Document Detail

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes.
Jump to Full Text
MedLine Citation:
PMID:  17969380     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.
Authors:
John M Stafford; Tom Elasy
Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Vascular health and risk management     Volume:  3     ISSN:  1176-6344     ISO Abbreviation:  -     Publication Date:  2007  
Date Detail:
Created Date:  2007-10-30     Completed Date:  2008-03-06     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  101273479     Medline TA:  Vasc Health Risk Manag     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  503-10     Citation Subset:  IM    
Affiliation:
Division of Diabetes Endocrinology and Metabolism,Vanderbilt University, Nashville, TN 37232-6303, USA. john.stafford@vanderbilt.edu
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Chromans / therapeutic use
Clinical Trials as Topic
Diabetes Mellitus, Type 2 / drug therapy*
Drug Therapy, Combination
Humans
Hypoglycemic Agents / therapeutic use*
Insulin Resistance
Metformin / therapeutic use*
Thiazolidinediones / therapeutic use*
Treatment Outcome
Chemical
Reg. No./Substance:
0/Chromans; 0/Hypoglycemic Agents; 0/Thiazolidinediones; 122320-73-4/rosiglitazone; 657-24-9/Metformin; 97322-87-7/troglitazone
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Vasc Health Risk Manag
Journal ID (publisher-id): Vascular Health and Risk Management
ISSN: 1176-6344
ISSN: 1178-2048
Publisher: Dove Medical Press
Article Information
Download PDF
© 2007 Dove Medical Press Limited. All rights reserved
Print publication date: Month: 8 Year: 2007
Volume: 3 Issue: 4
First Page: 503 Last Page: 510
ID: 2291335
PubMed Id: 17969380

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes
John M Stafford1
Tom Elasy2
1Division of Diabetes Endocrinology and Metabolism, Vanderbilt University
2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical Center
Correspondence: Correspondence: John Stafford Vanderbilt University Medical Center, 718 Preston Research Building, Nashville, TN 37232-6303, USA Tel +1 615 936 1653 Fax +1 615 936 1667 Email john.stafford@vanderbilt.edu

Rationale for the combined use of thiazolidinediones and metformin from a cardiovascular perspective

Type 2 diabetes mellitus (DM2) is characterized by defects both in insulin secretion and insulin action (Ginsberg et al 1975; DeFronzo et al 1985; Lillioja et al 1988). With the use of the euglycemic insulin clamp technique, over the past two decades, it has become clear that DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction (Ginsberg et al 1975; DeFronzo et al 1985; Lillioja et al 1988; and reviewed in Granner and O’Brien (1992) and DeFronzo (2004)). This progression has been demonstrated in many populations, and is strongly correlated with the progression of obesity (Lillioja et al 1988). The progression from normal glucose homeostasis to IGT is associated with an increase in fasting plasma insulin and glucose-stimulated insulin secretion (post-prandial), and a decrease in sensitivity to insulin action (Saad et al 1988, 1989). The progression from IGT to frank DM2 is associated with an inability of the pancreatic beta cells to continue this excess secretion of insulin (Polonsky et al 1996; Roe et al 1996), however significant beta cell dysfunction may occur much earlier (DeFronzo 2004). There is only a minimal additional worsening of insulin resistance at this stage of progression (DeFronzo 2004).

Cardiovascular disease is the primary morbidity for patients with DM2 (Howard et al 2002). The onset of insulin resistance itself seems to be an early event in the progression of DM2, precedes the development of overt hyperglycemia, and may contribute substantially to the development of cardiovascular disease independent of the hyperglycemia associated with DM2 (Meigs et al 2000; DeFronzo 2004). In the Framingham offspring study, elevated levels of fasting insulin were associated with impaired fibrinolysis and hypercoagulability, despite normal glucose tolerance (Meigs et al 2000). In the same study population, those with impaired fasting glucose had a 2.8 fold relative risk of cardiovascular events over a 4-year follow up period (Meigs et al 2002). Vascular dysfunction has been identified in several groups of patients with normal blood glucose levels but insulin resistance including; first degree relatives of patients with DM2 (Balletshofer et al 2000), patients with previous history of gestational diabetes (Bergholm et al 2003), patients with metabolic syndrome and patients with polycystic ovarian syndrome (reviewed in Caballero 2005). In the San Antonio heart study, impaired glucose tolerance was associated with hypertension, dyslipidemia, obesity and metabolic syndrome (Haffner et al 1990). Importantly, the risk of myocardial infarction (MI) in patients with known DM2, but without overt cardiovascular disease, is equal to patients who have had a previous MI but are free of diabetes (Haffner et al 1998). This observation has lead many to recommend the treatment of individuals with diabetes as comparable to an individual with known coronary heart disease. Still, insulin resistance itself appears to be an important risk factor for cardiovascular disease, even before the onset of hyperglycemia or DM2 (Wilson et al 2002, 2005).

