Dislipidemia no dm2 insulina x oad


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

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Dislipidemia no dm2 insulina x oad

  1. 1. Effects of insulin and other antihyperglycemic agents on lipid profiles of patientswith diabetesAjay Chaudhuri & Paresh DandonaMillard Fillmore Hospital, Buffalo, New YorkRunning Title: Glycemic Control and Lipid Profiles in DiabetesCorrespondence to:Dr Ajay ChaudhuriMillard Fillmore Hospital3 Gates CircleBuffalo, NY 14209Phone: 716-887-4523E-mail: achaudhuri@KaleidaHealth.orgThis is an Accepted Article that has been peer-reviewed and approved for publication in theDiabetes, 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. 2. ABSTRACTIncreased morbidity and mortality risk due to diabetes-associated cardiovascular diseasesis partly associated with hyperglycemia as well as dyslipidemia. Pharmacologic treatmentof 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 analogsand dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested toimprove lipid profiles in patients with diabetes. These effects may have benefits oncardiovascular risk beyond glucose-lowering actions. This review discusses the effects ofOADs, insulins, and incretin-based therapies on lipid variables along with the possiblemechanisms and clinical implications of these findings. The effects of intensive vs.conventional antihyperglycemic therapy on cardiovascular outcomes and lipid profilesare also discussed. A major conclusion of this review is that agents within the same classof OADs can have different effects on lipid variables and that contrary to the findings inexperimental models, insulin has been shown to have beneficial effects on lipid variablesin clinical trials. Further studies are needed to understand the precise effect and themechanisms of these effects of insulin on lipids. 2
  3. 3. IntroductionDiabetes confers an increased risk of morbidity and mortality due to cardiovasculardisorders [1,2], which appear to some degree related to glycemic control [3-5]. Patientswith type 2 diabetes mellitus (T2DM) tend to be dyslipidemic [6], and quantitative andqualitative lipid abnormalities have been observed in individuals with prediabetes whowere identified and followed prospectively prior to clinical presentation of T2DM [7].Lipid abnormalities associated with T2DM include high serum triglyceride (TG) levels, ahigh proportion of small dense low-density lipoprotein (LDL) particles [6], a highnumber of TG-enriched, very-low-density lipoprotein (VLDL) particles [8], and lowhigh-density lipoprotein cholesterol (HDL-C) levels [6,7], as well as glycation ofapolipoproteins and increased LDL oxidation, both of which contribute to foam-cellformation [9].Among US adults who have been diagnosed with diabetes, 55.7% achieve the AmericanDiabetes Association (ADA)–recommended glycated hemoglobin A1C (HbA1c) target of<7.0% (International Federation of Clinical Chemistry and Laboratory Medicineunits[10-12]: 53 mmol/mol), fewer than 40% achieve the blood pressure goal of <130/80mm Hg, and only 27.4, 36.0, and 65.0% are in the low-risk categories for HDL-C (>1.17mmol/l for men, >1.42 mmol/l for women), LDL-C (<2.59 mmol/l) and TGs (<2.26mmol/l), respectively [13,14]. Thus, patients with T2DM who do not achieve the targetsoutlined by clinical practice recommendations may have the greatest risk forcardiovascular disease. Adherence to treatment can perhaps account for some of the 3
  4. 4. discrepancies in goal achievement; however, many patients may also remain uncontrolledbecause they require a greater reduction in lipid measurements [15,16].Given the connections between glucose and lipid metabolism and the negativecardiovascular consequences of dyslipidemia in patients with T2DM, this review willexplore the impact of treatment with oral antidiabetic drugs (OADs), insulins, andincretin-based therapies on the lipid profiles of patients with diabetes and discuss possiblemechanisms and clinical implications. In addition, the effects of intensive vs.conventional antihyperglycemic therapy on cardiovascular outcomes and lipid profilesalso will be discussed.MethodsRandomized clinical trials (RCTs) examining the effects of the antidiabetic agents onlipid levels in adult patients with T2DM were identified using a PubMed search with keysearch terms, such as lipoprotein profile, lipids, cholesterol, TGs, free fatty acids (FFAs)and cardiovascular combined with insulin analogs, insulin, NPH, insulin glargine, insulindetemir, 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, includingAction to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes andVascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation(ADVANCE), United Kingdom Prospective Diabetes Study (UKPDS), Diabetes Controland Complications Trial/Epidemiology of Diabetes Interventions and Complications 4
