Artigo comparando drogas orais x insulina em DM2, mostra efeitos positivos da insulina sobre a dislipidemia, diferente de pesquisas em animais.

1. Effects of insulin and other antihyperglycemic agents on lipid profiles of patients
with diabetes
Ajay Chaudhuri & Paresh Dandona
Millard Fillmore Hospital, Buffalo, New York
Running Title: Glycemic Control and Lipid Profiles in Diabetes
Correspondence to:
Dr Ajay Chaudhuri
Millard Fillmore Hospital
3 Gates Circle
Buffalo, NY 14209
Phone: 716-887-4523
E-mail: achaudhuri@KaleidaHealth.org
This is an Accepted Article that has been peer-reviewed and approved for publication in the
Diabetes, Obesity and Metabolism, but has yet to undergo copy-editing and proof correction.
Please cite this article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01423.x
1

2. ABSTRACT
Increased morbidity and mortality risk due to diabetes-associated cardiovascular diseases
is partly associated with hyperglycemia as well as dyslipidemia. Pharmacologic treatment
of diabetic hyperglycemia involves the use of the older oral antidiabetic drugs (OADs:
biguanides, sulfonylureas, alpha glucosidase inhibitors and thiazolidinediones), insulin
(human and analogs), and/or incretin-based therapies (glucagon-like peptide-1 analogs
and dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested to
improve lipid profiles in patients with diabetes. These effects may have benefits on
cardiovascular risk beyond glucose-lowering actions. This review discusses the effects of
OADs, insulins, and incretin-based therapies on lipid variables along with the possible
mechanisms and clinical implications of these findings. The effects of intensive vs.
conventional antihyperglycemic therapy on cardiovascular outcomes and lipid profiles
are also discussed. A major conclusion of this review is that agents within the same class
of OADs can have different effects on lipid variables and that contrary to the findings in
experimental models, insulin has been shown to have beneficial effects on lipid variables
in clinical trials. Further studies are needed to understand the precise effect and the
mechanisms of these effects of insulin on lipids.
2

3. Introduction
Diabetes confers an increased risk of morbidity and mortality due to cardiovascular
disorders [1,2], which appear to some degree related to glycemic control [3-5]. Patients
with type 2 diabetes mellitus (T2DM) tend to be dyslipidemic [6], and quantitative and
qualitative lipid abnormalities have been observed in individuals with prediabetes who
were identified and followed prospectively prior to clinical presentation of T2DM [7].
Lipid abnormalities associated with T2DM include high serum triglyceride (TG) levels, a
high proportion of small dense low-density lipoprotein (LDL) particles [6], a high
number of TG-enriched, very-low-density lipoprotein (VLDL) particles [8], and low
high-density lipoprotein cholesterol (HDL-C) levels [6,7], as well as glycation of
apolipoproteins and increased LDL oxidation, both of which contribute to foam-cell
formation [9].
Among US adults who have been diagnosed with diabetes, 55.7% achieve the American
Diabetes Association (ADA)–recommended glycated hemoglobin A1C (HbA1c) target of
<7.0% (International Federation of Clinical Chemistry and Laboratory Medicine
units[10-12]: 53 mmol/mol), fewer than 40% achieve the blood pressure goal of <130/80
mm Hg, and only 27.4, 36.0, and 65.0% are in the low-risk categories for HDL-C (>1.17
mmol/l for men, >1.42 mmol/l for women), LDL-C (<2.59 mmol/l) and TGs (<2.26
mmol/l), respectively [13,14]. Thus, patients with T2DM who do not achieve the targets
outlined by clinical practice recommendations may have the greatest risk for
cardiovascular disease. Adherence to treatment can perhaps account for some of the
3

4. discrepancies in goal achievement; however, many patients may also remain uncontrolled
because they require a greater reduction in lipid measurements [15,16].
Given the connections between glucose and lipid metabolism and the negative
cardiovascular consequences of dyslipidemia in patients with T2DM, this review will
explore the impact of treatment with oral antidiabetic drugs (OADs), insulins, and
incretin-based therapies on the lipid profiles of patients with diabetes and discuss possible
mechanisms and clinical implications. In addition, the effects of intensive vs.
conventional antihyperglycemic therapy on cardiovascular outcomes and lipid profiles
also will be discussed.
Methods
Randomized clinical trials (RCTs) examining the effects of the antidiabetic agents on
lipid levels in adult patients with T2DM were identified using a PubMed search with key
search terms, such as lipoprotein profile, lipids, cholesterol, TGs, free fatty acids (FFAs)
and cardiovascular combined with insulin analogs, insulin, NPH, insulin glargine, insulin
detemir, alpha glucosidase inhibitors, sulfonylurea, glucagon-like peptide-1 (GLP-1),
incretin, exenatide, liraglutide, dipeptidyl peptidase 4 (DPP-4), metformin, rosiglitazone,
and pioglitazone. Additional searches were conducted for specific studies, including
Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and
Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation
(ADVANCE), United Kingdom Prospective Diabetes Study (UKPDS), Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and Complications
4