Thiazolidinediones (TZDs) comprise a class of oral agents for the management of DM2 that, in addition to improvements in glycemic control, improve insulin resistance and thus have potential cardiovascular benefits beyond glycemic control alone. TZDs emerged for clinical use in the late 1990s. TZDs are ligands for the transcription factor peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear receptor superfamily. PPARγ is expressed predominantly in adipose tissue, but also in macrophages, beta cells of the pancreas, endothelial cells and other tissues (Kato et al 1999Z; Kersten et al 2000). The Olefsky group noted increased insulin sensitivity and lower blood pressure in obese patients without diabetes who were treated with troglitazone (Nolan et al 1994). There is some evidence in animal models and in human studies that TZD treatment may preserve beta cell function, one of the important changes in the progression from IGT to DM2. Ovalle and colleagues studied a small group of DM2 patients poorly controlled on metformin and sulfonylurea and added either rosiglitazone or insulin. Both groups achieved similar glycemic control, but only the rosiglitazone group had improved beta cell function as indicated by several clinical measures (Ovalle and Bell 2004).

Most additional studies have noted lower fasting and postprandial blood glucose, free fatty acids and fasting insulin levels, suggesting that TZDs improve insulin sensitivity (reviewed in Yki-Jarvinen 2004). For women with gestational diabetes, a state which reflects IGT, TZD treatment prevented the progression to DM2 (TRIPOD/PIPOD) (Xiang et al 2006). Pioglitazone has been shown to be effective in secondary prevention of macrovascular events in patients with known macrovascular disease. Over a 34 month placebo-controlled RCT, Pioglitazone reduced risk in the secondary composite endpoint of all cause mortality, non fatal MI and stroke. A1C, triglycerides, LDL were all decreased and HDL was increased significantly. There was an increase in congestive heart failure on pioglitazone (Dormandy et al 2005). A meta-analysis of 23 RCTs revealed a similar decrease in A1C (1–1.5%), but with an increase in weight (approximately 3 kg). Pioglitazone decreased TG, increased HDL and had no effect on LDL or total cholesterol. Rosiglitazone increased HDL, but was neutral on triglycerides and increased TC and LDL (Chiquette et al 2004). A similar result on lipids is reported comparing addition of pioglitazone or rosiglitazone to patients on glimeperide which found pioglitazone addition lowered TC, LDL, TG and raised HDL, where rosiglitazone addition increased TC, LDL and TG, with no change on HDL (Derosa et al 2005a). This difference may be due to activation of PPARα by pioglitazone in addition to PPARγ, by contrast to rosiglitazone which more selectively activates PPARγ (Kersten et al 2000).

In addition to insulin resistance and beta cell failure, the other principle pathophysiologic defect in DM2 is excessive hepatic gluconeogenesis (Magnusson et al 1992). Metformin is a member of the biguanide class of antidiabetic agents. Its principle clinical efficacy lies in its action to block hepatic gluconeogensis, and increase hepatic insulin sensitivity, and to a lesser extent increase insulin-mediated glucose uptake in fat and muscle tissue (Rossetti et al 1990; Perriello et al 1994; Bailey and Turner 1996; Large and Beylot 1999; Hundal et al 2000). Biguanide-containing compounds have been used since ancient times for the treatment of diabetes. Metformin has been used clinically for over 40 years, though it has only been approved in the United States since 1995. Follow up of patients enrolled in United Kingdom prospective diabetes study (UKPDS 34) suggest that the complications of diabetes can be related to those caused by hyperglycemia and those related to insulin resistance. In this study, a subgroup of obese patients treated with metformin had significantly lower risk of any diabetes-related endpoint, all cause mortality, and stroke when compared to patients achieving similar glycemic control with a sulfonylurea or insulin therapy (UKPDS 1998).

Treatment or prevention of insulin resistance can prevent the progression from impaired glucose tolerance to overt diabetes. The diabetes prevention trial demonstrated that an intensive diet and exercise program for patients with IGT reduced the risk of progression to diabetes by 58%, and metformin treatment reduced progression to DM2 by 31% (Knowler et al 2002). Similarly, troglitazone or pioglitazone treatment of women with a history of gestational diabetes helped to prevent progression to overt DM2 and to preserve beta cell function (Xiang et al 2006). In the DREAM study, patients with impaired fasting glucose or impaired glucose tolerance, or both were randomized to receive rosiglitazone 8 mg daily or placebo and followed for three years. The composite outcome was a combination of development of diabetes or death. 26% of patients in the placebo group developed the primary outcome versus only 11% in the rosiglitazone group (Gerstein et al 2006). Since insulin resistance itself contributes to risk of cardiovascular disease, treatment of insulin resistance is a potential pathophyisiologic target for the prevention of CVD, not just diabetes. Combined use of metformin and TZDs has theoretical benefit as it targets two main pathophysiologic defects in DM2, increased gluconeogenesis and insulin resistance.


