Clinical Therapeutics/Volume 34, Number 6, 2012

Efficacy and Safety Profile Evaluation of Acarbose Alone and in Association With Other Antidiabetic Drugs: A Systematic Review

Giuseppe Derosa, MD, PhD; and Pamela Maffioli, MD Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

ABSTRACT cemia (P Ͻ 0.0001). Treatment with acarbose seemed Background: Epidemiologic studies have revealed to improve the lipid profile (P Ͻ 0.05), reduce circulat- that postprandial significantly contrib- ing levels of cell adhesion molecules (P Ͻ 0.05), reduce utes to high concentrations and intima-media thickness progression (P ϭ 0.01), and could be linked to the development of chronic diabetic reverse impaired tolerance to normal glucose complications. tolerance (P Ͻ 0.0001). Objective: The purpose of our review was to evalu- Conclusions: When current therapy is not adequate ate the clinical efficacy and safety profile of treatment to obtain glycemic control, acarbose could be an op- with acarbose alone and combined with other antidia- tion as monotherapy and as an add-on to other antidi- betic drugs. abetic drug treatment, especially when postprandial Methods: A systematic search strategy was devel- hyperglycemia is the main concern. Long-term studies oped to identify randomized controlled trials included are needed to determine whether the effects observed in MEDLINE and the Cochrane Register of Controlled with acarbose use are maintained over the years. (Clin Trials. The terms acarbose, ␣-glucosidase inhibitors, Ther. 2012;34:1221–1236) © 2012 Elsevier HS Jour- type 2 , adverse events, combination therapy, nals, Inc. All rights reserved. ␣ and postprandial glucose were incorporated into an Key words: acarbose, -glucosidase inhibitors, com- electronic search strategy that included the Dickersin bination therapy, glycemic control, postprandial hyper- filter for randomized controlled trials. To qualify for glycemia. inclusion, clinical trials had to be randomized trials comparing treatment with acarbose at any dosage with INTRODUCTION any other antidiabetic drug in patients with type 2 di- The importance of an early and aggressive approach to abetes mellitus or impaired glucose tolerance. Eligible metabolic control has been demonstrated by the long- trials had to present results on glycemic control or ad- term results of the United Kingdom Prospective Diabe- verse events. Trial participants needed to be affected by tes Study, which showed that the benefits of tight blood mellitus or have impaired glucose tol- glucose control extended well beyond the end of the erance, and the intervention had to include acarbose at study and persisted for 10 years.1 However, concern any dosage as monotherapy or combined with other emerged when, in February 2008, the glycemic arm of antidiabetic drugs. A validated 3-item scale was used to the ACCORD (Action to Control Cardiovascular Risk evaluate the overall reporting quality of the trials se- in Diabetes) study was terminated prematurely be- lected for inclusion in the present review. Nineteen tri- cause of the increased mortality rate observed in the als were included. group of diabetic individuals who were treated aggres- Results: Treatment with acarbose significantly re- sively with the aim of achieving a glycated hemoglobin duced glycated hemoglobin levels when given as mono- Ͻ (HbA1c) level 6%. An increased all-cause mortality therapy and as an add-on to other antidiabetic drug treatment (P Ͻ 0.0001). Acarbose treatment was effec- Accepted for publication April 12, 2012. tive in patients with uncontrolled type 2 diabetes and http://dx.doi.org/10.1016/j.clinthera.2012.04.012 in patients with apparently good metabolic control 0149-2918/$ - see front matter owing to its positive effect on postprandial hypergly- © 2012 Elsevier HS Journals, Inc. All rights reserved.

June 2012 1221 Clinical Therapeutics

Lifestyle measures

Then at each step, if not to target (glycated hemoglobin <7.0%) First-line therapy: Usual approach Alternative as per guidelines

Metformin or α-glucosidase inhibitor Second-line therapy: Usual approach Alternative as per guidelines

Sulfonylurea (if not first line), or , or DPP-4 inhibitor, or α-glucosidase inhibitor Third-line therapy: Usual approach Alternative as per guidelines

Basal or premixed insulin or GLP-1 mimetic thiazolidinedione, or DPP-4 inhibitor or α-glucosidase inhibitor Fourth-line therapy: Usual approach

Basal insulin + meal-time insulin

Figure 1. Diabetes therapy management. DPP-4 ϭ dypeptidil peptidase-4; GLP-1 ϭ glucagon-like peptide-1.

rate in the aggressively treated group resulted from According to several trials and reviews reported in increased cardiovascular mortality, even if there was a the literature,6–11 when lifestyle interventions do not decrease in the number of nonfatal myocardial infarc- achieve or maintain the metabolic goals because of fail- tions.2 In contrast, the ADVANCE (Action in Diabetes ure to lose weight, weight regain, progressive disease, and Vascular Disease: Preterax and Diamicron Modi- or a combination of factors, metformin therapy should fied Release Controlled Evaluation) and the Veterans be initiated. If lifestyle intervention and administration Affairs Diabetes Trial showed no change in the rates of of the maximal tolerated dose of metformin do not all-cause mortality and cardiovascular mortality in the achieve or sustain the glycemic goals, another medica- intensively treated groups.3,4 All data considered, ac- tion should be added within 2 to 3 months of initiation cording to the latest American Diabetes Association of therapy or at any time when the target HbA1c level is 5 guidelines, lowering HbA1c levels to below or approx- not achieved (Figure 1). imately 7% has been shown to reduce microvascular Currently, many antidiabetic drugs are available, and neuropathic complications of diabetes and, if im- and the choice should be made on the basis of the plemented soon after the diagnosis of diabetes, is asso- characteristics of the various drugs (Table I). Bigua- ciated with a long-term reduction in macrovascular nides were the first antidiabetic drugs to become avail- disease. able, and the most used drug in this class is metformin,

1222 Volume 34 Number 6 G. Derosa and P. Maffioli

Table I. Characteristics of various antidiabetic drugs.