  5. 5. (DCCT/EDIC) and Veterans Affairs Diabetes Trials (VADTs). Studies reporting lipidvariables were selected if the changes in lipid variables from baseline to endpoint andbetween comparators (ie insulin vs. an OAD) were reported in the abstract or assecondary efficacy measurements. Studies were also identified using review (includingsystematic reviews) articles and meta-analyses comparing the efficacy of variousantidiabetic agents. Only human studies published in English were considered. We didnot limit the search to a specific range in years since some antidiabetic agents have beenavailable for several years. We acknowledge the limitation of using this strict criterion toselect studies and the possibility that we may have overlooked studies reporting lipidvariabes only in the text of the published manuscript.Oral Agents and Lipid ProfileMetforminOADs are the first line of therapy for patients with T2DM [17]. The effect of treatmentwith 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 shownpositive effects on lipid variables in patients with T2DM, including reduced fasting totalcholesterol (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 thatmetformin 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 plusglibenclamide (glyburide) also showed significant improvement in these lipid 5
  6. 6. measurements when metformin was given as monotherapy in place of glyburide or wasadded to existing glyburide therapy, compared with patients who continued takingglyburide as monotherapy. In both patient groups in this study, changes in HDL-C levelswere 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. Asystematic review and meta-analysis of up to 38 randomized controlled trials (whichincluded DeFronzo et al. but not Dailey et al.) reported that, when compared withcontrols, 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 = 0.021and p = 0.018, respectively) were reported by Lund and coworkers in patients with type 1diabetes mellitus (T1DM) [24]. Metformin has also been shown to reduce HbA1c andlipid measures in nonobese patients with T2DM. In a study with 96 randomized patientswith baseline BMI of 24.8 kg/m2, metformin significantly (p < 0.05) reduced fasting andpostprandial levels of plasma TC, LDL-C, and non-HDL-C in addition to the significantreductions in plasma glucose [25]. These results suggest that the effects of metformin onlipid profiles are independent of body weight. Metformin has also been shown tosignificantly lower LDL-C levels in patients with impaired glucose tolerance [26].The mechanisms by which metformin exerts its effect on lipoprotein profiles is not fullyunderstood. However, studies have suggested that metformin increases the activation of 6
  7. 7. AMP-activated protein kinase (AMPK), which leads to the inactivation of acetyl-CoAcarboxylase [27,28]. Stimulation of AMPK increases glucose uptake in muscle while alsoinhibiting hepatic glucose production, cholesterol and TG synthesis, and lipogenesis [28].In vitro studies also have shown that metformin suppresses the transcription factors thatencode lipogenic enzymes [27].Alpha glucosidase inhibitorsChanges 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 ofjejunum that serve to break down complex carbohydrates [29]. Therefore, alphaglucosidase inhibitors slow the intestinal breakdown of ingested complex carbohydratesinto simpler carbohydrates, such as sucrose and glucose. Consequently, the availability ofpostprandial glucose in the plasma is reduced and delayed [29,30]. A 4-week study byMatsumoto et al. reported that administration of the alpha glucosidase inhibitor voglibosealone or with a sulfonylurea in 14 patients with T2DM significantly reduced TG frombaseline (p < 0.01); TC levels also were reduced, but not significantly [31]. Anotherstudy that included 31 patients showed that after 24 weeks of treatment, acarbose reducedTG, TC and LDL-C levels and slightly increased HDL-C [32]. These somewhat differentresults were also noted in a systematic review by Buse et al. Of the 3 alpha glucosidaseinhibitors examined in their review (voglibose, acarbose, and miglitol), voglibosereduced TGs and acarbose reduced LDL-C. No consistent effects on any other lipidvariables were identified [33]. Comparing acarbose to sulfonylurea in a systematicreview, Bolen et al. reported that sulfonylurea reduced LDL-C better than acarbose and 7