Clinical trials of combination use metformin/thiazolidinediones
Effects on glycemic control

As of May 2006, at least twelve clinical trials have been published in peer-reviewed journals designed to evaluate addition of TZD to metformin for the treatment of diabetes (Inzucchi et al 1998; Einhorn et al 2000; Fonseca et al 2000; Gomez-Perez et al 2002; Dailey et al 2004; Charbonnel et al 2005; Matthews et al 2005; Derosa et al 2005b; Weissman et al 2005; Kendall et al 2006; Rosenstock et al 2006; Umpierrez et al 2006). The initial study that demonstrated efficacy and metabolic effects of the combined use of metformin and TZDs was performed by the Shulman group at Yale (Inzucchi et al 1998). This study of 29 patients randomized to receive either metformin or troglitazone for three months, after which they were placed on both agents. Postprandial glucose was measured by mixed meal test. Insulin sensitivity was assessed with hyperinsulinemic-eugylcemic clamp at baseline, after three months of monotherapy and after three months of combination therapy. After three months of monotherapy, both metformin and troglitazone had similar decreases in fasting and postprandial plasma glucose levels. Metformin decreased endogenous glucose production, while troglitazone did not, consistent with the known effects of metformin on hepatic gluconeogeneis. Metformin had a 13% increase in insulin-mediated glucose disposal, while troglitazone had a 54% increase. Thus as single agents, metformin and troglitazone achieved similar glycemic control, metformin primarily through decreasing hepatic glucose production and troglitazone by improving insulin sensitivity. During combination therapy FPG was decreased an additional 41 mg/dl (18%), and postprandial glucose was decreased and additional 54 mg/dl (21%), both significant changes from monotherapy. Adding troglitazone to metformin did not further decrease endogenous glucose production, however significantly increased glucose disposal. The addition of metformin to the troglitazone group produced only a modest increase in glucose disposal (Inzucchi et al 1998). Thus the main efficacy of combined therapy seemed to be the effect of metformin to decrease endogenous glucose production and that of troglitazone to improve insulin sensitivity, together targeting two pathophysiologic defects in DM2.

Troglitazone was taken off the market in 1999 because of concerns for hepatic toxicity. Subsequent studies of TZDs were with either rosiglitazone or pioglitazone. The first randomized controlled trial of the combined use of metformin with TZD in a large population was with rosiglitazone, published in 2000. In this study, 348 diabetic patients were randomized to metformin plus placebo, metformin plus 4 mg/d rosiglitazone or metformin plus 8 mg/d rosiglitazone for 26 weeks. The primary endpoint was glycemic control. In this interval, addition of 4 mg rosiglitazone to metformin lowered FPG by 33 mg/dl, A1C by 0.56. The 8 mg dose of rosiglitazone, lowered FPG by 48 mg/dl and A1C by 0.78, all statistically significant changes. Treatment effects were seen by as early as 4 weeks of treatment. Insulin sensitivity was assessed by the homeostasis model of assessment (HOMA), and both groups had increased sensitivity compared to the metformin-placebo group (Fonseca et al 2000).

A RCT with pioglitazone randomized 328 patients to pioglitazone-metformin or metformin-placebo for 16 weeks and found the pioglitazone group had a significant A1c decrease of 0.83% compared to placebo-metformin. There was a significant improvement in insulin resistance by HOMA-IR (Einhorn et al 2000). When a sulfonylurea is used with metformin as a control group rather than placebo-metformin, several studies have demonstrated similar glycemic control (Charbonnel et al 2005; Matthews et al 2005; Umpierrez et al 2006). Two studies by the same group compared more long term combination use of pioglitazone added to metformin (Charbonnel et al 2005; Matthews et al 2005). One was a one year double blind study that compared metformin-pioglitazone combination with metformin-gliclazide. The authors found similar decreases in A1C and FPG with each treatment (Matthews et al 2005). The study that went for two years also found similar reductions in A1C, and slightly better FPG with metformin-pioglitazone combination compared with metformin-gliclazide (Charbonnel et al 2005). These results suggest that the glycemic effects of combination therapy with metformin-pioglitazone can be sustained for at least two years.

Of note, similar improvements in glycemic control with the combined use of metformin and thiazolidinediones were noted in Mexicans, who have a significant burden of diabetes (Gomez-Perez et al 2002). Weissman and colleagues in a multi-center double blind RCT with 766 subjects compared adding rosiglitazone to 1000 mg of metformin with dose escalation of metformin for 24 weeks. They found improvements in FPG and A1C with rosiglitazone-metformin over metformin dose escalation (Weissman et al 2005), a potential benefit for patients unable to tolerate full dose metformin. In an open labeled RCT, Dailey and colleagues added rosiglitazone vs. placebo to patients already on metformin and glyburide. They found improved A1C and FPG with the addition of rosiglitazone (Dailey et al 2004). In a randomized, open-label parallel trial either insulin glargine or rosiglitazone was added to patients with inadequate glycemic control on metformin plus sulfonylurea. These authors found similar improvements in glycemic control with both regimens (Rosenstock et al 2006).