5. (DCCT/EDIC) and Veterans Affairs Diabetes Trials (VADTs). Studies reporting lipid
variables were selected if the changes in lipid variables from baseline to endpoint and
between comparators (ie insulin vs. an OAD) were reported in the abstract or as
secondary efficacy measurements. Studies were also identified using review (including
systematic reviews) articles and meta-analyses comparing the efficacy of various
antidiabetic agents. Only human studies published in English were considered. We did
not limit the search to a specific range in years since some antidiabetic agents have been
available for several years. We acknowledge the limitation of using this strict criterion to
select studies and the possibility that we may have overlooked studies reporting lipid
variabes only in the text of the published manuscript.
Oral Agents and Lipid Profile
Metformin
OADs are the first line of therapy for patients with T2DM [17]. The effect of treatment
with OADs on lipids in patients with T2DM is variable (table 1) [18-21]. Metformin—
either as monotherapy or in combination with a sulfonylurea—has generally shown
positive effects on lipid variables in patients with T2DM, including reduced fasting total
cholesterol (TC), TG and LDL-C levels and increased HDL-C [19,22,23].
In patients with T2DM previously treated with diet alone, DeFronzo et al reported that
metformin significantly reduced TC, LDL-C, and TG levels after 29 weeks of therapy vs.
placebo in moderately obese individuals [19]. Patients previously treated with diet plus
glibenclamide (glyburide) also showed significant improvement in these lipid
5

6. measurements when metformin was given as monotherapy in place of glyburide or was
added to existing glyburide therapy, compared with patients who continued taking
glyburide as monotherapy. In both patient groups in this study, changes in HDL-C levels
were not significant [19]. The same was true in a study by Dailey and coworkers [18],
who found significant reductions in TC, LDL-C, and TG levels but little change in HDL-
C levels in patients with diabetes who had been treated with glyburide and metformin. A
systematic review and meta-analysis of up to 38 randomized controlled trials (which
included DeFronzo et al. but not Dailey et al.) reported that, when compared with
controls, metformin therapy significantly decreased plasma TGs (-0.13 mmol/L, p =
0.003), TC (-0.26 mmol/L, p < 0.0001), and LDL-C (-0.22 mmol/L, p < 0.0001).
Nonsignificant increases in HDL-C also were observed (0.01 mmol/L, p = 0.50) [22].
Similar reductions in TC and LDL-C for metformin compared with placebo (p = 0.021
and p = 0.018, respectively) were reported by Lund and coworkers in patients with type 1
diabetes mellitus (T1DM) [24]. Metformin has also been shown to reduce HbA1c and
lipid measures in nonobese patients with T2DM. In a study with 96 randomized patients
with baseline BMI of 24.8 kg/m2, metformin significantly (p < 0.05) reduced fasting and
postprandial levels of plasma TC, LDL-C, and non-HDL-C in addition to the significant
reductions in plasma glucose [25]. These results suggest that the effects of metformin on
lipid profiles are independent of body weight. Metformin has also been shown to
significantly lower LDL-C levels in patients with impaired glucose tolerance [26].
The mechanisms by which metformin exerts its effect on lipoprotein profiles is not fully
understood. However, studies have suggested that metformin increases the activation of
6

7. AMP-activated protein kinase (AMPK), which leads to the inactivation of acetyl-CoA
carboxylase [27,28]. Stimulation of AMPK increases glucose uptake in muscle while also
inhibiting hepatic glucose production, cholesterol and TG synthesis, and lipogenesis [28].
In vitro studies also have shown that metformin suppresses the transcription factors that
encode lipogenic enzymes [27].
Alpha glucosidase inhibitors
Changes in lipids have also been observed for alpha glucosidase inhibitors (table 1).
These agents inhibit the action of enzymes that reside in the brush border enterocytes of
jejunum that serve to break down complex carbohydrates [29]. Therefore, alpha
glucosidase inhibitors slow the intestinal breakdown of ingested complex carbohydrates
into simpler carbohydrates, such as sucrose and glucose. Consequently, the availability of
postprandial glucose in the plasma is reduced and delayed [29,30]. A 4-week study by
Matsumoto et al. reported that administration of the alpha glucosidase inhibitor voglibose
alone or with a sulfonylurea in 14 patients with T2DM significantly reduced TG from
baseline (p < 0.01); TC levels also were reduced, but not significantly [31]. Another
study that included 31 patients showed that after 24 weeks of treatment, acarbose reduced
TG, TC and LDL-C levels and slightly increased HDL-C [32]. These somewhat different
results were also noted in a systematic review by Buse et al. Of the 3 alpha glucosidase
inhibitors examined in their review (voglibose, acarbose, and miglitol), voglibose
reduced TGs and acarbose reduced LDL-C. No consistent effects on any other lipid
variables were identified [33]. Comparing acarbose to sulfonylurea in a systematic
review, Bolen et al. reported that sulfonylurea reduced LDL-C better than acarbose and
7

8. the effects of the 2 agents on TGs were similar. However, effects of acarbose on HDL-C
was better than that of sulfonylurea [34]. Both systematic reviews examined the effects
of other OADs on glycemic and lipid variables as well [33,34]. Lipid data obtained from
the STOP-NIDDM trial failed to demonstrate an effect of acarbose on total cholesterol,
HDL-C, LDL-C, or TG in patients with impaired glucose tolerance [35].
Sulfonylurea
Data regarding the effects of sulfonylurea therapy on lipid measurements are less clear
(table 1). In a systematic analysis of published research, Buse et al. showed a wide
variation in the effects of gliclazide on lipid variables. In their analysis, significant
reductions in TC from baseline were reported in some studies with durations of 3 months
(p < 0.05) and 3 years (p < 0.0001), but not in other studies of 3-month, 24-week, or 2-
year duration. Significant reductions in TG from baseline also were observed in studies
lasting 3 months, 2 years, and 3 years, but not in another 3-month study nor in a 24-week
study [33]. Some clinical studies in patients with T2DM have indicated a beneficial effect
of sulfonylurea therapy on fasting TC and TG levels [23]. However, a small study of
Japanese patients with T2DM poorly controlled on diet alone, who were treated for 6
months with glyburide or pioglitazone monotherapy, showed no significant effect of
glibenclamide on measures of insulin resistance or TG, HDL-C, or adiponectin levels
[36]. This is in contrast to the results of a study by Araki et al, in which a different
sulfonylurea—glimepiride—was shown to significantly increase adiponectin and HDL-C
levels (p = 0.041) in all T2DM patients in the study, particularly in patients with low
pretreatment adiponectin levels (p = 0.011) [37]. The authors attributed this effect to the
8