  8. 8. the effects of the 2 agents on TGs were similar. However, effects of acarbose on HDL-Cwas better than that of sulfonylurea [34]. Both systematic reviews examined the effectsof other OADs on glycemic and lipid variables as well [33,34]. Lipid data obtained fromthe 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].SulfonylureaData 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 widevariation in the effects of gliclazide on lipid variables. In their analysis, significantreductions 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 studieslasting 3 months, 2 years, and 3 years, but not in another 3-month study nor in a 24-weekstudy [33]. Some clinical studies in patients with T2DM have indicated a beneficial effectof sulfonylurea therapy on fasting TC and TG levels [23]. However, a small study ofJapanese patients with T2DM poorly controlled on diet alone, who were treated for 6months with glyburide or pioglitazone monotherapy, showed no significant effect ofglibenclamide 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 differentsulfonylurea—glimepiride—was shown to significantly increase adiponectin and HDL-Clevels (p = 0.041) in all T2DM patients in the study, particularly in patients with lowpretreatment adiponectin levels (p = 0.011) [37]. The authors attributed this effect to the 8
  9. 9. dual activity of glimepiride as a potent peroxisome proliferator–activated receptor(PPAR)–γ agonist as well as insulin secretagogue [37]. PPARs are transcription factorsbelonging to the nuclear receptor superfamily [38]. The PPAR-γ receptors are found inadipose tissue, skeletal muscle, vascular tissue, and in the pancreas. Activation of thePPAR-γ is thought to normalize glucose uptake and to increase the expression of insulinreceptors. PPAR- γ receptor activation also may lower triglyceride levels by increasingthe clearance of fatty acids in adipose tissue [38].ThiazolidinedionesThe case of thiazolidinediones (TZDs) is complicated by the observation thatpioglitazone and rosiglitazone, while having similar effects on glycemic control, seem toshow marked differences in their effects on lipid metabolism. Although rosiglitazone(added to existing OAD therapy in patients with T2DM) decreased postprandial TG andFFA levels compared with placebo in an 8-week crossover study, it had no effect onfasting 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 andpostprandial TG levels [23]. The Prospective Pioglitazone Clinical Trial inMacrovascular Events (PROactive) Study showed that pioglitazone (added to other OADtherapy) 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. 10. increase in LDL-C levels, there was an overall significant decrease in the LDL-C:HDL-Cratio (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 anddecrease triglycerides in patients with impaired glucose tolerance [41].These differences between rosiglitazone and pioglitazone regarding their impact on lipidprofiles have been confirmed in studies directly comparing the two TZD agents whenadded to sulfonylurea therapy. Derosa and colleagues [20] found that combinationtreatment 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 andmetabolic syndrome; however, treatment with glimepiride and rosiglitazone inducedsignificant increases in TC, LDL-C, and TG levels. In addition, a study by Chogtu et alcomparing the combination of glimepiride with either pioglitazone or rosiglitazone alsoreported that TC, TG, and LDL values significantly improved in patients receiving thepioglitazone/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 berelated to the differences in their mechanism of action. Pioglitazone and rosiglitazone arepotent PPAR ligands, specifically for the gamma (γ) receptor subtype. Pioglitazone,however, also likely has PPAR-α agonistic effects; the PPAR-α receptor has an importantrole 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. 