Cardiovascular effects of combined use of metformin-TZDs

The RCT by Fonseca and colleagues with rosiglitazone described above also looked at secondary endpoints known to be important for cardiovascular health with metformin-rosiglitazone (Fonseca et al 2000). There were small but statistically significant increases in HDL cholesterol. There were no changes in triglycerides. Total cholesterol and LDL levels were statistically increased with either rosiglitazone group (LDL levels increased from 112 mg/dl to 133 mg/dl in the 8 mg/d rosiglitazone-metformin group). Free fatty acid levels, which are a potential mediator of insulin resistance, were decreased in both rosiglitazone groups. Both rosiglitazone groups had a small but significant decrease in hemoglobin levels, weight gain (Fonseca et al 2000). Several other RCTs found worsening lipid profiles with the addition of rosiglitazone to metformin (Gomez-Perez et al 2002; Weissman et al 2005; Rosenstock et al 2006). The weight gain and increase in LDL are important considerations in patients already at risk for cardiovascular disease.

Two RCTs published with pioglitazone revealed statistically significant improvements in TGs and HDL, but little change in TC or LDL (Einhorn et al 2000; Betteridge and Verges 2005), whereas two others from the same group found that at one year of combined therapy with metformin-pioglitazone, TC, HDL and TG were improved, but LDL was elevated (Matthews et al 2005), but at two years pioglitazone-metformin group had improved TG, HDL and no change in LDL (Charbonnel et al 2005). These studies are somewhat consistent with the more beneficial lipid profile of pioglitazone compared to rosiglitazone as single agents (Chiquette et al 2004). Additionally, pioglitazone influences LDL particle size with an increase in large LDL particles and a decrease in small particles, consistent with a potentially less atherogenic cholesterol profile (Perez et al 2004).

Insulin resistance is a central feature of the metabolic syndrome. An Italian study evaluated addition of glimepiride or rosiglitazone to metformin therapy for patients with poorly controlled DM2, hypertension, obesity and dyslipidemia. They found that addition of rosiglitazone to metformin brought about more rapid improvements in A1C and FPG, but glycemic control was similar at 12 months compared to addition of glimepiride to metformin. They did find modest but statistically significant improvements in systolic blood pressure and diastolic blood pressure in patients on metformin-rosiglitazone compared to the metformin-glimepiride group (Derosa et al 2005b).

Side effects and contraindications

Weight gain, edema and, depending on which TZD is selected, worsened lipid profiles are the most common side effects of adding a TZD to metformin and are similar to the side effects of the TZDs as single agents. The average weight gain on TZDs is 2.7 kg, with a range of 0.7 kg in a Japanese study to more than 3kd in non-Japansese studies (Chiquette et al 2004). In the largest study of TZD combined with metformin, weight gain of about 2 kg occurred on the highest rosiglitazone dose with metformin (Fonseca et al 2000). Frank edema was present in about 4% of patients (GlaxoSmithKline 2007; Takeda Pharmaceuticals 2007), and body water retention is felt to contribute to about 75% of the weight gain on TZDs (Basu et al 2006). Insulin is a potent anti-natriuretic hormone (DeFronzo et al 1976), it may be that TZD treatment sensitizes to the anti-natriuretic actions of insulin, contributing to edema. Anemia was present in 4% – likely the result of hemodilution associated with fluid retention. Interestingly, a smaller part of weight gain comes from a re-distribution of fat from the visceral compartment to subcutaneous compartment (Miyazaki et al 2002). This visceral fat is classically considered more pathogenic in diabetes than subcutaneous fat, thus fat re-distribution is likely one of the major mechanisms by which TZDs mediate their beneficial effects on insulin sensitivity (Gastaldelli et al 2002). According to manufactures’ prescribing information, TZD/metformin is contraindicated in patient that exhibit clinical evidence of active liver disease or increased serum transaminase levels, renal disease or renal dysfunction (eg, as suggested by serum creatinine levels ≥1.5 mg/dL (males), ≥1.4 mg/dL (females), acute or chronic metabolic acidosis. Although TZDs are contraindicated in acute liver disease, their insulin sensitizing effects may prove to be beneficial in the treatment of non-alcoholic fatty liver disease (reviewed in Caldwell et al (2006)). TZDs should be avoided in patients with CHF, severe edema or macular edema. TZDs are considered class C for pregnancy (GlaxoSmithKline 2007; Takeda Pharmaceuticals 2007). Any metformin containing drug should be stopped before radiologic procedures with iodinated IV contrast for risk of lactic acidosis. No data is available for combined use of metformin-TZD in pediatric patients.

Rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, CYP2C9. Gemfiborzil increases rosiglitazone levels. Rifampin reduceds rosiglitazone levels. Furosimide increases metformin levels, as does Nifedipine. Cationic drugs (eg, amiloride, digoxin, morphine, trimethoprim, and vancomycin and others) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing renal excretion (GlaxoSmithKline 2007). Pioglitazone is metabolized by CYP2C8 and to a lesser extent CYP3A4, thus drug interactions include midazolam, nifedipine ER, ketoconazole, atorvastatin (Takeda Pharmaceuticals 2007). Full details of cautions, contraindications, drug interactions and pharmacokinetics are available in the prescribing information from the manufactures (GlaxoSmithKline 2007; Takeda Pharmaceuticals 2007).

Availability

Rosiglitazone-metformin (Avandamet™) is available in the following doses of rosiglitazone/metformin, respectively; 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg, 2 mg/1000 mg, 4 mg/1000 mg. Rosiglitazone-metformin can be titrated up to a maximal total daily dose of 8 mg/2000 mg (GlaxoSmithKline 2007). One published study of healthy volunteers received; metformin 500 mg, rosiglitazone 2 mg, or each twice daily for four days. Coadministration of rosiglitazone and metformin had no effects on steady state pharmacokinetics of either drug (Di Cicco et al 2000). Pioglitazone-metformin (Actoplus Met™) is available in doses of pioglitazone/metformin, respectively of; 15 mg/500 mg or 15 mg/850 mg with recommended maximal daily dosing of 45 mg/2550 mg (Takeda Pharmaceuticals 2007).

Mechanisms of action

The glucose lowering effects of metformin are largely attributable to an increase in glucose uptake by muscle and decrease in hepatic glucose production (Perriello et al 1994; Bailey and Turner 1996; Large and Beylot 1999; Hundal et al 2000). TZDs primarily act to improve insulin sensitivity (reviewed in Yki-Jarvinen 2004). Detailed summaries of the mechanisms of action of both metformin and TZDs have been reviewed elsewhere and are beyond the scope of this review (Bailey and Turner 1996; Kirpichnikov et al 2002; Yki-Jarvinen 2004). This section focuses on potential cellular and molecular mechanisms by which the combined use of metformin and TZD may be beneficial, and also mechanisms of possible side effects.

AMP-activated protein kinase (AMPK) is a heterotrimeric complex which responds to the energy status of the cell in that an increase in the AMP:ATP ratio causes threonine phosphorylation, and thus activation of AMPK (Hawley et al 1996). In response to AMPK activation the cell decreases ATP-consuming and increases ATP-producing pathways, thus a potential metabolic sensor for the cell (Hardie et al 1998). Both Metformin and TZDs activate AMPK through distinct pathways, thus AMPK may be a mediator of the protective effects of metformin and TZDs on insulin action (Fryer et al 2002).

The efficacy of combination of TZD and metformin may be in part due to prevention of fatty-acid induced insulin resistance, or lipotoxicity (the concept of lipotoxicity is reviewed in Unger (2005)). Ye and colleagues demonstrated by hyperinsulinemic clamp studies in rats that both metformin and rosiglitazone improved insulin sensitivity, by improving insulin-mediated suppression of hepatic glucose output (Ye et al 2004). Rosiglitazone additionally enhanced free fatty acid (FFA) clearance, measured by 3H-R-bromopalmitate tracer technique (Ye et al 2004). Rosiglitazone increased FFA uptake by adipose and reduced uptake by the liver and muscle, as well as decreased liver long-chain CoA accumulation, a potential mediator of fatty-acid induced insulin resistance (Lee et al 1994; Ye et al 2004). Additionally this group has demonstrated that pioglitazone protects from FFA-induced insulin resistance in the liver (Ye et al 2002).

In addition to fatty acids, many inflammatory mediators, when elevated, can cause insulin resistance in animal models and may contribute to the pathogenesis of DM2. These include CRP, an important protein in leptin action (Chen et al 2006), and TNFα (reviewed in Moller 2000). In one double blind RCT of patients with metabolic syndrome, rosiglitazone 8 mg qd for 12 wks, increased adiponectin, lowered resistin, CRP and TNFα (Samaha et al 2006). Adiponectin levels are inversely correlated with cardiovascular risk, thus an increase would be predicted to benefit cardiovascular health (Pischon et al 2004). Lowering levels of resistin, CRP and TNFα should contribute to improved insulin resistance. In the study by Samaha, however, despite beneficial changes in inflammatory mediators of insulin resistance, there was very little improvement in other clinical parameters known to contribute to cardiovascular risk, with an increase in total cholesterol, and no significant changes in HDL or LDL (Samaha et al 2006).

