Full text of DOI:10.2165/00002512-200017060-00004

Drugs & Aging 2000 Dec; 17 (6): 463-476
1170-229X/00/0012-0463/$20.00/0
REVIEW ARTICLE
© Adis International Limited. All rights reserved.
Beneficial and Detrimental Effects of
Intensive Glycaemic Control, with
Emphasis on Type 2 Diabetes Mellitus
Pauline Camacho,1 Shailesh Pitale1 and Carlos Abraira2
1
2
Loyola University Medical Center, Maywood, Illinois, USA
Miami Veterans Affairs Medical Center, Miami, Florida, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
1. Intensive Glycaemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
1.1 Insulin Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
1.2 Oral Antihyperglycaemic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
2. Benefits of Intensive Glycaemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
2.1 Microvascular and Neuropathic Complications . . . . . . . . . . . . . . . . . . . . . . . . . . 466
2.2 Macrovascular Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
2.3 Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
3. Detrimental Effects and Limitations of Intensive Glycaemic Control . . . . . . . . . . . . . . . . . 470
3.1 Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.2 Cardiovascular Issues with Oral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.3 Hyperinsulinaemia and Ischaemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.4 Adverse Effects of Rapid Glycaemic Improvement . . . . . . . . . . . . . . . . . . . . . . . . 471
3.5 Bodyweight Gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
3.6 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
4. Who Will Benefit from Intensive Glycaemic Control? . . . . . . . . . . . . . . . . . . . . . . . . . . 471
5. Other Aspects of the Management of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . 472
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Diabetes mellitus is a major health problem in the world. Several clinical trials
have shown that some of the major complications of diabetes mellitus can be
partially prevented or delayed by intensive glycaemic control. However, there are
benefits and risks in aiming for near normal blood glucose levels.
Abstract
Intensive glycaemic control delays the onset and progression of retinopathy,
nephropathy and neuropathy. Epidemiological and observational studies have
shown that cardiovascular events may be correlated with the severity and duration
of diabetes mellitus, but major randomised trials have only shown weak and
nonsignificant benefits of intensive glycaemic management in decreasing event
rates. A modest improvement in lipid profile results from blood glucose control
although, in the majority of cases, not enough to reach current targets.
Detrimental effects of intensive glycaemic control include bodyweight gain
and hypoglycaemia. Controversial issues in the management of patients with
diabetes mellitus include the unproven increase in cardiovascular morbidity from

464
Camacho et al.
sulphonylureas and hyperinsulinaemia, and the still unknown long term effects
of newer oral antihyperglycaemic agents alone or in combination with traditional
therapies (such as sulphonylureas and metformin).
It is important to individualise management in setting glycaemic goals. Con-
trol of cardiovascular risk factors through blood pressure and lipid control and
treatment with aspirin (acetylsalicylic acid) and ACE inhibitors have consistently
shown benefits in the prevention of both macro- and microvascular complications
in patients with diabetes mellitus; these measures deserve priority.
Diabetes mellitus is a major health problem in
apy remains unsettled,[13-15] and trials addressing
this issue are currently in the planning stage in the
US.
the world. In 1995, 135 million adults were diag-
nosed as having diabetes mellitus and this is pro-
jected to rise to 300 million by the year 2025.[1] The
overwhelming majority of patients with diabetes
mellitus have type 2 diabetes mellitus; previously
known as non–insulin-dependent diabetes mellitus
or adult-onset diabetes. The incidence of type 2
diabetes mellitus increases linearly with advancing
age, with the majority of people with the disease
≥65 years of age.[1] Diabetes mellitus ranks as the
seventh most prevalent cause of death in the US,
with cardiovascular complications accounting for
almost 70% of diabetes-related hospitalisations.[2]
Serious complications such as end-stage renal
disease (ESRD) from diabetic nephropathy, blind-
ness from retinopathy and nontraumatic amputa-
tions may be caused by the disease. The incidence
of strokes and coronary events is 2- to 4-fold higher
in patients with diabetes mellitus compared with
the nondiabetic population.[3-9] Because of these
complications, the yearly mortality rate of patients
with diabetes mellitus is 2- to 3-fold higher than
that of age-matched controls.[6] The healthcare cost
of diabetes mellitus is thus astounding, approach-
ing $US100 billion in the US during 1997.[10]
The American Diabetes Association (ADA) cur-
rently recommends a preprandial goal of whole
blood serum glucose levels of 80 to 120 mg/dl (4.4
to 6.7 mmol/L), premeal or bedtime serum glu-
cose of 100 to 140 mg/dl (5.6 to 7.8 mmol/L) and
a glycosylated haemoglobin (HbA1c) of <7% (nor-
mal 4 to 6%), with intensification or change of phar-
macological strategy when HbA1c exceeds 8%.[16]
These are general guidelines for all persons with
diabetes mellitus, but some individuals may war-
rant different treatment goals. The presence of
comorbid diseases, such as pre-existing cardiovas-
