14/national-diabetes-report-web.
pdf (accessed 11 February 2015).
2. American Diabetes Association. Standards
of medical care in diabetes 2015. Diabetes
Care, 2015;38:S49S66.
3. James PA, Oparil S, Carter BL et al. 2014
evidence-based guidelines for the management of high blood pressure in adults:
report from the panel members appointed
to the Eighth Joint National Committee
(JNC 8). JAMA, 2014;311:507520.
4. The ALLHAT Collaborative Research
Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium
channel blocker vs. diuretic: the antihypertensive and lipid-lowering treatment to
prevent heart attack trial (ALLHAT). JAMA,
2002;288:29812997.
5. UK Prospective Diabetes Study Group.
Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ,
1998;317:703713.
6. Cummings DM, Letter AJ, Howard G et al.
Generic medications and blood pressure
control in diabetic hypertensive subjects.
Diabetes Care, 2013;36:591597.
7. Gross JL, De Azevedo MJ, Silveiro SP,
Canani LH, Caramori ML, Zelmanovitz T.
Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care,
2005;28:164176.
8. The Diabetes Control and Complications
Trial Research Group. The effect of intensive
treatment of diabetes on the development
and progression of long-term complications
in insulin-dependent diabetes mellitus. N
Engl J Med, 1993;329:977986.
9. UK Prospective Diabetes Study Group.
Intensive blood-glucose control with sulfonylureas or insulin compared with con-

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

ventional
treatment
and
risk
of
complications in patients with type 2 diabetes: UKPDS 33. Lancet, 1998;352:837853.
Hansson L, Zanchetti A, Carruthers SG et al.
Effects of intensive blood-pressure lowering
and low-dose aspirin in patients with
hypertension: principle results of the hypertension optimal trial (HOT) randomized
trial. Lancet, 1998;351:17551762.
American Diabetes Association. Diabetic
nephropathy. Diabetes Care, 2002;25:S85
S89.
American Diabetes Association. Nephropathy in diabetes. Diabetes Care, 2004;27:S79
S83.
Bruno G, Merletti F, Biggeri A et al. Progression to overt nephropathy in type 2
diabetes: The Casale Monferrato Study.
Diabetes Care, 2003;26:21502155.
Chang TI, Li S, Chen S et al. Risk factors for
ESRD in individuals with preserved estimated GFR with and without albuminuria:
results from the kidney early evaluation
program (KEEP). Am J Kidney Dis, 2013;61
(S2):S4S11.
Kramer HJ, Nguyen QD, Curhan G, Hsu Y.
Renal insufciency in the absence of albuminuria and retinopathy among adults with
type 2 diabetes mellitus. JAMA, 2003;289:
32733277.
Tanaka N, Babazono T, Takagi M et al.
Albuminuria and reduced glomerular ltration rate for predicting the renal outcomes
in type 2 diabetic patients. Nephrology,
2015;20:531538.
Knobler H, Zornitzki T, Vered S et al.
Reduced glomerular ltration rate in
asymptomatic diabetic patients: predictor
of increased risk for cardiac events independent of albuminuria. J Am Coll Cardiol,
2004;44:21422148.
Perkins BA, Krolewski AS. Early nephropathy in type 1 diabetes: the importance of
early reanl function decline. Curr Opin
Nephrol Hypertens, 2009;18:233240.
Ekinci EI, Jerums G, Skene A et al. Renal
structure in normoalbuminuric and albu-

2016 John Wiley & Sons Ltd

20.

21.

22.

23.

24.

25.

26.

27.

28.