9. dual activity of glimepiride as a potent peroxisome proliferator–activated receptor
(PPAR)–γ agonist as well as insulin secretagogue [37]. PPARs are transcription factors
belonging to the nuclear receptor superfamily [38]. The PPAR-γ receptors are found in
adipose tissue, skeletal muscle, vascular tissue, and in the pancreas. Activation of the
PPAR-γ is thought to normalize glucose uptake and to increase the expression of insulin
receptors. PPAR- γ receptor activation also may lower triglyceride levels by increasing
the clearance of fatty acids in adipose tissue [38].
Thiazolidinediones
The case of thiazolidinediones (TZDs) is complicated by the observation that
pioglitazone and rosiglitazone, while having similar effects on glycemic control, seem to
show marked differences in their effects on lipid metabolism. Although rosiglitazone
(added to existing OAD therapy in patients with T2DM) decreased postprandial TG and
FFA levels compared with placebo in an 8-week crossover study, it had no effect on
fasting TG levels and actually increased fasting TC and LDL-C levels [39]. In contrast,
pioglitazone has been shown to increase HDL-C levels and decrease fasting and
postprandial TG levels [23]. The Prospective Pioglitazone Clinical Trial in
Macrovascular Events (PROactive) Study showed that pioglitazone (added to other OAD
therapy) reduced TGs compared with placebo (median percent change –11.4
[interquartile range, –34.4 to 18.3] and 1.8 [–23.7 to 33.9], respectively, p < 0.0001;
median baseline for both groups 1.8 mmol/l [interquartile range 1.3 to 2.6]). In addition,
HDL-C increased (median percent change 19.0 [6.6 to 33.3] and 10.1 [–1.7 to 21.4], p <
0.0001; median baseline for both groups 1.1 mmol/l [0.9 to 1.3]). Despite a small
9

10. increase in LDL-C levels, there was an overall significant decrease in the LDL-C:HDL-C
ratio (median percent change –9.5 [–27.3 to 10.1] and –4.2 [–21.7 to 15.8], respectively;
p < 0.0001) [40]. Pioglitazone has also been shown to increase HDL-C levels and
decrease triglycerides in patients with impaired glucose tolerance [41].
These differences between rosiglitazone and pioglitazone regarding their impact on lipid
profiles have been confirmed in studies directly comparing the two TZD agents when
added to sulfonylurea therapy. Derosa and colleagues [20] found that combination
treatment with glimepiride and pioglitazone resulted in significant reductions in TC,
LDL-C, and TGs, as well as in an increase in HDL-C in patients with T2DM and
metabolic syndrome; however, treatment with glimepiride and rosiglitazone induced
significant increases in TC, LDL-C, and TG levels. In addition, a study by Chogtu et al
comparing the combination of glimepiride with either pioglitazone or rosiglitazone also
reported that TC, TG, and LDL values significantly improved in patients receiving the
pioglitazone/glimepiride combination (p = 0.004, p = 0.002 and p = 0.005, respectively)
vs. the rosiglitazone/glimepiride combination [42].
The differences in lipoprotein effects between pioglitazone and rosiglitazone may be
related to the differences in their mechanism of action. Pioglitazone and rosiglitazone are
potent PPAR ligands, specifically for the gamma (γ) receptor subtype. Pioglitazone,
however, also likely has PPAR-α agonistic effects; the PPAR-α receptor has an important
role in lipid metabolism and mediates the lipid lowering effects of fibrates [38,43-46].
Pioglitazone is thought to increase the expression of lipoprotein lipase mediated by
10

11. activation of the PPAR-α receptor, which may explain the differences in pioglitazone’s
effects on lipid profiles compared with rosiglitazone. Lipoprotein lipase is an enzyme that
facilitates the decomposition of plasma-derived triglyceride-rich lipoproteins into FFAs.
Consequently, increasing the expression of lipoprotein lipase would increase lipoprotein
breakdown. The enzyme is expressed in many tissues, including skeletal muscle and
adipose tissue [47]. Like PPAR-γ, PPAR-α receptors are found in adipose tissue, skeletal
muscle, and in vascular tissue; however, PPAR-α receptors also are located in the liver,
whereas PPAR-γ receptors are not [38,43-46]. Thus, the activation of PPAR-α receptors
in the liver also may help to explain the similarities in the lipid-lowering effects between
pioglitazone and fibrates.
Incretin-Based Therapies
GLP-1 analogs
The injectable GLP-1 receptor agonist, exenatide, also has been studied for its effect on
cardiovascular risk factors (table 2). Patients with T2DM from 3 trials were enrolled into
1 open-ended, open-label clinical trial and were randomized to twice-daily injections of
placebo or 5 or 10 μg of exenatide. In a subset of patients who were exposed to exenatide
for 3.5 years (n = 151), there was a decrease in TGs (12%, p < 0.0003), TC (5%, p =
0.0007), LDL-C (6%, p < 0.001), and an increase in HDL-C (24%, p < 0.0001; all
compared with placebo) [48]. The addition of exenatide to insulin for 26 weeks has been
shown to significantly reduce TGs by 26.0% (p = 0.01) and TC by 8.6% (p = 0.03) from
baseline [49]. When stratified by baseline HbA1c level, significant reductions in TGs of
22.4% were observed in patients with HbA1c >6.5% (48 mmol/mol) and of 33.8% (p =
11