cular complications, evidence of advanced micro-
vascular complications, advanced age and the pa-
tient’s inability to carry out the advised treatment,
attenuate the ADA goals and lessen the intensity of
treatment,[16] indicating the need to tailor therapy
for specific patients with diabetes mellitus. The
overall prevalence of glycaemic control is still fall-
ing short of the above goals, with reported mean
HbA1c values of 8.5 to 10%.[17,18] Perhaps due to
the widespread use of the newer oral antihyper-
glycaemic agents however, there has been im-
provement in the overall glycaemic control. Veter-
ans Affairs’ (VA) data from the US show that
almost half of patients diagnosed as having diabe-
tes mellitus, regardless of treatment, have mean
HbA1c values below 8% and relatively few patients
exceed 9%. However, insulin-treated patients still
have mean levels of 8.7%.[19]
1. Intensive Glycaemic Control
The results of major randomised prospective tri-
als have shown that intensive glycaemic control
toward near-normal blood sugar levels can delay
the onset and progression of several indicators of
microvascular and neurological diabetic compli-
cations.[11-13] However, the question of whether
cardiovascular mortality may be improved, un-
changed or worsened as a result of intensive ther-
In type 1 diabetes mellitus, intensive glycaemic
control to near normal HbA1c levels may be
achieved by using continuous insulin infusion via
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Drugs & Aging 2000 Dec; 17 (6)

Intensive Glycaemic Control in Diabetes Mellitus
465
insulin pumps, or multiple daily injections of in-
sulin along with bedtime long-acting insulin.[20]
In patients with type 2 diabetes mellitus, double
or triple therapy with various oral agents, and
ultimately insulin, may frequently be needed to
achieve the blood glucose and HbA1c goals.[21]
1.2 Oral Antihyperglycaemic Agents
The choices for oral diabetic agents have been
recently expanded with the appearance of new
drug classes. The following are currently available
in the US for type 2 diabetes mellitus:
• sulphonylureas [glimepiride, glipizide,
glibenclamide (glyburide)]
1.1 Insulin Preparations
• meglitinide analogue (repaglinide)
• biguanide (metformin)
Awide variety of insulin types are available that
have different durations of action (table I).
• thiazolidinediones (rosiglitazone, pioglitazone)
• α-glucosidase inhibitors (acarbose, miglitol).
The earliest and better documented agents are
the sulphonylureas, which lower glucose levels by
acting on ATP-sensitive potassium channels, in-
creasing cytosolic calcium and thus enhancing in-
sulin secretion by the β cells in the pancreas. Al-
though the majority of patients may be initially
controlled with these agents, the vast majority even-
tually require the addition of another oral agent
and/or insulin for good glucose control. Many fac-
tors may participate in the loss of responsiveness
(tachyphylaxis, diet, physical activity, concomi-
tant medications) but the results of the United
Kingdom Prospective Diabetes Study (UKPDS)
clearly document that there is progressive loss of
β cell function in type 2 diabetes mellitus, regard-
less of the therapy used.[13]
The meglitinide agent, repaglinide, acts simi-
larly to the sulphonylureas, stimulating insulin re-
lease by the pancreas, but through different β cell
receptors. The drug should be taken with meals,
since the insulin-releasing effect is short-acting
and stimulated by a glucose load. Repaglinide may
be more effective in lowering postprandial blood
glucose levels than sulphonylureas and may cause
fewer hypoglycaemic episodes than the latter
agents,[27] but it has to be given in multiple daily
doses.
Insulin lispro is a relatively new short-acting
insulin that is rapidly replacing regular insulin
in use. It is shorter acting than regular insulin,
mimicking the physiological surge of insulin with
meals, and has less of the hypoglycaemic reactions
that are associated with the peaks that occur with
regular insulin.[23] The newer insulin aspart, an-
other short-acting analogue, has similar properties.
Newer insulins that are currently being mar-
keted include a long acting insulin, insulin glarg-
ine, and inhaled insulins. Insulin glargine is a mod-
ified human insulin in which glycine is substituted
for asparagine at the A21 position, and two argi-
nines are added to the B30 position of the mole-
cule. These alterations shift the isoelectric point to
a slightly acidic pH, resulting in low solubility at
neutral pH.[24] Its advantage is the flat, peakless,
nearly 24-hour action.[25]
Inhaled powder insulin is another insulin ana-
logue that will be marketed soon. It has a rapid
onset and short duration of action, which should
provide coverage of meals.[26]
Table I. Available insulin preparations (adapted from American
Diabetes Association[22]
Insulin preparation
)
Onset of
action
Peak
action
Duration of
action
Rapid acting (e.g. insulin Minutes
lispro)
45 min
4-5h
In the biguanide class, only metformin is used.
The primary effect is on the liver, decreasing he-
patic glucose output. There is also a minor second-
ary effect of enhancing glucose uptake and utilisa-
tion by peripheral tissues. The effect on glycaemic
control is comparable to that of sulphonylureas,
and it confers an additional effect when added to
Short acting (regular)
Intermediate acting
(NPH, Lente)
30 min
1-3h
2-5h
6-12h
5-8h
16-24h
Long acting (Ultralente)
Mixtures (70/30, 50/50)
4-6h
30 min
8-20h
7-12h
24-28h
16-24h
h = hours; NPH = neutral protamine Hagedorn (insulin suspension
isophane).