In addition to the effects on FFA flux and glucose, TZD treatment may have beneficial effects on vascular health directly. PPAR gamma is expressed in endothelial cells, and may have important role in vascular restenosis (reviewed in (Bruemmer et al 2005). In cultured endothelial cells ligand activation of PPAR gamma has been shown to inhibit thrombin-induced endothelin-1 production (Delerive et al 1999) and plasminogen activator inhibitor type 1 expression (Kato et al 1999). In people, progression of carotid intima-media thickness, a marker of atherosclerotic disease, is improved with pioglitazone (Mazzone et al 2006). In one double blind RCT, diabetic patients were treated with metformin or rosiglitazone. In the rosiglitazone group, intra-arterial acethylcholine-mediated vasoidailation (an indicator of arterial endothelial function) was improved by 40% and correlated with a decrease in FFA and TNFα (Natali et al 2004).

In summary, the combined use of metformin and a TZD have significant improvements in glycemic control. The main efficacy of combined therapy seems to be the effect of metformin to decrease endogenous glucose production and that of TZDs to improve insulin sensitivity, together targeting two key pathophysiologic defects in DM2. Single pill combinations of both rosiglitazone-metformin (Avandamet™), and pioglitazone-metformin (Actoplus Met™) are available in Europe and the US. It is important to emphasize that potential cardiovascular benefits from the combined use of metformin and a TZD are not established in clinical trials. While there is data on the cardiovascular benefit of both drugs individually, UKPDS for metformin and PROactive for pioglitazone (UKPDS 1998; Dormandy et al 2005), little distal outcome data for the combined use of these agents in terms of morbidity or mortality is currently available. The RECORD (rosiglitazone evaluated for cardiac outcomes and regulation of glycemia in diabetes) study is underway, one arm of which will test rosiglitazone added to metformin for cardiovascular outcomes and progression of diabetes (Ovalle and Bell 2004).


Search criteria

In addition to the authors’ personal knowledge of the literature in this field, databases reviewed include medline/pubmed 1966 to May Week 5 2006, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, EBM Reviews-Database of Abstracts of Reviews of Effects, ACP Journal Club 1991 to May/June 2006. Search terms included Rosiglitazone/troglitazone/pioglitazone AND Metformin, thiazolidinedione, vascular, cardiovascular, endothelial, diabetes, insulin resistance.


Abbreviations

Thiazolidinedione (TZD), type two diabetes mellitus (DM2), impaired glucose tolerance (IGT), total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), free fatty acids (FFA), fasting plasma glucose (FPG), hemoglobin A1C (A1C), randomized control trial (RCT), Cardiovascular disease (CVD), congestive heart failure (CHF).