12. 0.09, NS) in patients with HbA1c ≤6.5% (48 mmol/mol) [49]. The lipid effects of
exenatide also are thought to be due to activation of PPAR-α [50]. Although the specific
mechanisms by which incretins affect lipoprotein profiles are incompletely understood,
the actions of incretins and DPP-4 inhibitors involve promoting adipose triacylglycerol
catabolism and attenuating postprandial triacylglycerol secretion [51].
Liraglutide is a human GLP-1 analog that has 97% homology to the native GLP-1
[52,53]. The structural differences between liraglutide and GLP-1 limit DPP-4
degradation of liraglutide [53]. In a study evaluating three doses of liraglutide (0.65-,
1.25,- or 1.90-mg) therapy, only the highest and lowest doses resulted in significant
reduction of TG levels compared with placebo (p = 0.011 and p = 0.0304, respectively) in
patients with T2DM [54]. It should be noted that these doses are slightly higher than the
‘standard’ therapeutic doses of 0.6, 1.2, and 1.8 mg [55]. As with many other
medications, liraglutide is often combined with other antidiabetic agents. As part of the
Liraglutide Effect and Action in Diabetes (LEAD) program, treatment combining
metformin and a TZD with liraglutide led to significant mean (± standard error)
reductions vs. placebo in TGs (–0.38 ± 0.10 mmol/l), LDL-C (–0.28 ± 0.07 mmol/l), and
FFAs (–0.03 ± 0.02 mmol/l) (p < 0.05 for all) [56]. A 26-week, randomized, open-label
study in adult patients with T2DM, the LEAD-6 study reported that liraglutide therapy
significantly reduced TGs (p = 0.0485) and FFAs (p = 0.0014) compared with exenatide
[52]. Total cholesterol and LDL-C were reduced as well following liraglutide treatment
compared with exenatide, but these differences were not significant. Interestingly, the
LEAD-6 study also reported that VLDL-C increased from baseline to week 26, which
12

13. was significantly higher for patients given exenatide vs liraglutide (p = 0.0277) [52].
However, as Friedewald et al. has explained, the concentration of VLDL-C in relation to
TG is relatively constant at about 5:1 in normal individuals and patients with high
lipoprotein levels [57]. Thus, any change in VLDL-C should be in the same direction
(positive or negative) relative to changes in TG. Consequently, the significant decrease in
TG should also have reflected a decrease in VLDL as well. Although not addressed in the
LEAD-6 paper, this apparent discrepancy could be related to differences in the
methodology for VLDL-C assessment.
Although development has currently been postponed, taspoglutide therapy has shown
promising reductions in baseline lipid variable levels including TC, LDL-C, and TGs
[58]. The greatest reductions in TGs (-58 mg/dL) were seen in the group given 20 mg
taspoglutide once weekly. Also reported was a trend for minimal decrease of HDL-C
over an 8-week treatment period [58]. In a 16-week study, Rosenstock et al. reported that
albiglutide therapy administered weekly, biweekly, or monthly did not significantly affect
lipid measurements [59].
DPP-4 inhibitors
Vildagliptin, sitagliptin, and saxagliptin are selective inhibitors of the DPP-4 enzyme that
result in increased levels of GLP-1. In patients with T2DM, vildagliptin reduced
postprandial total plasma TG levels (between-group difference –3.1 ± 1.2 mmol/l • h
[mean ± SD], p = 0.011; baseline for vildagliptin group 6.1 ± 1.1 mmol/l • h; baseline for
placebo group 6.2 ± 0.6 mmol/l • h) and chylomicron cholesterol (between-group
13

14. difference –0.13 ± 0.05 mmol/l • h, p = 0.020; baseline for vildagliptin group 0.20 ± 0.06
mmol/l • h; baseline for placebo group 0.22 ± 0.05 mmol/l • h) when compared with
placebo but had no significant effect on VLDL and intermediate-density lipoprotein
(IDL) TG and total plasma cholesterol [60]. Treatment with sitagliptin also has been
reported to have a differential effect on lipid levels. Compared with glipizide, treatment
with sitagliptin led to a significant increase in HDL levels from baseline (3.7 vs. 1.2%,
respectively; least squares mean change from baseline, 95% confidence interval [CI] =
2.5% [0.6, 4.3]). However, no other between-group differences were observed for any
other measured lipid variable [61]. Interestingly, although numerical differences have
been reported, treatment with saxagliptin has not been shown to significantly or clinically
affect lipid levels in patients with T2DM [62-65].
In a retrospective analysis of electronic medical records in patients with T2DM, Horton et
al examined the relationship between weight loss, glycemic control and changes in lipid
measurements following exenatide, sitagliptin, or insulin therapy (the specific type of
insulin—analog or human—was not noted) [66]. Not surprisingly, the patients initiating
exenatide lost more weight (–3.0 ± 7.33 kg) compared with those initiating sitagliptin (–
1.1 ± 5.39 kg), whereas patients initiating insulin gained weight (0.6 ± 9.49 kg).
Glycemic variables, including HbA1c and fasting blood glucose, improved in all three
treatment groups. Lipid variables, including TGs, LDL-C, and TC, also improved in all
three treatment groups (tables 2 and 3), with patients receiving insulin experiencing the
greatest reductions. However, HDL was relatively unchanged. For the patients initiating
exenatide, the improvements in TGs, LDL and TC were significantly associated with the
14