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Drugs & Aging 2000 Dec; 17 (6)

466
Camacho et al.
sulphonylureas. Metformin does not cause body-
weight gain, which is a common adverse effect of
sulphonylureas. When used as monotherapy, met-
formin does not cause hypoglycaemia; however,
when combined with sulphonylureas, it confers at
least as high a risk, or possibly a higher risk, than
sulphonylureas alone. Metformin has a consistent
antihypertriglyceridaemic effect and lowers levels
of plasminogen activator inhibitor 1 (PAI-1),[28,29]
a circulating atherogenic factor, independent of
glycaemic control. Metformin is contraindicated in
patients with renal insufficiency (serum creatinine
level >1.5 mg/dl) because it has a rare but often
fatal adverse effect of lactic acidosis if used in such
patients. For the same reason, patients with conges-
tive heart failure, liver disease, risk of hypotension,
or other diseases that can predispose to hypoxae-
mia should not use metformin. It is recommended
that the drug be withheld for 48 hours after admin-
istration of dye for angiographic procedures.
during the first few weeks of treatment with a
thiazolidinedione. Troglitazone has been discon-
tinued because of its association with liver toxicity.
Finally, the α-glucosidase inhibitors cause blood
glucose lowering by inhibiting the enzyme in the
small intestine, slowing the digestion and absorp-
tion of glucose. The reduction in HbA1c is small,
and the drugs, especially acarbose, are often poorly
tolerated because of their gastrointestinal adverse
effects.[31]
2. Benefits of Intensive
Glycaemic Control
The benefits of tight blood glucose control in
preventing diabetic complications have been sup-
ported by numerous observational studies and sev-
eral randomised controlled trials.
2.1 Microvascular and Neuropathic
Complications
Thiazolidinediones are insulin-sensitising agents,
lowering glucose levels by potentiating the effect
of insulin in the muscle, liver and adipose tissues.
This class of drug may be very effective in control-
ling blood glucose levels, resulting in lowered
insulin requirements, but causes bodyweight gain
and some blood volume expansion. However, the
thiazolidinedione troglitazone has been associated
with a rare idiosyncratic hepatocellular injury
that is reversible with discontinuation of the drug,
but that may lead to irreversible liver failure or
death.[30] Thus, pretreatment liver function testing
and liver enzyme monitoring (alanine aminotrans-
ferase determination once monthly for troglitazone
and once every other month for rosiglitazone and
pioglitazone for the first year) are recommended
whenever the thiazolidinediones are used. The in-
cidence of abnormal liver function tests with ros-
iglitazone and pioglitazone is about 5 to 10 times
lower than the 0.2% seen with troglitazone, and it
is hoped that this will make them much less likely
to cause irreversible damage. The liver toxicity that
has been reported can be very rapid in onset, and
thus patients should be properly cautioned to im-
mediately inform their physician if they become ill
Microvascular complications include retinopa-
thy, nephropathy and neuropathy; the latter also
has other biochemical and structural pathogenesis.
Major randomised controlled trials have proven
that tight glycaemic control is beneficial in reduc-
ing microvascular complications of diabetes melli-
tus. The Diabetes Control and Complications Trial
(DCCT) was a landmark trial that aimed to deter-
mine whether intensive glucose control in type
1 diabetes mellitus reduced diabetic complica-
tions.[11,12] The mean HbA1c reached was 7.2%,
and mean blood glucose level was 155 mg/dl in the
intensive group, with a separation from the stand-
ard treatment group of 1.9% of HbA1c. After an
average follow-up of 7 years, there was an approx-
imately 60% reduction in risk of development or
progression of indicators of diabetic retinopathy,
nephropathy and neuropathy.
The Kumamoto Study[32] was a trial that ran-
domised 110 Japanese patients with type 2 diabetes
mellitus into intensive and conventional groups
and followed them for a mean of 6 years. The mean
HbA1c was 7.1% in the former group compared to
9.4% in the conventional group. After a 6-year fol-
low up, intensive glycaemic control with multiple
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Drugs & Aging 2000 Dec; 17 (6)

Intensive Glycaemic Control in Diabetes Mellitus
467
insulin injections was found to decrease the pro-
gression of retinopathy, (7.7 vs 32%, p = 0.039) and
nephropathy (7.7 vs 28%, p = 0.049). Significant
differences in nerve conduction velocities were
also seen between the two groups. It should be
noted that the patient population in the study was
different from what is usually encountered in the
US. They were younger (40 to 50 years, compared
with the sixth and seventh decade peak prevalence
in the US), leaner [mean body mass index (BMI)
20 kg/m2], more insulin sensitive (about 20 to 25
units/day), and had no hyperlipidaemia, hyperten-
sion or electrocardiogram abnormalities. The num-
ber of cardiovascular events in both groups was
very small (only 5 events or <1%/year), making it
difficult to reach a conclusion from the lack of dif-
ferences in the rate of combined cardiovascular
events in the study.