11. activation of the PPAR-α receptor, which may explain the differences in pioglitazone’seffects on lipid profiles compared with rosiglitazone. Lipoprotein lipase is an enzyme thatfacilitates the decomposition of plasma-derived triglyceride-rich lipoproteins into FFAs.Consequently, increasing the expression of lipoprotein lipase would increase lipoproteinbreakdown. The enzyme is expressed in many tissues, including skeletal muscle andadipose tissue [47]. Like PPAR-γ, PPAR-α receptors are found in adipose tissue, skeletalmuscle, 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 receptorsin the liver also may help to explain the similarities in the lipid-lowering effects betweenpioglitazone and fibrates.Incretin-Based TherapiesGLP-1 analogsThe injectable GLP-1 receptor agonist, exenatide, also has been studied for its effect oncardiovascular risk factors (table 2). Patients with T2DM from 3 trials were enrolled into1 open-ended, open-label clinical trial and were randomized to twice-daily injections ofplacebo or 5 or 10 μg of exenatide. In a subset of patients who were exposed to exenatidefor 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; allcompared with placebo) [48]. The addition of exenatide to insulin for 26 weeks has beenshown to significantly reduce TGs by 26.0% (p = 0.01) and TC by 8.6% (p = 0.03) frombaseline [49]. When stratified by baseline HbA1c level, significant reductions in TGs of22.4% were observed in patients with HbA1c >6.5% (48 mmol/mol) and of 33.8% (p = 11
  12. 12. 0.09, NS) in patients with HbA1c ≤6.5% (48 mmol/mol) [49]. The lipid effects ofexenatide also are thought to be due to activation of PPAR-α [50]. Although the specificmechanisms by which incretins affect lipoprotein profiles are incompletely understood,the actions of incretins and DPP-4 inhibitors involve promoting adipose triacylglycerolcatabolism 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-4degradation 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 significantreduction of TG levels compared with placebo (p = 0.011 and p = 0.0304, respectively) inpatients 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 othermedications, liraglutide is often combined with other antidiabetic agents. As part of theLiraglutide Effect and Action in Diabetes (LEAD) program, treatment combiningmetformin 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), andFFAs (–0.03 ± 0.02 mmol/l) (p < 0.05 for all) [56]. A 26-week, randomized, open-labelstudy in adult patients with T2DM, the LEAD-6 study reported that liraglutide therapysignificantly 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 treatmentcompared with exenatide, but these differences were not significant. Interestingly, theLEAD-6 study also reported that VLDL-C increased from baseline to week 26, which 12
  13. 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 toTG is relatively constant at about 5:1 in normal individuals and patients with highlipoprotein 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 inTG should also have reflected a decrease in VLDL as well. Although not addressed in theLEAD-6 paper, this apparent discrepancy could be related to differences in themethodology for VLDL-C assessment.Although development has currently been postponed, taspoglutide therapy has shownpromising 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 mgtaspoglutide once weekly. Also reported was a trend for minimal decrease of HDL-Cover an 8-week treatment period [58]. In a 16-week study, Rosenstock et al. reported thatalbiglutide therapy administered weekly, biweekly, or monthly did not significantly affectlipid measurements [59].DPP-4 inhibitorsVildagliptin, sitagliptin, and saxagliptin are selective inhibitors of the DPP-4 enzyme thatresult in increased levels of GLP-1. In patients with T2DM, vildagliptin reducedpostprandial 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 forplacebo group 6.2 ± 0.6 mmol/l • h) and chylomicron cholesterol (between-group 13
  14. 14. difference –0.13 ± 0.05 mmol/l • h, p = 0.020; baseline for vildagliptin group 0.20 ± 0.06mmol/l • h; baseline for placebo group 0.22 ± 0.05 mmol/l • h) when compared withplacebo but had no significant effect on VLDL and intermediate-density lipoprotein(IDL) TG and total plasma cholesterol [60]. Treatment with sitagliptin also has beenreported to have a differential effect on lipid levels. Compared with glipizide, treatmentwith 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 anyother measured lipid variable [61]. Interestingly, although numerical differences havebeen reported, treatment with saxagliptin has not been shown to significantly or clinicallyaffect lipid levels in patients with T2DM [62-65].In a retrospective analysis of electronic medical records in patients with T2DM, Horton etal examined the relationship between weight loss, glycemic control and changes in lipidmeasurements following exenatide, sitagliptin, or insulin therapy (the specific type ofinsulin—analog or human—was not noted) [66]. Not surprisingly, the patients initiatingexenatide 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 threetreatment groups. Lipid variables, including TGs, LDL-C, and TC, also improved in allthree treatment groups (tables 2 and 3), with patients receiving insulin experiencing thegreatest reductions. However, HDL was relatively unchanged. For the patients initiatingexenatide, the improvements in TGs, LDL and TC were significantly associated with the 14