15. changes in weight (p = 0.007, p = 0.005, and p < 0.001, respectively). For patients
initiating sitagliptin, weight changes were significantly related to improvements in TGs
(p = 0.001) and TC (p < 0.001), whereas for insulin a significant relationship was found
between weight increase and TC reduction (p = 0.02) [66]. Thus, despite the increased
weight gain, insulin therapy was associated with greater glycemic and lipid lowering
benefits than exenatide or sitagliptin.
Insulin and Lipid Profile
In many patients with T2DM, insulin replacement is necessary. Insulin also has been
shown to affect lipid variables, and studies examining the mechanisms of action of
several of these medications point to links between glucose and lipid metabolism that
could explain such effects. For example, as a potent activator of lipoprotein lipase, insulin
plays an important role in the regulation of lipid metabolism [9]. Insulin suppresses the
production of TGs and VLDL by hepatocytes in vitro [67,68] and in vivo [69,70] and
promotes LDL clearance [71,72]. Insulin also produces a 2.3-fold increase in adipose
tissue lipoprotein-lipase activity (p < 0.001) [73] and, therefore, would be expected to
have a significant effect on lipid metabolism in patients with T2DM. Insulin also is
known to promote Apo lipoprotein A and HDL biosynthesis by hepatocytes, in vitro
[74,75]. Insulin suppresses lipolysis and prevents the release of FFAs from adipose
tissue. In addition, it increases the clearance of FFAs from plasma. These actions of
insulin are consistent with the increases in TG and FFA levels in the insulin-resistant
states of obesity and T2DM. These actions also indicate that the administration of insulin
and insulin sensitizers in insulin-resistant states could reduce plasma TG and FFA
15

16. concentrations. Although studies in experimental models have suggested that
hyperinsulinemia stimulates the activation of enzymes involved in de novo lipogenesis
and, thus, may result in increased TG accumulation in the liver and availability for VLDL
production [76], we have not found any evidence of such an effect in human studies.
Intensive insulin therapy using long-acting insulin and prandial coverage with either
regular insulin or insulin lispro resulted in significant decreases in TC levels and LDL-
C:HDL-C ratio (p < 0.05 vs. baseline for both) in patients with T1DM (N = 10) in a small
study [77]. Alterations in 2-hour postprandial VLDL composition were improved after
administration of regular insulin and completely normalized after administration of
insulin lispro (p < 0.05). Despite small differences in effect observed with the two
prandial insulins, both types of insulin were associated with similar improvements in
lipoprotein metabolism. In the DCCT (N = 1441), the 42% reduction in risk of a
macrovascular event experienced by patients in the intensive-treatment group was
associated with significant reductions in lipid-related macrovascular risk factors only in
the secondary-treatment cohort, which had a longer duration of disease at baseline
compared with the primary cohort (8.8 vs. 2.6 years) and, thus, a longer exposure to the
atherogenic environment of diabetes [78]. There was a significant reduction in TC, LDL-
C, and TG levels in the intensive-treatment group (p ≤ 0.01) and a reduction in the
development of LDL-C levels >4.1 mmol/l.
In clinical trials, patients with newly diagnosed or inadequately controlled T2DM
experienced improvements in lipid profile following the initiation of insulin therapy
16

17. (table 3). Amongst the earliest observations of the lipid lowering effects of insulin
therapy, Agardh and colleagues [79] reported significant decreases in TC (10%, p <
0.01), LDL-C (8%, p < 0.05), and TG levels (40%, p < 0.05), as well as increased HDL-C
levels (12%, p < 0.01) in patients with T2DM (N = 26) following 3 to 4 months of insulin
therapy. In a separate study, treatment with NPH insulin at bedtime for 16 weeks resulted
in significant improvements in TC (p < 0.002), LDL-C (p < 0.01), VLDL-C (p < 0.01),
and TG (p < 0.01) levels, as well as HDL-C:TC ratio (p < 0.001) and HDL-C:LDL-C
ratio (p < 0.01) in obese men with T2DM (N = 12) [80]. In the Veterans Affairs
Cooperative Study in Diabetes Mellitus [81], patients with T2DM (N = 153) who
received intensive insulin therapy (target HbA1c 4.0 to 6.1% [20 to 43 mmol/mol] ) or
standard insulin therapy (target HbA1c <13.0% [119 mmol/mol]) experienced significant
improvements in lipid levels. After 2 years of treatment, TG and TC levels were
significantly decreased (p = 0.03 and p = 0.06, respectively) in the intensive-treatment
group. Patients in the standard-treatment group had a significant decrease in LDL-C (p =
0.02). The LDL-C to apolipoprotein B ratio increased significantly in both treatment arms
(p < 0.001 and p < 0.003, respectively), suggesting an increase in larger, less dense, less
atherogenic particles. Intensive insulin treatment was found to reduce TG and TC levels
and increase HDL-C levels in a study of 18 patients with T2DM. However, abnormalities
in lipoprotein surface constituents and core lipids persisted after intensive insulin therapy
despite normalization of plasma lipid levels [82].
In studies in which patients have achieved HbA1c targets of approximately 7.0% (53
mmol/mol), insulin has been shown to positively affect lipoprotein values as well. In the
17