The results of the Veterans Affairs Cooperative
Study on Diabetes Mellitus (VACSDM) Feasibil-
ity Trial[33] further supported earlier findings that
long term glycaemic control provides a significant
protection against progression of microalbuminu-
ria. 153 patients with poorly controlled type 2 dia-
betes mellitus were randomised into an intensive
arm (HbA1c goal of 4 to 6.1%) and standard arm
(HbA1c goal <2 standard deviations above the
mean) of insulin treatment and followed for an
average of 27 months (range 18 to 35 months). The
mean HbA1c difference of 2.1% was larger than in
other US or European trials.[15]
difference in the deterioration of visual acuity or
blindness. Among the different intensive groups,
no difference in microvascular complication rate
was seen.
Drawbacks of the UKPDS study include the
narrow median HbA1c separation (0.9%) between
the intensive and conventional groups and the
considerable overlap of treatments given to the 2
groups. 702 out of the 1138 patients in the conven-
tional group were eventually given sulphonylurea,
insulin or metformin.
Table II summarises the major randomised stud-
ies comparing intensive versus standard glycaemic
control.
2.2 Macrovascular Complications
Cardiovascular disease is the leading cause of
death in patients with diabetes mellitus, and most
of this is from coronary disease. The lifetime risk
of dying of cardiovascular causes is far higher than
that from end-stage renal disease (fig. 1); in the
UKPDS, it was 70-fold higher.[13] Mechanisms
that have been proposed to cause the worse prog-
nosis in patients with diabetes mellitus include
more severe and diffuse coronary disease,[35-38]
decreased vasodilatory reserve,[39-41] decreased fi-
brinolytic activity,[42,43] elevated platelet aggrega-
tion[44,45] and coagulation factor levels.[46,47] Inde-
pendent risk factors for cardiovascular disease
such as hypertension, hyperlipidaemia and obesity
are also more frequent in patients with diabetes
mellitus and may contribute to the increased car-
diovascular event rate.[48] However, further inves-
tigation is needed because randomised controlled
trials of intensive glycaemic control have failed to
reduce macrovascular complications,[11-14] and ob-
servational and epidemiological studies correlating
the duration of diabetes mellitus and the severity
of hyperglycaemia with cardiovascular morbidity
have shown conflicting results.[3-5,7,15,49,50]
The UKPDS[13] is so far the longest and largest
study of glycaemic control in individuals with type
2 diabetes mellitus. It included 3867 patients with
newly diagnosed diabetes mellitus and with a mean
follow-up of 10 years. Patients were randomised
into intensive treatment with sulphonylurea or in-
sulin or to conventional diet therapy. The intensive
group had a median HbA1c of 7.0% compared to
7.9% in the conventional group. The overall micro-
vascular complication rate was decreased by 25%
(p = 0.001) in the intensive group; the most impor-
tant clinical correlate was a difference of 0.03%
in photocoagulation (9/1000 in the intensive vs
12/1000 in the conventional group). There was no
In the setting of an acute myocardial infarct
(MI), the presence of diabetes mellitus is an inde-
pendent correlate of early and late mortality, with
patients with diabetes mellitus having a rela-
tive risk that is double that of the nondiabetic co-
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Drugs & Aging 2000 Dec; 17 (6)

468
Camacho et al.
Table II. Major randomised studies comparing intensive versus standard glycaemic control in diabetes mellitus
Study
No. of
patients
Average
follow-up (y) separation
(%)
HbA1c
Microvascular complications
Macrovascular complications
Type 1 diabetes mellitus
DCCT[11]
1441
6.5
1.9
Occurrence of retinopathy ↓ 76%
(CI 62-85%)
Progression of retinopathy ↓ 54%
(CI 39-66%)
Reduction in pooled major
cardiovascular and peripheral
vascular events by 41% (not
statistically significant)
Occurrence of microalbuminuria ↓ 39%
(CI 21-52%)
Albuminuria ↓ 54% (CI 19-74%)
Clinical neuropathy ↓ 60% (CI 38-74%)
Type 2 diabetes mellitus
Kumamoto
110
6
2.3
Occurrence of retinopathy ↓ 76%
Progression of retinopathy ↓ 56%
Microalbuminuria ↓ 57%
Number of patients too small to
be statistically significant
Study[32]
Albuminuria ↓ 100%
Improved nerve conduction velocity
Aggregate microvascular end-points ↓
25% (CI 7-40%)
Any diabetes-related end-point risk ↓ 12%
(CI 1-21%)
Decrease in nephropathy
UKPDS[13]
3867
153
10
0.9
2.1
Trend for reduction in MI (p =
0.052) in intensive group
VACSDM[15,33]
2.25
Trend for increase in major
cardiovascular events (p = 0.1)
in intensive group
CI = confidence interval; DCCT = Diabetes Control and Complications Trial; HbA1c = glycosylated haemoglobin; MI = myocardial infarction;
UKPDS = United Kingdom Prospective Diabetes Study; VACSDM = Veterans Affairs Cooperative Study on Diabetes Mellitus; ↓ indicates
decrease.