  15. 15. changes in weight (p = 0.007, p = 0.005, and p < 0.001, respectively). For patientsinitiating 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 foundbetween weight increase and TC reduction (p = 0.02) [66]. Thus, despite the increasedweight gain, insulin therapy was associated with greater glycemic and lipid loweringbenefits than exenatide or sitagliptin.Insulin and Lipid ProfileIn many patients with T2DM, insulin replacement is necessary. Insulin also has beenshown to affect lipid variables, and studies examining the mechanisms of action ofseveral of these medications point to links between glucose and lipid metabolism thatcould explain such effects. For example, as a potent activator of lipoprotein lipase, insulinplays an important role in the regulation of lipid metabolism [9]. Insulin suppresses theproduction of TGs and VLDL by hepatocytes in vitro [67,68] and in vivo [69,70] andpromotes LDL clearance [71,72]. Insulin also produces a 2.3-fold increase in adiposetissue lipoprotein-lipase activity (p < 0.001) [73] and, therefore, would be expected tohave a significant effect on lipid metabolism in patients with T2DM. Insulin also isknown to promote Apo lipoprotein A and HDL biosynthesis by hepatocytes, in vitro[74,75]. Insulin suppresses lipolysis and prevents the release of FFAs from adiposetissue. In addition, it increases the clearance of FFAs from plasma. These actions ofinsulin are consistent with the increases in TG and FFA levels in the insulin-resistantstates of obesity and T2DM. These actions also indicate that the administration of insulinand insulin sensitizers in insulin-resistant states could reduce plasma TG and FFA 15
  16. 16. concentrations. Although studies in experimental models have suggested thathyperinsulinemia stimulates the activation of enzymes involved in de novo lipogenesisand, thus, may result in increased TG accumulation in the liver and availability for VLDLproduction [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 eitherregular 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 smallstudy [77]. Alterations in 2-hour postprandial VLDL composition were improved afteradministration of regular insulin and completely normalized after administration ofinsulin lispro (p < 0.05). Despite small differences in effect observed with the twoprandial insulins, both types of insulin were associated with similar improvements inlipoprotein metabolism. In the DCCT (N = 1441), the 42% reduction in risk of amacrovascular event experienced by patients in the intensive-treatment group wasassociated with significant reductions in lipid-related macrovascular risk factors only inthe secondary-treatment cohort, which had a longer duration of disease at baselinecompared with the primary cohort (8.8 vs. 2.6 years) and, thus, a longer exposure to theatherogenic 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 thedevelopment of LDL-C levels >4.1 mmol/l.In clinical trials, patients with newly diagnosed or inadequately controlled T2DMexperienced improvements in lipid profile following the initiation of insulin therapy 16
  17. 17. (table 3). Amongst the earliest observations of the lipid lowering effects of insulintherapy, 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-Clevels (12%, p < 0.01) in patients with T2DM (N = 26) following 3 to 4 months of insulintherapy. In a separate study, treatment with NPH insulin at bedtime for 16 weeks resultedin 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-Cratio (p < 0.01) in obese men with T2DM (N = 12) [80]. In the Veterans AffairsCooperative Study in Diabetes Mellitus [81], patients with T2DM (N = 153) whoreceived intensive insulin therapy (target HbA1c 4.0 to 6.1% [20 to 43 mmol/mol] ) orstandard insulin therapy (target HbA1c <13.0% [119 mmol/mol]) experienced significantimprovements in lipid levels. After 2 years of treatment, TG and TC levels weresignificantly decreased (p = 0.03 and p = 0.06, respectively) in the intensive-treatmentgroup. 