18. LANMET study of 110 insulin-naïve patients with T2DM, both insulin glargine plus
metformin and NPH insulin plus metformin significantly reduced TG (p < 0.001) and
increased HDL-C (p < 0.02), but failed to affect LDL -C after 9 months of treatment [83].
In a study comparing the effects of insulin and sulfonylurea (glibenclamide) therapy in
patients achieving similar glucose control, Romano et al. demonstrated that insulin
therapy results in significantly greater reductions in TG (0.9 ± 0.1 vs. 1.1 ± 0.1 mmol/l,
respectively, p < 0.05), VLDL (50.1 ± 12.2 vs. 63.6 ± 12.3 mg/dl, p < 0.02), and
increased HDL-C (25.2 ± 1.6 vs. 20.3 ± 1.3 mg/dl, p < 0.03) [84]. The same group of
investigators added to these finding by reporting that insulin therapy also reduced small
LDL particles, which was positively related to the reduction in VLDL (r=0.67, p < 0.04).
The authors concluded that these changes in lipid measurements were independent of
glucose control [85]. However, these results are based on only 9 subjects [84,85]. More
studies are needed to determine whether the effects of antihyperglycemic medications,
including insulin, on lipoprotein metabolism are due to an improvement in glycemic
control or independent of it. The ORIGIN trial (Outcome Reduction with an Initial
Glargine Intervention) discussed later may provide answers to some of these questions.
Impact of OADs vs. Insulin on Lipid Profile
The effect of treatment with OADs vs. insulin on lipids in patients with T2DM was
evaluated in several studies. During an observational study involving patients with T2DM
treated with a sulfonylurea, a sulfonylurea plus metformin, or insulin for at least 3
months, Habib and colleagues [86] found that patients in the OAD treatment groups had
higher serum levels of TC, TGs, and LDL cholesterol, as well as an increased LDL-
18

19. C:HDL-C ratio compared with patients treated with insulin therapy. HDL-C was
significantly higher in insulin therapy patients compared with those taking a sulfonylurea
plus metformin (p < 0.05). In the INSIGHT Study of 405 patients with T2DM on either
no OADs or submaximal doses of metformin and/or sulfonylurea, insulin glargine
treatment led to a significantly greater reduction in TG, TC, and non-HDL-C compared
with conventional therapy with OADs for 24 weeks [87]. In a study of 208 obese patients
with T2DM after SU failure, TG was lowered significantly with either insulin therapy
alone or with insulin added to SU treatment after 24 weeks. HDL-C was increased by
both regimens and to a greater extent in the presence of insulin (p < 0.05), whereas LDL-
C was unchanged by either treatment [88]. Reynolds and coworkers [89] compared the
lipid effects of add-on therapy with rosiglitazone or insulin in patients with T2DM
inadequately controlled with sulfonylurea and metformin therapy. Patients who received
insulin experienced a significant reduction in TC and LDL-C, whereas those treated with
rosiglitazone experienced a transient increase in TC. Similarly, insulin has been shown to
have a positive effect on TG levels and LDL subfractions (defined by increasing density
and decreasing size-small dense particles, which are thought to be more vulnerable to
oxidative damage) compared with a sulfonylurea in patients with diabetes but without
hyperlipidemia [85]. Cholesterol (0.63 ± 0.05 vs. 0.51 ± 0.049 mmol/l insulin vs.
glibenclamide, respectively, p < 0.05), phospholipids (14.8 ± 1.7 vs. 11.9 ± 1.7 mmol/l, p
< 0.006) and total lipid concentrations (44.5 ± 3.6 vs. 36.5 ± 3.7 mg/dl, p < 0.02) of large
LDL subfractions were significantly higher with insulin therapy, while the total lipid
concentration of small LDL subfractions decreased after insulin therapy (1.53 ± 0.25 vs.
1.97 ± 0.44 mmol/l, p = not significant). This reduction of small LDL was significantly
19

20. associated with changes in large VLDL; the greater the decrease in large VLDL in
patients using insulin, the greater the reduction in small LDL particles (r = 0.67, p <
0.04). Since the smallest LDL particles are proposed to be more atherogenic, these data
suggest that insulin therapy produces a shift toward an LDL profile that is associated with
less atherogenesis.
In a study of 217 patients with T2DM uncontrolled with a sulfonylurea and metformin,
24-week treatment with insulin glargine was superior to rosiglitazone in improving TG
and LDL-C levels, inferior for improving HDL-C, and similarly beneficial in reducing
FFA levels [90]. In another study of 389 patients with T2DM uncontrolled with a
sulfonylurea and metformin, treatment with insulin glargine was superior to pioglitazone
in improving lipid status related to TC, whereas LDL-C and TG were similarly improved
with both treatments. In contrast, HDL-C was more significantly increased with
pioglitazone versus insulin glargine [91]. In a separate study, both insulin glargine and
pioglitazone were found to be effective in improving lipid profiles in patients with
T2DM, with insulin glargine achieving greater reductions in FFAs and pioglitazone
achieving greater increases in HDL-C levels [92]. This difference in HDL profile
between insulin glargine and pioglitazone is consistent with an earlier study by Aljabri et
al. in which pioglitazone treatment resulted in significantly greater changes from baseline
in HDL vs. NPH insulin (p = 0.02) [93]. However, significant differences between the
treatment groups were not observed for cholesterol, LDL, or TGs [93]. Conversely, 2
studies comparing NPH insulin with sulfonylureas reported that lipoprotein profiles were
generally unchanged from baseline and between treatment groups [94,95].
20