hort.[51-64] The Global Utilisation of Streptokinase
and Tissue Plasminogen Activator for Occluded
Coronary Arteries (GUSTO) study showed that the
30-day mortality rate for insulin-treated patients
with diabetes mellitus was 12.5%, for non–insulin-
treated patients with diabetes mellitus was 9.7%
and for patients without diabetes mellitus was
6.2% (p < 0.001).[65] Likewise, the mortality rate
for patients admitted with unstable angina is twice
as high in patients with diabetes mellitus compared
with patients without diabetes mellitus.[66]
A recently published meta-analysis of random-
ised studies comparing intensive and conventional
therapies in type 1 diabetes mellitus showed a de-
crease in the number of macrovascular events
(odds ratio 0.55, 95% confidence interval –0.35 to
0.88, p = 0.015) in the intensively treated patients.
However, no significant difference was demon-
strated in the macrovascular mortality rate or the
number of patients who developed macrovascular
disease.[67]
The Swedish Diabetes Mellitus and Insulin
Glucose Infusion in Acute Myocardial Infarction
(DIGAMI) study was an interesting trial that
randomised 620 patients with diabetes mellitus
into a placebo group and a group that received
insulin-glucose infusions during an acute MI.[68-70]
The patients in the latter group were also adminis-
tered more intensive insulin treatment for at least
3 months after discharge, with a resulting HbA1c
difference of only 0.5% (both groups had near nor-
mal HbA1c). The treatment effect was most pro-
nounced in the subgroup of patients who had not
had prior insulin medication and were at lower car-
diovascular risk. The in-hospital mortality was re-
duced by 58% (p < 0.05) and the 1-year mortality
by 52% (p < 0.02). There was a 28% reduction in
the long term mortality rate in the intensively man-
aged group; it appears likely that these results, if
confirmed, are perhaps due to myocardial protec-
tion and reduction of injury in the peri-infarction
period by the subacute insulin-glucose infusion.[68-70]
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Drugs & Aging 2000 Dec; 17 (6)

Intensive Glycaemic Control in Diabetes Mellitus
469
The UKPDS study in newly diagnosed patients
with type 2 diabetes mellitus found no difference
between the intensive and conventional groups in
the combined macrovascular endpoints, but there
was a nonsignificant trend toward fewer nonfatal
myocardial infarctions in the intensive group.[13]
In a separate analysis (UKPDS 34), which studied
the use of metformin in overweight individuals, the
investigators found a 39% lower risk (p = 0.010)
of MI and 41% lower risk of stroke (p = 0.032)
in the metformin group versus conventional treat-
ment.[71] Patients/months exposure to metformin
(81 and 83%) was similar in both arms. Further-
more, compared with the sulphonylurea alone
group, the addition of metformin was associated
with a significantly higher number of fatal MIs and
twice the diabetes-related death and all-cause mor-
tality. Interestingly, microvascular complications
in the metformin substudy were not significantly
different from those in controls. However, the ad-
dition of metformin to sulphonylurea was not part
of the primary randomisation, but rather a late
randomisation of a subset who underwent step-up
therapy. The issue of the safety of this combination
remains an important one, as the largest use of
metformin in the US is in combination with sul-
phonylureas.
In the DCCT trial,[11] there was no statistically
significant effect on macrovascular complications
and this was presumed to be due to the small num-
ber of complications observed and the younger
population in this study of patients with type 1 dia-
betes mellitus. The reduction in the macrovascular
events was primarily due to peripheral vascular
events and not coronary artery events. Afollow-up
study of the DCCT cohort failed to show a rela-
tionship between previous intensive treatment or
HbA1c and carotid wall intimal thickness.[72]
The VACSDM Feasibility Trial of obese pa-
tients with poorly controlled type 2 diabetes mel-
litus found a borderline trend towards increased
nonfatal cardiovascular events in the intensive
treatment arm (35 versus 26 events, p = 0.10).[15]
2.3 Lipids
Dyslipidaemia is seen in 40 to 50% of patients
with diabetes mellitus. The lipid profile is usually
characterised by increased triglycerides, decreased
high-density lipoprotein (HDL) and normal to
moderately increased low-density lipoprotein
(LDL) levels.[73]
The VACSDM study, a feasibility study, pro-
spectively evaluated the effect of intensive insu-
lin therapy on lipid levels. A sustained decrease
in serum triglyceride and total cholesterol levels
was noted and HDL and LDL levels remained un-
changed. However, there was a significant increase
in the LDL-cholesterol/apolipoprotein B ratio,
which is a less atherogenic profile.[74]
The experience of the VACSDM indicates that
the response of the altered lipid profile to inten-
sive glycaemic therapy alone is not sufficient, and
lipid-lowering agents are frequently needed to
achieve the recommended lipid goals for these
patients.[75]
70
60
50
40
30
20
10
0
CV death
ESRD
Fig. 1. Comparative risk of end-stage renal disease (ESRD)
versus cardiovascular (CV) mortality in type 2 diabetes mellitus.