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, lessatherogenic particles. Intensive insulin treatment was found to reduce TG and TC levelsand increase HDL-C levels in a study of 18 patients with T2DM. However, abnormalitiesin lipoprotein surface constituents and core lipids persisted after intensive insulin therapydespite normalization of plasma lipid levels [82].In studies in which patients have achieved HbA1c targets of approximately 7.0% (53mmol/mol), insulin has been shown to positively affect lipoprotein values as well. In the 17
  18. 18. LANMET study of 110 insulin-naïve patients with T2DM, both insulin glargine plusmetformin and NPH insulin plus metformin significantly reduced TG (p < 0.001) andincreased 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 inpatients achieving similar glucose control, Romano et al. demonstrated that insulintherapy 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), andincreased HDL-C (25.2 ± 1.6 vs. 20.3 ± 1.3 mg/dl, p < 0.03) [84]. The same group ofinvestigators added to these finding by reporting that insulin therapy also reduced smallLDL 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 ofglucose control [85]. However, these results are based on only 9 subjects [84,85]. Morestudies are needed to determine whether the effects of antihyperglycemic medications,including insulin, on lipoprotein metabolism are due to an improvement in glycemiccontrol or independent of it. The ORIGIN trial (Outcome Reduction with an InitialGlargine Intervention) discussed later may provide answers to some of these questions.Impact of OADs vs. Insulin on Lipid ProfileThe effect of treatment with OADs vs. insulin on lipids in patients with T2DM wasevaluated in several studies. During an observational study involving patients with T2DMtreated with a sulfonylurea, a sulfonylurea plus metformin, or insulin for at least 3months, Habib and colleagues [86] found that patients in the OAD treatment groups hadhigher serum levels of TC, TGs, and LDL cholesterol, as well as an increased LDL- 18
  19. 19. C:HDL-C ratio compared with patients treated with insulin therapy. HDL-C wassignificantly higher in insulin therapy patients compared with those taking a sulfonylureaplus metformin (p < 0.05). In the INSIGHT Study of 405 patients with T2DM on eitherno OADs or submaximal doses of metformin and/or sulfonylurea, insulin glarginetreatment led to a significantly greater reduction in TG, TC, and non-HDL-C comparedwith conventional therapy with OADs for 24 weeks [87]. In a study of 208 obese patientswith T2DM after SU failure, TG was lowered significantly with either insulin therapyalone or with insulin added to SU treatment after 24 weeks. HDL-C was increased byboth 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 thelipid effects of add-on therapy with rosiglitazone or insulin in patients with T2DMinadequately controlled with sulfonylurea and metformin therapy. Patients who receivedinsulin experienced a significant reduction in TC and LDL-C, whereas those treated withrosiglitazone experienced a transient increase in TC. Similarly, insulin has been shown tohave a positive effect on TG levels and LDL subfractions (defined by increasing densityand decreasing size-small dense particles, which are thought to be more vulnerable tooxidative damage) compared with a sulfonylurea in patients with diabetes but withouthyperlipidemia [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 largeLDL subfractions were significantly higher with insulin therapy, while the total lipidconcentration 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. 20. associated with changes in large VLDL; the greater the decrease in large VLDL inpatients 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 datasuggest that insulin therapy produces a shift toward an LDL profile that is associated withless 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 TGand LDL-C levels, inferior for improving HDL-C, and similarly beneficial in reducingFFA levels [90]. In another study of 389 patients with T2DM uncontrolled with asulfonylurea and metformin, treatment with insulin glargine was superior to pioglitazonein improving lipid status related to TC, whereas LDL-C and TG were similarly improvedwith both treatments. In contrast, HDL-C was more significantly increased