References
Bailey CJ,Turner RC. MetforminN Engl J Med 1996;334:574–9. [pmid: 8569826]
Balletshofer BM,Rittig K,Enderle MD,et al. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistanceCirculation 2000;101:1780–4. [pmid: 10769277]
Basu A,Jensen MD,McCann F,et al. Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynamics in type 2 diabetesDiabetes Care 2006;29:510–14. [pmid: 16505497]
Bergholm R,Tiikkainen M,Vehkavaara S,et al. Lowering of LDL cholesterol rather than moderate weight loss improves endothelium-dependent vasodilatation in obese women with previous gestational diabetesDiabetes Care 2003;26:1667–72. [pmid: 12766091]
Betteridge DJ,Verges B. Long-term effects on lipids and lipoproteins of pioglitazone versus gliclazide addition to metformin and pioglitazone versus metformin addition to sulphonylurea in the treatment of type 2 diabetesDiabetologia 2005;48:2477–81. [pmid: 16283239]
Bruemmer D,Blaschke F,Law RE. New targets for PPARgamma in the vessel wall: implications for restenosisInt J Obes (Lond) 2005;29(Suppl 1):S26–30. [pmid: 15711579]
Caballero AE. Metabolic and vascular abnormalities in subjects at risk for type 2 diabetes: the early start of a dangerous situationArch Med Res 2005;36:241–9. [pmid: 15925014]
Caldwell SH,Argo CK,Al-Osaimi AM. Therapy of NAFLD: insulin sensitizing agentsJ Clin Gastroenterol 2006;40:S61–6. [pmid: 16540770]
Charbonnel B,Schernthaner G,Brunetti P,et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetesDiabetologia 2005;48:1093–4. [pmid: 15889234]
Chen K,Li F,Li J,et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptinNat Med 2006;12:425–32. [pmid: 16582918]
Chiquette E,Ramirez G,Defronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factorsArch Intern Med 2004;164:2097–104. [pmid: 15505122]
Dailey GE 3rd,Noor MA,Park JS,et al. Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trialAm J Med 2004;116:223–9. [pmid: 14969649]
DeFronzo RA. Pathogenesis of type 2 diabetes mellitusMed Clin North Am 2004;88:787–835. ix. [pmid: 15308380]
DeFronzo RA,Goldberg M,Agus ZS. The effects of glucose and insulin on renal electrolyte transportJ Clin Invest 1976;58:83–90. [pmid: 932211]
DeFronzo RA,Gunnarsson R,Bjorkman O,et al. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitusJ Clin Invest 1985;76:149–55. [pmid: 3894418]
Delerive P,Martin-Nizard F,Chinetti G,et al. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathwayCirc Res 1999;85:394–402. [pmid: 10473669]
Derosa G,Cicero AF,Gaddi A,et al. A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndromeDiabetes Res Clin Pract 2005a;69:5–13. [pmid: 15955382]
Derosa G,Cicero AF,Gaddi AV,et al. Long-term effects of glimepiride or rosiglitazone in combination with metformin on blood pressure control in type 2 diabetic patients affected by the metabolic syndrome: a 12-month, double-blind, randomized clinical trialClin Ther 2005b;27:1383–91. [pmid: 16291411]
Di Cicco RA,Allen A,Carr A,et al. Rosiglitazone does not alter the pharmacokinetics of metforminJ Clin Pharmacol 2000;40:1280–5. [pmid: 11075314]
Dormandy JA,Charbonnel B,Eckland DJ,et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trialLancet 2005;366:1279–89. [pmid: 16214598]
Einhorn D,Rendell M,Rosenzweig J,et al. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study GroupClin Ther 2000;22:1395–409. [pmid: 11192132]
Fonseca V,Rosenstock J,Patwardhan R,et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trialJAMA 2000;283:1695–702. [pmid: 10755495]
Fryer LG,Parbu-Patel A,Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathwaysJ Biol Chem 2002;277:25226–32. [pmid: 11994296]
Gastaldelli A,Miyazaki Y,Pettiti M,et al. Metabolic effects of visceral fat accumulation in type 2 diabetesJ Clin Endocrinol Metab 2002;87:5098–103. [pmid: 12414878]
Gerstein HC,Yusuf S,Bosch J,et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trialLancet 2006;368:1096–105. [pmid: 16997664]
Ginsberg H,Kimmerling G,Olefsky JM,et al. Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemiaJ Clin Invest 1975;55:454–61. [pmid: 1117064]
GlaxoSmithKline. Avandamet: summary of product characteristics [online]2007 URL:
Gomez-Perez FJ,Fanghanel-Salmon G,Antonio Barbosa J,et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetesDiabetes Metab Res Rev 2002;18:127–34. [pmid: 11994904]
Granner DK,O’Brien RM. Molecular physiology and genetics of NIDDM. Importance of metabolic stagingDiabetes Care 1992;15:369–95. [pmid: 1559407]
Haffner SM,Lehto S,Ronnemaa T,et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarctionN Engl J Med 1998;339:229–34. [pmid: 9673301]
Haffner SM,Stern MP,Hazuda HP,et al. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?JAMA 1990;263:2893–8. [pmid: 2338751]
Hardie DG,Carling D,Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?Annu Rev Biochem 1998;67:821–55. [pmid: 9759505]
Hawley SA,Davison M,Woods A,et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinaseJ Biol Chem 1996;271:27879–87. [pmid: 8910387]
Howard BV,Rodriguez BL,Bennett PH,et al. Prevention Conference VI: Diabetes and Cardiovascular disease: Writing Group I: epidemiologyCirculation 2002;105:e132–7. [pmid: 11994263]
Hundal RS,Krssak M,Dufour S,et al. Mechanism by which metformin reduces glucose production in type 2 diabetesDiabetes 2000;49:2063–9. [pmid: 11118008]
Inzucchi SE,Maggs DG,Spollett GR,et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitusN Engl J Med 1998;338:867–72. [pmid: 9516221]
Kato K,Satoh H,Endo Y,et al. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: A possible role for PPARgamma in endothelial functionBiochem Biophys Res Commun 1999;258:431–5. [pmid: 10329404]
Kendall DM,Rubin CJ,Mohideen P,et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative studyDiabetes Care 2006;29:1016–23. [pmid: 16644631]