The risk of cardiovascular death represents averages (no effect
of glycaemia). The lifetime risk of end-stage renal disease is at
age 55 years, glycosylated haemoglobin of 11% (data from
Geiss et al.[2] and Vijan et al.[34]).
Some of the newer oral antihyperglycaemic
agents in the US, such as metformin and the thia-
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Drugs & Aging 2000 Dec; 17 (6)

470
Camacho et al.
zolidinediones, are known to improve lipid profile,
increasing HDL and decreasing triglyceride levels.
associated with increased cardiovascular mortal-
ity.[14]
Molecular mechanisms explaining the increased
cardiovascular morbidity with sulphonylureas have
been proposed. Potential adverse effects include
prolonged myocardial refractoriness leading to
dysrhythmias, worsening of vascular reactivity and
induction of vasoconstriction, increase in infarct
size, increase in insulin levels and promotion of
bodyweight gain.[77] There have been studies sug-
gesting an adverse effect on coronary angioplasty
outcomes.[78] However no definitive results are
available and conclusions cannot be made about
the cardiovascular safety of sulphonylureas in ev-
ery situation. In the UKPDS, there was no apparent
adverse cardiovascular effect of sulphonylureas
compared with insulin.[13] Concerns regarding
combination of sulphonylureas and metformin are
discussed in section 2.2.
3. Detrimental Effects and Limitations
of Intensive Glycaemic Control
3.1 Hypoglycaemia
The major limitation of tight glucose manage-
ment is hypoglycaemia, particularly in patients
with type 1 diabetes mellitus. In the DCCT, the risk
of hypoglycaemia was 3-fold higher in the inten-
sively treated group.[11] In the UKPDS, the rates of
any hypoglycaemia were also significantly higher
in the intensive groups (11% in those who received
chlorpropramide, 17.7% glibenclamide, 36.5% in-
sulin compared with 1.2% in those who received
diet alone). The prevalence of severe hypoglycae-
mia was much lower: 0.4% for chlorpropramide,
0.6% for glibenclamide, 2.3% for insulin, 0.1%
for diet,[13] similar to that in the VACSDM.[15] The
feared consequences of hypoglycaemia are numer-
ous, including coma, seizures, strokes and even
heart attacks in the elderly. This association is, how-
ever, seldom documented; and in the VACSDM,
there was no correlation between hypoglycaemic
episodes and new cardiovascular events.[15]
Repeated episodes of even mild hypoglycaemic
episodes may play a role in the development of
hypoglycaemia unawareness.[76] This is a condi-
tion where the threshold for the release of counter-
regulatory hormones and initiation of symptoms is
shifted downwards, manifesting as neuroglyco-
penia and unconsciousness without warning symp-
toms despite low blood glucose levels. Thus, it
is important that the risk of hypoglycaemia be
weighed against the goal of maintaining near nor-
mal blood sugar levels.
3.3 Hyperinsulinaemia and Ischaemic
Heart Disease
The role played by hyperinsulinaemia in the
development of ischaemic heart disease, indepen-
dent of other related risk factors, is still controver-
sial.[79] Studies have shown that insulin has potent
vascular effects, characterised by a dose-dependent
dilation that is mediated by the endothelium-
derived nitric oxide, and that is impaired in insulin-
resistant states.[80] Other effects of insulin on the
arterial wall that may be atherogenic include stim-
ulation of growth factors, proliferation of smooth
muscle cells and interference with plaque regres-
sion.[81] Also, there is evidence for a direct athero-
genic role of insulin via glycation and glycoxi-
dation of proteins and alteration of haemostatic
function.[82]
The results of clinical studies are conflicting.
Fontbonne et al.[83,84] reported that hyperinsulinae-
mia was not associated with an increased risk of
ischaemic heart disease unless accompanied by
increased triglyceride levels. On the other hand,
5 prospective studies have found that elevated
plasma insulin levels are associated with increased
risk of ischaemic heart disease.[49,85-88] The level of
3.2 Cardiovascular Issues with Oral Agents
The University Group Diabetes Program (UGDP)
data, which was published in 1970, was the first
study that raised concerns of increased cardiovas-
cular mortality with sulphonylureas. The agents
used in the study were the sulphonylurea tolbuta-
mide and the biguanide phenformin, and both were
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Drugs & Aging 2000 Dec; 17 (6)

Intensive Glycaemic Control in Diabetes Mellitus
471
fibrinogen, a powerful predictor of cardiovascular
events, has been reported to be increased with
higher insulin levels.[89] In the VACSDM, the
intensive treatment arm showed increased fibrino-
gen levels at 1 year,[74] but this was not correlated
with insulin dose, and the effect reverted by the
second year.
and this can probably be explained by the com-
bined anorectic effect of the drug and the hyper-
insulinaemia that results from sulphonylurea and
insulin treatment. In the VACSDM there was no
difference in bodyweight gain between the inten-
sive and standard treatment arms.[75]
More recent analysis of the DCCT results
showed that the group that gained the most body-
weight also had the greatest increases in insulin
doses, total cholesterol, LDL and apolipoprotein
levels and systolic blood pressure.[97] Similarly, a
recently published epidemiological study analysed
the relationships among bodyweight gain and gly-
caemic control in patients with type 1 diabetes mel-
litus and found that there was a correlation between
HbA1c improvement and bodyweight gain. (r =
–0.21, p < 0.001).[98] Bodyweight gain still re-
sulted in a favourable effect on the lipid profile, if
associated with improved glycaemic control, but
adversely affected it in the absence of glycaemic
improvement.