21. Impact of Antihyperglycemic Treatment on Cardiovascular Outcomes
Because of the substantial cardiovascular risk associated with diabetes, the ultimate goal
of diabetes management is to improve macrovascular as well as microvascular outcomes
of the disease. The effects of antihyperglycemic medications on lipid profiles, as
discussed in this review, contribute to the expectation that these agents may in fact have
positive effects on cardiovascular risk beyond their glucose-lowering actions. However,
the long-term data on cardiovascular outcomes of these agents are still insufficient and
continue to generate controversy.
Available data for the TZD agents suggest that, in this case, differential effects of
pioglitazone and rosiglitazone on lipid profile (as discussed above) may indeed be
reflected by differences in cardiovascular outcomes [42]. In the PROactive Study,
patients randomized to pioglitazone therapy demonstrated significantly reduced
composite measures of all-cause mortality, nonfatal myocardial infarction, and stroke
(hazard ratio [HR] 0.84, 95% CI: 0.72–0.98; p = 0.027) [40]. Rosiglitazone, on the other
hand, has been associated with increased cardiovascular risk [96] and in September 2010
concerns about its safety lead the US Food and Drug Administration to restrict access to
the medication to patients with T2DM not already taking rosiglitazone who cannot
achieve glycemic control with other medications [97]. The European Medicines Agency
also has recommended the withdrawal of rosiglitazone [98]. In the RECORD study,
rosiglitazone was associated with an increased risk of heart failure (HR 2.10; 95% CI:
1.35–3.27). However, the HRs for all-cause deaths, fatal or non-fatal myocardial
21

22. infarction or other ischemic events were not significantly different between rosiglitazone-
treated patients and active controls [99]. In two large meta-analyses, but not in
prospective randomized trials, rosiglitazone also has been associated with increased risk
of myocardial infarction and myocardial ischemia [96,100,101]. Fluid accumulation,
edema, and heart failure are also associated with pioglitazone. Higher doses of both
TZDs lead to a greater tendency to weight gain and edema. Thus, although both
pioglitazone and rosiglitazone are TZDs, it has become clear that these OADs have
divergent cardiovascular effects, with the safety issues of rosiglitazone being distinct
from the beneficial cardiovascular outcomes associated with the use of pioglitazone.
In the ACCORD, ADVANCE, and VADT studies, as well as the UKPDS and the
DCCT/EDIC studies, no significant difference was reported between the standard and the
intensive treatment groups for the lipid levels that included LDL-C and HDL-C, TGs
and/or TC [4,102-105]. The DCCT and UKPDS have reported results consistent with
beneficial effects of improved diabetic control and insulin use. In the DCCT, intensive
glycemic control (treatment with sulfonylurea+insulin or metformin) reduced the risk of
cardiovascular events in patients with T1DM by 42% (p = 0.02) and the risk of nonfatal
MI, stroke or death from cardiovascular disease by 57% (p = 0.02) [4]. In addition, the
DCCT/EDIC Research Group compared carotid intima-media thickness, a measure of
atherosclerosis, in patients with T1DM treated with insulin therapy [106]. After adjusting
for risk factors, patients who received intensive treatment (1 to 2 insulin injections daily,
maintaining mean HbA1c of 7.2% [55 mmol/mol]) showed significantly less progression
of intima-media thickness compared with the conventional therapy group (3 or more
22

23. insulin injections daily, maintaining mean HbA1c of 9.0% [75 mmol/mol]) after 6 years
(combined intima-media thickness of common and internal carotid arteries –0.155 vs.
0.007 mm, respectively; p = 0.01) [106]. In a 10-year follow-up of the UKPDS, where
patients with T2DM were randomized to receive either conventional therapy (dietary
restrictions) or intensive therapy (either sulfonylurea or insulin or, in overweight patients,
metformin), revealed significant risk reductions in myocardial infarction (15% reduction
following sulfonylurea or insulin therapy, p = 0.01; 33% reduction after metformin
therapy, p = 0.005; compared with conventional therapy) and in death from any cause
(13%, p = 0.007) in the intensive therapy groups despite observing nonsignificant
between-group HbA1c differences after the first year [107].
In light of the many unanswered questions regarding antihyperglycemic therapy and
cardiovascular outcomes, the ORIGIN trial was designed to specifically assess whether or
not basal insulin therapy (or ω-3 fatty acid supplements, in a separate arm) can reduce the
risk of cardiovascular events in patients with evidence of cardiovascular disease and
impaired glucose tolerance (IGT), impaired fasting glucose, or early T2DM (currently
taking 0 or 1 OAD) [108]. In the insulin arm, patients are randomized to standard
glycemic care or 1 daily injection of insulin glargine titrated to achieve fasting plasma
glucose levels of ≤95 mg/dl. Primary outcomes are composites of major cardiovascular
events [108]. The trial is estimated to be completed in 2012.
Conclusions
23

24. Dyslipidemia is a common risk associated with T2DM. In addition to the reductions in
glucose-related variables, antidiabetic medications, including OADs, the GLP-1 agonists,
and insulin, all appear to have effects on lipid measurements. However, the precise
mechanisms of action on lipoprotein profiles are not completely understood for most of
these medications. Moreover, the nature of the effect on lipid profiles can vary
considerably within a specific drug class, as is the case for pioglitazone and rosiglitazone.
In addition, drugs within the same class (ie, pioglitazone and rosiglitazone), can have
very different effects where one agent has been associated with beneficial cardiovascular
outcomes and the other linked to increased safety concerns. It has been hypothesized that
insulin may have adverse effects on lipids on the basis of experimental models, however
clinical studies have consistently demonstrated a beneficial effect of insulin on all lipid
variables. Since the goals of glycemic control cannot be achieved without the use of
insulin in most patients with T2DM, it is also important to establish the precise effect of
insulin on the lipid variables. Such investigations should be organized prospectively and
should include insulin therapy with or without statin therapy for patients with T2DM.
Clearly, more studies, such as the ORIGIN trial, need to be designed to specifically
examine the effects of OADs and/or insulin therapy on lipid profiles as a primary
treatment outcome. Long-term studies assessing the effects of antihyperglycemic therapy
on cardiovascular outcomes are also needed.
24