withpioglitazone versus insulin glargine [91]. In a separate study, both insulin glargine andpioglitazone were found to be effective in improving lipid profiles in patients withT2DM, with insulin glargine achieving greater reductions in FFAs and pioglitazoneachieving greater increases in HDL-C levels [92]. This difference in HDL profilebetween insulin glargine and pioglitazone is consistent with an earlier study by Aljabri etal. in which pioglitazone treatment resulted in significantly greater changes from baselinein HDL vs. NPH insulin (p = 0.02) [93]. However, significant differences between thetreatment groups were not observed for cholesterol, LDL, or TGs [93]. Conversely, 2studies comparing NPH insulin with sulfonylureas reported that lipoprotein profiles weregenerally unchanged from baseline and between treatment groups [94,95]. 20
  21. 21. Impact of Antihyperglycemic Treatment on Cardiovascular OutcomesBecause of the substantial cardiovascular risk associated with diabetes, the ultimate goalof diabetes management is to improve macrovascular as well as microvascular outcomesof the disease. The effects of antihyperglycemic medications on lipid profiles, asdiscussed in this review, contribute to the expectation that these agents may in fact havepositive effects on cardiovascular risk beyond their glucose-lowering actions. However,the long-term data on cardiovascular outcomes of these agents are still insufficient andcontinue to generate controversy.Available data for the TZD agents suggest that, in this case, differential effects ofpioglitazone and rosiglitazone on lipid profile (as discussed above) may indeed bereflected by differences in cardiovascular outcomes [42]. In the PROactive Study,patients randomized to pioglitazone therapy demonstrated significantly reducedcomposite 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 otherhand, has been associated with increased cardiovascular risk [96] and in September 2010concerns about its safety lead the US Food and Drug Administration to restrict access tothe medication to patients with T2DM not already taking rosiglitazone who cannotachieve glycemic control with other medications [97]. The European Medicines Agencyalso 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. 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 inprospective randomized trials, rosiglitazone also has been associated with increased riskof myocardial infarction and myocardial ischemia [96,100,101]. Fluid accumulation,edema, and heart failure are also associated with pioglitazone. Higher doses of bothTZDs lead to a greater tendency to weight gain and edema. Thus, although bothpioglitazone and rosiglitazone are TZDs, it has become clear that these OADs havedivergent cardiovascular effects, with the safety issues of rosiglitazone being distinctfrom the beneficial cardiovascular outcomes associated with the use of pioglitazone.In the ACCORD, ADVANCE, and VADT studies, as well as the UKPDS and theDCCT/EDIC studies, no significant difference was reported between the standard and theintensive treatment groups for the lipid levels that included LDL-C and HDL-C, TGsand/or TC [4,102-105]. The DCCT and UKPDS have reported results consistent withbeneficial effects of improved diabetic control and insulin use. In the DCCT, intensiveglycemic control (treatment with sulfonylurea+insulin or metformin) reduced the risk ofcardiovascular events in patients with T1DM by 42% (p = 0.02) and the risk of nonfatalMI, stroke or death from cardiovascular disease by 57% (p = 0.02) [4]. In addition, theDCCT/EDIC Research Group compared carotid intima-media thickness, a measure ofatherosclerosis, in patients with T1DM treated with insulin therapy [106]. After adjustingfor 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 progressionof intima-media thickness compared with the conventional therapy group (3 or more 22