3.4 Adverse Effects of Rapid
Glycaemic Improvement
Intensive glycaemic control may cause deterio-
ration of pre-existing retinopathy[90] as well as pro-
teinuria[91] in type 1 diabetes mellitus. These phe-
nomena have also been reported in patients with
type 2 diabetes mellitus.[92] On the other hand, the
VACSDM found no statistically significant deteri-
oration of retinopathy after 2 years of intensive in-
sulin treatment,[93] and in fact showed a reduction
of the progression of microalbuminuria.[33] How-
ever, the intensive treatment arm displayed a
slightly higher reduction of creatinine clearance
than the conventional treatment arm. Furthermore,
the appearance of combined new cardiovascular
events had a borderline statistical correlation (p =
0.05) with low attained HbA1c levels at the time of
the event.[15] It is not clear what factors affect these
potential adverse effects of glycaemic improve-
ment; a possible role of insulin-like growth factor-
1 in the aggravation of retinopathy[94] and de-
stabilisation of glycated products in the vascular
plaques by glucose lowering in microangiopathy
have been proposed.[95]
3.6 Quality of Life
To achieve intensive glucose control, the use of
multiple daily injections and insulin pumps in pa-
tients with type 1 diabetes mellitus, and multiple
oral agents alone or in combination with insulin in
patients with type 2 diabetes mellitus, may be nec-
essary. These require more frequent blood sugar
monitoring, and regular blood tests for the thia-
zolidinediones. Stricter dietary management, to
which some patients find difficult to adhere, is also
advised to prevent bodyweight gain. Nonetheless,
quality of life assessments in prospective studies
indicate favourable profiles with intensive treat-
ment in type 1[12] and type 2[99] diabetes mellitus.
3.5 Bodyweight Gain
Bodyweight gain is a potential consequence of
intensive glycaemic control. In the DCCT, the in-
tensively treated group had a 14% higher preva-
lence of obesity (BMI >27.8 kg/m2 for men and
>27.3 kg/m2 for women) than the conventional
group.[96] The UKPDS found that bodyweight gain
was also significantly higher in the intensive
groups (mean of 2.9kg, p < 0.001), being highest
in those who received insulin (4kg).[13] In patients
who were overweight, metformin resulted in less
bodyweight gain than insulin and sulphonylureas
4. Who Will Benefit from Intensive
Glycaemic Control?
As discussed, the benefits of intensive glycae-
mic control are always accompanied by potential
risks. In elderly individuals with type 2 diabetes
mellitus, the question arises as to how aggressive
glycaemic management should be. Vijan et al.[34]
calculated the lifetime risk of clinical microvascu-
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Drugs & Aging 2000 Dec; 17 (6)

472
Camacho et al.
HbA1c
lar end-points, applying to type 2 diabetes mellitus
the rate of progression in the patients with type 1
diabetes mellitus who were involved in the DCCT.
These calculations are a ‘worst case’ scenario.
They do not take into consideration the 90% visual
sparing effects of yearly ophthalmological exami-
nations,[100] now a standard of care. They also do
not take in account the highly protective effect of
blood pressure control. The risk of developing end-
stage outcomes were highest in those who devel-
oped diabetes mellitus at a younger age and those
who had poor glucose control, and thus the most
marked benefit was observed in this group (figures
2 to 4).
5
4
3
2
1
0
7%
8%
9%
10%
11%
45
55
65
75
Age at diagnosis (years)
Fig. 3. Estimated lifetime risk of end-stage renal disease in pa-
tients with type 2 diabetes mellitus according to glycosylated
haemoglobin (HbA1c) level (data from Vijan et al.[34]).
For example, figure 2 shows that in patients who
develop diabetes mellitus at 45 years of age, a 2%
improvement in HbA1c from 9 to 7% results in a
2.3% decrease in lifetime risk of blindness, com-
pared to only a 0.5% decrease in those who devel-
oped diabetes mellitus at the age of 65 years.[34] For
renal disease, the lifetime risk of end-stage renal
disease was decreased by 1.5% in the 45-year-old
group compared to 0% in the 75-year-old group
when HbA1c was improved from 9 to 7% (fig. 3).
Thus, the management of elderly patients with
type 2 diabetes mellitus, particularly those already
with multiple complications, may be different from
that of younger patients. The potential cardiovas-
cular benefit of glycaemic control remains un-
proven, but possible, since cardiovascular mortal-
ity correlates with glycaemia in the elderly.[50] Poor
glycaemic control, i.e. an HbA1c above 8%, is prob-
ably undesirable at any age, and the need for at least
moderate glycaemic control in the elderly is rec-
ommended by the 2000 ADA guidelines.[16]
5. Other Aspects of the Management
of Diabetes Mellitus
It is important to remember that the manage-
ment of diabetes mellitus should go beyond blood
glucose control. Other risk factors, such as hyper-
tension and hyperlipidaemia, are possibly more im-
portant, and should be as aggressively managed.
