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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

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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.

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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

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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

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(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

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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

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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

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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

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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

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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

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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 =

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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

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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

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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

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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

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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

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(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

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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-

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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

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].

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

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

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

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.

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.

26

Table 1. Impact of treatment with OADs on lipid levels (mean change from baseline) in patients with T2DM

Drug Class/Treatment

TC (change from

baseline)

LDL-C (change from

baseline)

HDL-C (change from

baseline)

TGs (change from

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]

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.

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;

no change for

fasting)

[60]

*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.

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/

Insulin (regimen not specified)

↓

↓

↑

↓

[79]

Cusi 1995/

Bedtime NPH insulin

↓

↓

No change*

↓

[80]

Veterans Affairs Cooperative Study in

Type 2 Diabetes 1998/

Intensive insulin treatment

Standard insulin treatment

↓

No change at 1 y; ↓ at 2 y

No change

↓

No change

↓

↓

No change

[81]

Bagdade 1998/

Intensive insulin treatment

↓

No change

↑

↓

[82]

Horton 2010/

Insulin

↓

↓

No change

↓

[66]

Yki-Jarvinen 2006/

Insulin glargine + metformin

NPH insulin + metformin

Not reported

Not reported

No change

No change

↑

↑

↓

↓

[83]

Romano 1997/

Insulin

No change

No change

↑†

↓

[84]

Rivellese 2000/

Insulin

No change

↓‡

No change

↓

[85]

*HDL-C:TC ratio significantly improved.

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.

31

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