  23. 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, wherepatients with T2DM were randomized to receive either conventional therapy (dietaryrestrictions) or intensive therapy (either sulfonylurea or insulin or, in overweight patients,metformin), revealed significant risk reductions in myocardial infarction (15% reductionfollowing sulfonylurea or insulin therapy, p = 0.01; 33% reduction after metformintherapy, p = 0.005; compared with conventional therapy) and in death from any cause(13%, p = 0.007) in the intensive therapy groups despite observing nonsignificantbetween-group HbA1c differences after the first year [107].In light of the many unanswered questions regarding antihyperglycemic therapy andcardiovascular outcomes, the ORIGIN trial was designed to specifically assess whether ornot basal insulin therapy (or ω-3 fatty acid supplements, in a separate arm) can reduce therisk of cardiovascular events in patients with evidence of cardiovascular disease andimpaired glucose tolerance (IGT), impaired fasting glucose, or early T2DM (currentlytaking 0 or 1 OAD) [108]. In the insulin arm, patients are randomized to standardglycemic care or 1 daily injection of insulin glargine titrated to achieve fasting plasmaglucose levels of ≤95 mg/dl. Primary outcomes are composites of major cardiovascularevents [108]. The trial is estimated to be completed in 2012.Conclusions 23
  24. 24. Dyslipidemia is a common risk associated with T2DM. In addition to the reductions inglucose-related variables, antidiabetic medications, including OADs, the GLP-1 agonists,and insulin, all appear to have effects on lipid measurements. However, the precisemechanisms of action on lipoprotein profiles are not completely understood for most ofthese medications. Moreover, the nature of the effect on lipid profiles can varyconsiderably 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 havevery different effects where one agent has been associated with beneficial cardiovascularoutcomes and the other linked to increased safety concerns. It has been hypothesized thatinsulin may have adverse effects on lipids on the basis of experimental models, howeverclinical studies have consistently demonstrated a beneficial effect of insulin on all lipidvariables. Since the goals of glycemic control cannot be achieved without the use ofinsulin in most patients with T2DM, it is also important to establish the precise effect ofinsulin on the lipid variables. Such investigations should be organized prospectively andshould 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 specificallyexamine the effects of OADs and/or insulin therapy on lipid profiles as a primarytreatment outcome. Long-term studies assessing the effects of antihyperglycemic therapyon cardiovascular outcomes are also needed. 24
  25. 25. AcknowledgmentsThe contents of the paper and opinions expressed within are those of the authors, and itwas the decision of the authors to submit the manuscript for publication. All authorscontributed to the writing of this manuscript, including critical review and editing of eachdraft, and approval of the submitted version. Editorial support was provided by RichardFay, PhD, of Embryon and was funded by sanofi-aventis U.S.DisclosureA.C. has received research support from, and is a consultant and on the advisory panelfor, the sanofi-aventis U.S. Group. He is on the speakers bureau for Eli Lilly andCompany, 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 AmylinPharmaceuticals, Inc., Merck & Co., Inc. and the sanofi-aventis U.S. Group. He is on thespeakers bureau for Amylin Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc.and the sanofi-aventis U.S. Group. 25
  26. 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 fromDrug Class/Treatment baseline) baseline) baseline) baseline) ReferencesMET ↓ ↓ 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. 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 werevariable depending on duration.LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MET, metformin; NR, not reported; NS, notstatistically significant; OADs, oral antidiabetic drugs; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TGs,triglycerides; TZD, thiazolidinedione. 27
  28. 28. Table 2. Impact of treatment with incretin-based therapies on lipid levels* in patients with T2DMDrug class/treatment TC LDL-C HDL-C TGs ReferencesGLP-1 analogExenatide ↓ ↓ ↑ ↓ [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 inhibitorsSitagliptin 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-densitylipoprotein cholesterol; NR, not reported; NS, not statistically significant; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TGs,triglycerides. 28
  29. 29. Table 3. Impact of insulin therapy on lipid levels in patients with T2DMStudy/Treatment TC LDL-C HDL-C TGs ReferencesAgardh 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 changeBagdade 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. 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, totalcholesterol; TGs, triglycerides. 30
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