In contrast with the marginal clinical outcomes
of glycaemic control in the UKPDS, improvement
of hypertension in that study, by 10 and 5mm Hg
systolic and diastolic, respectively, caused a 34%
reduction in risk of deterioration of retinopathy,
47% reduction in risk of deterioration of visual
acuity, 44% reduction in risk of stroke and 32%
reduction in cardiovascular mortality.[101] A target
blood pressure of <130/85mm Hg and systolic
blood pressure of <160mm Hg is recommended by
the ADA, although this may not be easily achiev-
able.[16] Combination antihypertensive therapy is
HbA1c
8
7
6
5
4
3
2
1
0
7%
8%
9%
10%
11%
45
55
65
75
Age at diagnosis (years)
Fig. 2. Estimated lifetime risk of blindness in patients with type
2 diabetes mellitus according to glycosylated haemoglobin
(HbA1c) level (data from Vijan et al.[34]).
© Adis International Limited. All rights reserved.
Drugs & Aging 2000 Dec; 17 (6)

Intensive Glycaemic Control in Diabetes Mellitus
473
frequently utilised to try to achieve or maintain
these goals. Dyslipidaemia in patients with dia-
betes mellitus has been proven to increase the
risk of complications, and the results of manage-
ment of lipid disorders in diabetic subsets have
shown a significant reduction of macrovascular
events.[102-104] It is recommended that LDL should
be lowered to <100 mg/dl and triglycerides to <200
mg/dl.[17]
Screening for nephropathy should be performed
annually, and if there is evidence of microalbu-
minuria (>30 mg/g of creatinine) in type 1 diabetes
mellitus, or clinical proteinuria in type 2 diabetes
mellitus, ACE inhibitor therapy should be initi-
ated.[16] This class of antihypertensives is known
to delay the progression of diabetic nephropathy
and is usually the first choice for hypertension in
the diabetic population, even if microalbuminuria
is not present. However the UKPDS showed no
advantages in using captopril over atenolol, imply-
ing that blood pressure lowering in itself may be
more important than the treatment used.[105]
Studies have proven the benefit of aspirin (ace-
tylsalicylic acid) therapy,[72,106] and the ADA ad-
vises those persons with diabetes melllitus who are
above the age of 30 years to take an aspirin a
day.[16]
Lastly, preventive care, such as annual eye ex-
aminations, foot care and immunisations, are
equally important in the management of the patient
with diabetes mellitus.
6. Conclusion
Intensive glycaemic control has been shown to
decrease the microvascular complications of dia-
betes mellitus. The effect on macrovascular dis-
ease is not established, although there is some sup-
porting preliminary evidence for a favourable
effect of intensive glycaemic control in the litera-
ture. Additional beneficial effects of intensive
glycaemic control include modest improvement
of lipid profiles. Detrimental effects include body-
weight gain, the risk of hypoglycaemia and the
unproven risk of cardiovascular morbidity and
mortality from hyperinsulinaemia and sulphonyl-
ureas. It is thus recommended that the benefits of
intensive glycaemic control be weighed against
the risks, and appropriate therapy to meet specific
goals be tailored to the needs of the individual
patient.
In the US, a Department of Veterans Affairs’
7-year prospective study of glycaemic control and
complications in type 2 diabetes mellitus began in
July 2000. This study aims to clarify whether the
benefits of glycaemic control outweigh the risks in
a population already poorly responsive to conven-
tional therapy and who have an expected high prev-
alence of pre-existing cardiovascular disease, obe-
sity and insulin resistance.[107,108] A separate trial
is being proposed by the Heart, Lung and Blood
Institute of the National Institutes of Health to in-
vestigate the benefits of intensification of blood
pressure and lipid control beyond current recom-
mendations; in a factorial design, these will be
compared to the benefits of intensification of
glycaemic control alone in patients not yet treated
with insulin. Both North American studies comple-
ment each other and are likely to answer therapeu-
tic questions not yet resolved.
Reduction in HbA1c
3
8 to 7%
9 to 8%
10 to 9%
11 to 10%
2
1
0
45
55
65
75
Age (years)
Fig. 4. Absolute reduction in risk of blindness with 1% reduction
in glycosylated haemoglobin (HbA1c) level (data from Vijan et
al.[34]).
© Adis International Limited. All rights reserved.
Drugs & Aging 2000 Dec; 17 (6)

474
Camacho et al.
20. Zinman B. Insulin regimens and strategies for IDDM. Diabetes
Care 1993; 16 Suppl. 3: 24-8
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Correspondence and offprints: Dr Carlos Abraira, Research
Service (151), Miami Veterans Affairs Medical Center, 1201
N.W. 16th Street, Miami, FL 33146, USA.
E-mail: Cabraira@med.miami.edu
© Adis International Limited. All rights reserved.
Drugs & Aging 2000 Dec; 17 (6)