Kersten S,Desvergne B,Wahli W. Roles of PPARs in health and diseaseNature 2000;405:421–4. [pmid: 10839530]
Kirpichnikov D,McFarlane SI,Sowers JR. Metformin: an updateAnn Intern Med 2002;137:25–33. [pmid: 12093242]
Knowler WC,Barrett-Connor E,Fowler SE,et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metforminN Engl J Med 2002;346:393–403. [pmid: 11832527]
Large V,Beylot M. Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metforminDiabetes 1999;48:1251–7. [pmid: 10342812]
Lee Y,Hirose H,Ohneda M,et al. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationshipsProc Natl Acad Sci USA 1994;91:10878–82. [pmid: 7971976]
Lillioja S,Mott DM,Howard BV,et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima IndiansN Engl J Med 1988;318:1217–25. [pmid: 3283552]
Magnusson I,Rothman DL,Katz LD,et al. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance studyJ Clin Invest 1992;90:1323–7. [pmid: 1401068]
Matthews DR,Charbonnel BH,Hanefeld M,et al. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative studyDiabetes Metab Res Rev 2005;21:167–74. [pmid: 15386821]
Mazzone T,Meyer PM,Feinstein SB,et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trialJAMA 2006;296:2572–81. [pmid: 17101640]
Meigs JB,Larson MG,D’Agostino RB,et al. Coronary artery calcification in type 2 diabetes and insulin resistance: the framingham offspring studyDiabetes Care 2002;25:1313–9. [pmid: 12145227]
Meigs JB,Mittleman MA,Nathan DM,et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring StudyJAMA 2000;283:221–8. [pmid: 10634338]
Miyazaki Y,Mahankali A,Matsuda M,et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patientsJ Clin Endocrinol Metab 2002;87:2784–91. [pmid: 12050251]
Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetesTrends Endocrinol Metab 2000;11:212–7. [pmid: 10878750]
Natali A,Baldeweg S,Toschi E,et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetesDiabetes Care 2004;27:1349–57. [pmid: 15161787]
Nolan JJ,Ludvik B,Beerdsen P,et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazoneN Engl J Med 1994;331:1188–93. [pmid: 7935656]
Ovalle F,Bell DS. Effect of rosiglitazone versus insulin on the pancreatic beta-cell function of subjects with type 2 diabetesDiabetes Care 2004;27:2585–9. [pmid: 15504990]
Perez A,Khan M,Johnson T,et al. Pioglitazone plus a sulphonylurea or metformin is associated with increased lipoprotein particle size in patients with type 2 diabetesDiab Vasc Dis Res 2004;1:44–50. [pmid: 16305056]
Perriello G,Misericordia P,Volpi E,et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose productionDiabetes 1994;43:920–8. [pmid: 8013758]
Pischon T,Girman CJ,Hotamisligil GS,et al. Plasma adiponectin levels and risk of myocardial infarction in menJAMA 2004;291:1730–7. [pmid: 15082700]
Polonsky KS,Sturis J,Bell GI. Seminars in Medicine of the Beth Israel Hospital, Boston. Non-insulin-dependent diabetes mellitus – a genetically programmed failure of the beta cell to compensate for insulin resistanceN Engl J Med 1996;334:777–83. [pmid: 8592553]
Roe MW,Worley JF 3rd,Tokuyama Y,et al. NIDDM is associated with loss of pancreatic beta-cell L-type Ca2+ channel activityAm J Physiol 1996;270:E133–40. [pmid: 8772485]
Rosenstock J,Sugimoto D,Strange P,et al. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patientsDiabetes Care 2006;29:554–9. [pmid: 16505505]
Rossetti L,DeFronzo RA,Gherzi R,et al. Effect of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlationsMetabolism 1990;39:425–35. [pmid: 2157941]
Saad MF,Knowler WC,Pettitt DJ,et al. The natural history of impaired glucose tolerance in the Pima IndiansN Engl J Med 1988;319:1500–6. [pmid: 3054559]
Saad MF,Knowler WC,Pettitt DJ,et al. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetesLancet 1989;1:1356–9. [pmid: 2567374]
Samaha FF,Szapary PO,Iqbal N,et al. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndromeArterioscler Thromb Vasc Biol 2006;26:624–30. [pmid: 16357312]
Takeda Pharmaceuticals Actosplus Met. Prescribing information [online] Accessed 25 July 2007. URL:
UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) GroupLancet 1998;352:854–65. [pmid: 9742977]
Umpierrez G,Issa M,Vlajnic A. Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trialCurr Med Res Opin 2006;22:751–9. [pmid: 16684436]
Unger RH. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famineBiochimie 2005;87:57–64. [pmid: 15733738]
Weissman P,Goldstein BJ,Rosenstock J,et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE StudyCurr Med Res Opin 2005;21:2029–35. [pmid: 16368054]
Wilson PW,D’ Agostino RB,Parise H,et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitusCirculation 2005;112:3066–72. [pmid: 16275870]
Wilson PW,D’ Agostino RB,Sullivan L,et al. Overweight and obesity as determinants of cardiovascular risk: the Framingham experienceArch Intern Med 2002;162:1867–72. [pmid: 12196085]
Xiang AH,Peters RK,Kjos SL,et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetesDiabetes 2006;55:517–22. [pmid: 16443789]
Ye JM,Dzamko N,Cleasby ME,et al. Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metforminDiabetologia 2004;47:1306–13. [pmid: 15232684]
Ye JM,Frangioudakis G,Iglesias MA,et al. Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation: role of the liverEndocrinology 2002;143:4527–35. [pmid: 12446579]
Yki-Jarvinen H. ThiazolidinedionesN Engl J Med 2004;351:1106–18. [pmid: 15356308]

Article Categories:
  • Review

Keywords: thiazolidinediones, metformin, Type 2 diabetes.

Previous Document:  Apolipoproteins A-I and B: biosynthesis, role in the development of atherosclerosis and targets for ...
Next Document:  The burden of type 2 diabetes: strategies to prevent or delay onset.