minuric patients with type 2 diabetes and

impaired renal function. Diabetes Care,
2013;36:36203626.
Lewis EJ, Hunsicker LG, Bain RP, Rohde
RD. The effect of angiotensin-converting
enzyme inhibition on diabetic nephropathy:
the Collaborative Study Group. N Engl J
Med, 1993;329:14561462.
Lewis EJ, Hunsicker LG, Clarke WR et al.
Renoprotective effect of angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl
J Med, 2001;345:851860.
Brenner BM, Cooper ME, de Zeeuw D et al.
Effects of losartan on renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy. N Engl J Med,
2001;345:861869.
Parving HH, Lehnert H, Brchner-Mortensen J et al. The effect of irbesartan on the
development of diabetic nephropathy in
patients with type 2 diabetes. N Engl J
Med, 2001;345:870878.
The ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with
type 1 diabetes mellitus and microalbuminuria receive angiotensin converting enzyme
inhibitors? A meta-analysis of individual
patient data. Ann Intern Med, 2001;134:370
379.
Viberti G, Wheeldon NM, Alcolado JC et al.
Microalbuminuria reduction with valsartan
in patients with type 2 diabetes mellitus.
Circulation, 2002;106:672678.
Weber MA, Schiffrin EL, White WB et al.
Clinical practice guidelines for the management of hypertension in the community: a
statement by the American Society of
Hypertension and International Society of
Hypertension. J Clin Hypertens (Greenwich),
2014;16:1426.
Mancia G, Fagard R, Narkiewicz K et al.
2013 ESH/ESC guidelines for the management of arterial hypertension. Eur Heart J,
2013;34:21592219.
Rosendorff C, Black HR, Cannon CP et al.
Treatment of hypertension in the prevention

Journal of Clinical Pharmacy and Therapeutics, 2016

4

A. N. Isaacs and A. Vincent

Preventing diabetic nephropathy

29.

30.

31.

32.

and management of ischemic heart disease: a

scientic statement from the American Heart
Association Council for High Blood Pressure
Research and the Councils on Clinical Cardiology and Epidemiology and Prevention.
Circulation, 2007;115:27612788.
Torre JJ, Bloomgarden ZT, Dickey RA et al.
American Association of Clinical Endocrinologists medical guidelines for clinical
practice for the diagnosis and treatment of
hypertension. Endocr Pract, 2006;12:193222.
Levey AS, Rocco MV, Anderson S et al. K/
DOQI clinical practice guidelines on hypertension and antihypertensive agents in
chronic kidney disease. Am J Kidney Dis,
2004;43:S1S290.
Brunton L, Blumenthal D, Buxton I, Parker
K, eds. Goodman & Gilmans manual of
pharmacology and therapeutics. New York,
NY: McGraw-Hill, 2008.
Fujisawa T, Ikegami H, Noso S et al. Renoprotective effect of N-type Ca channel
blockade in diabetic nephropathy. J Diabetes
Complications, 2007;21:252257.

33. Fried LF, Emanuele N, Zhang JH et al.

Combined angiotensin inhibition for the
treatment of diabetic nephropathy. N Engl
J Med, 2013;368:18921903.
34. Staton RC. Combined use of angiotensin
converting enzyme inhibitors and angiotensin receptor blockers in diabetic nephropathy. Curr Diab Rep, 2013;13:567573.
35. Esteras R, Perez-Gomez MV, RodriguezOsorio L, Ortiz A, Fernandez-Fernandez B.
Combination use of medicines from two
classes of renin-angiotensin system blocking
agents: risk of hyperkalemia, hypotension,
and impaired renal function. Ther Adv Drug
Saf, 2015;6:166176.
36. EUCLID study group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent
diabetes and normoalbuminuria or microalbuminuria. Lancet, 1997;349:17871792.
37. Chan JC, Cockram CS, Nicholls MG, Cheung CK, Swaminathan R. Comparison of
enalapril and nifedipine in treating noninsulin dependent diabetes associated with

2016 John Wiley & Sons Ltd

38.

39.

40.

41.

42.

hypertension: one year analysis. BMJ,

1992;305:981985.
Estacio RO, Jeffers BW, Gifford N, Schrier
RW. Effect of blood pressure control on
diabetic microvascular complications in
patients with hypertension and type 2
diabetes. Diabetes Care, 2000;23(S2):B54B64.
Baba S; J-MIND Study Group. Nifedipine
and enalapril equally reduce the progression of nephropathy in hypertensive type 2
diabetics.
Diabetes
Res
Clin
Pract,
2001;54:191201.
Haller H, Ito S, Izzo J et al. Olmesartan for
the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med,
2011;364:907917.
Ruggenenti P, Fassi A, Ilieva AP et al.
Preventing microalbuminuria in type 2 diabetes. N Engl J Med, 2004;351:19411951.
Chobanian AV, Bakris GL, Black HR et al.
The seventh report of the Joint National
Committee on Prevention, Detection, and
Treatment of High Blood Pressure: the JNC
7 report. JAMA, 2003;289:25602572.

Journal of Clinical Pharmacy and Therapeutics, 2016

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