25. Acknowledgments
The contents of the paper and opinions expressed within are those of the authors, and it
was the decision of the authors to submit the manuscript for publication. All authors
contributed to the writing of this manuscript, including critical review and editing of each
draft, and approval of the submitted version. Editorial support was provided by Richard
Fay, PhD, of Embryon and was funded by sanofi-aventis U.S.
Disclosure
A.C. has received research support from, and is a consultant and on the advisory panel
for, the sanofi-aventis U.S. Group. He is on the speakers bureau for Eli Lilly and
Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation and the sanofi-
aventis U.S. Group.
P.D. is on the advisory panel for Merck & Co., Inc., and the sanofi-aventis U.S. Group,
and is a consultant for Novo Nordisk Inc. He has received research support from Amylin
Pharmaceuticals, Inc., Merck & Co., Inc. and the sanofi-aventis U.S. Group. He is on the
speakers bureau for Amylin Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc.
and the sanofi-aventis U.S. Group.
25

26. Table 1. Impact of treatment with OADs on lipid levels (mean change from baseline) in patients with T2DM
TC LDL-C HDL-C TGs
(change from (change from (change from (change from
Drug Class/Treatment baseline) baseline) baseline) baseline) References
MET ↓ ↓ Variable ↓ [18,19,21,25]
Alpha glucosidase inhibitor
Acarbose ↓ ↓ No change to ↑ ↓ [32,109,110]
Miglitol No change NR NR ↓(NS) [111,112]
Voglibose ↓(NS) NR No change ↓ [31]
SU*
Glibenclamide alone ↑(NS) NR ↓(NS) ↓(NS) [36]
Glyburide alone ↑(NS) ↑(NS) No change ↑(NS) [113]
Gliclazide alone ↓(NS) ↓ No change ↓(NS) [109]
Glyburide + MET ↓ ↓ No change ↓ [18,113]
TZD
Pioglitazone alone ↑(NS) NR ↑ ↓ [36]
SU + TZD
Glimepiride + pioglitazone ↓ ↓ ↑ ↓ [20,42]
Glimepiride + rosiglitazone Variable No change to ↑ No change No change to ↑ [20][42]
Glimepiride + rosi or pio + MET ↓(NS) ↓(NS) No change ↓(NS) [21]
Pioglitazone + MET or SU ↑(NS) ↓(NS) ↑(NS) ↓(NS) [91]
26

27. (glyburide, glipizide, glimepiride)
Rosiglitazone + MET + SU ↑(NS) Variable ↑(NS) Variable [89,90]
No change = mean changes from baseline ≤0.05 mmol/l (≤1 mg/dl). Variable = directional changes in studies did not agree. *Effects were
variable depending on duration.
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MET, metformin; NR, not reported; NS, not
statistically significant; OADs, oral antidiabetic drugs; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TGs,
triglycerides; TZD, thiazolidinedione.
27

28. Table 2. Impact of treatment with incretin-based therapies on lipid levels* in patients with T2DM
Drug class/treatment TC LDL-C HDL-C TGs References
GLP-1 analog
Exenatide ↓ ↓ ↑ ↓ [48]
Exenatide ↓ ↓ No change ↓ [66]
Liraglutide 0.65 mg No change No change No change ↓ [52]
Liraglutide 1.25 mg No change No change No change ↓ (NS) [52]
Liraglutide 1.90 mg No change No change No change ↓ [52]
Taspoglutide ↓ ↓ ↓ ↓ [58]
Albiglutide No change No change No change No change [59]
Selective DPP-4 inhibitors
Sitagliptin No change No change ↑ No change [61]
Sitagliptin ↓ ↓ No change ↓ [66]
Saxagliptin No change No change No change No change [62-64]
Vildagliptin No change NR NR ↓ (postprandial; [60]
no change for
fasting)
*Reported as change from baseline, except for liraglutide and vildagliptin (change vs. placebo).
DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density
lipoprotein cholesterol; NR, not reported; NS, not statistically significant; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TGs,
triglycerides.
28

29. Table 3. Impact of insulin therapy on lipid levels in patients with T2DM
Study/Treatment TC LDL-C HDL-C TGs References
Agardh 1982/ [79]
Insulin (regimen not specified) ↓ ↓ ↑ ↓
Cusi 1995/ [80]
Bedtime NPH insulin ↓ ↓ No change* ↓
Veterans Affairs Cooperative Study in [81]
Type 2 Diabetes 1998/
Intensive insulin treatment ↓ No change No change ↓
Standard insulin treatment No change at 1 y; ↓ at 2 y ↓ ↓ No change
Bagdade 1998/ [82]
Intensive insulin treatment ↓ No change ↑ ↓
Horton 2010/ [66]
Insulin ↓ ↓ No change ↓
Yki-Jarvinen 2006/ [83]
Insulin glargine + metformin Not reported No change ↑ ↓
NPH insulin + metformin Not reported No change ↑ ↓
Romano 1997/ [84]
Insulin No change No change ↑† ↓
Rivellese 2000/ [85]
Insulin No change ↓‡ No change ↓
*HDL-C:TC ratio significantly improved.
29

30. †
Change observed with HDL2 subfraction.
‡
Change observed with small LDL subfraction.
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; T2DM, type 2 diabetes mellitus; TC, total
cholesterol; TGs, triglycerides.
30

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