Main Agents of Antidiabetic Class the Class Mechanism of Action Adverse Events

Biguanides Metformin Decrease hepatic glucose Gastrointestinal events output and consequently lower fasting glycemia , Enhance insulin secretion , , and Glinides and Enhance insulin secretion Hypoglycemia binding to a different site in the sulfonylurea receptor ␣-Glucosidase Acarbose and Delay the breakdown of Increased gas production inhibitors in the gut, and gastrointestinal inhibiting ␣-glucosidase symptoms Act as peroxisome Weight gain and fluid proliferator activated retention receptor gamma modulators Glucagon-like peptide- and Bind to the receptor for Nausea, vomiting, or 1 agonists GLP-1 Dypeptidil peptidase-4 , Inhibit the enzyme DPP- Increase in upper inhibitors , 4, increasing incretin’s respiratory tract , and time of action infections

DPP-4 ϭ dypeptidil peptidase-4; GLP-1 ϭ glucagon-like peptide-1.

which acts by decreasing hepatic glucose output and enhance insulin secretion, although they bind to a dif- consequently lowering fasting glycemia values. Typi- ferent site in the sulfonylurea receptor.15 cally, metformin monotherapy lowers HbA1c levels by Glinides have a shorter circulating half-life than do 1.5 percentage points.12,13 It is generally well toler- sulfonylureas. Of the 2 glinides currently available in ated, with the most common adverse effects being gas- the United States, repaglinide is almost as effective as trointestinal. After metformin, sulfonylureas (glipiz- metformin and sulfonylureas, decreasing HbA1c levels ide, glibenclamide, glimepiride, and gliclazide) became by 1.5 percentage points. The major adverse effect of available. They lower glycemia values by enhancing treatment with sulfonylureas is hypoglycemia. On the insulin secretion. In terms of efficacy, they seem to be other hand, ␣-glucosidase inhibitors (acarbose and similar to metformin, lowering HbA1c levels by 1.5 miglitol) reduce postprandial hyperglycemia, delaying percentage points.14 The major adverse effect is hypo- the breakdown of carbohydrates in the gut and, con- glycemia, which can be prolonged and life threatening, sequently, slowing the absorption of . They are but such episodes, characterized by a need for assis- less effective at lowering glycemia values than are met- tance, coma, or seizure, are rare. Similar to sulfonyl- formin and sulfonylureas, reducing HbA1c levels by 0.5 ureas are glinides (repaglinide and nateglinide), which to 0.8 percentage points16; however, these agents in-

June 2012 1223 Clinical Therapeutics duce a significant decrease in the postprandial rise in showed that liraglutide use provided significantly glucose levels without increasing circulating insulin greater improvements in glycemic control than did levels and without causing hypoglycemia.17 Since car- exenatide use and was generally better tolerated.24 bohydrates are absorbed more distally, malabsorption However, a new formulation of exenatide has recently and weight loss do not occur; however, increased de- become available. This formulation is an extended-re- livery of carbohydrates to the colon commonly results lease medication for type 2 diabetes designed to deliver in increased gas production and gastrointestinal continuous therapeutic levels of exenatide in a single symptoms. weekly dose. Regarding this new formulation, the Thiazolidinediones (pioglitazone), instead, are per- soon-to-be-published DURATION-6 trial compared oxisome proliferator activated receptor gamma modu- the efficacy of subcutaneous injection of the new for- lators; they increase the sensitivity of muscle, fat, and mulation of exenatide once weekly (2 mg/wk) and li- liver to endogenous and exogenous insulin (“insulin raglutide (forced titration to 1.8 mg/d). The results sensitizers”).18 The data regarding the blood glucose– showed that patients receiving exenatide once a week lowering effectiveness of thiazolidinediones when used experienced a reduction in HbA1c levels of 1.3% from as monotherapy have demonstrated a 0.5– to 1.4–per- baseline compared with a reduction of 1.5% for those centage point decrease in HbA1c levels. The thiazoli- taking liraglutide. However, gastrointestinal adverse dinediones seem to have a more durable effect on events occurred more often in patients receiving lira- glycemic control, particularly compared with sulfonyl- glutide (nausea was reported in 20% of patients, vom- ureas.6 The most common adverse effects with thiazo- iting in 11%, and diarrhea in 13%) compared with lidinedione use are weight gain and fluid retention, those taking exenatide once a week (nausea, 9%; vom- with peripheral edema and a 2-fold increased risk of iting, 4%; and diarrhea, 6%).25 congestive heart failure19; however, the weight gain The DPP-4 inhibitors (sitagliptin, vildagliptin, saxa- can be reduced by the use of combined thiazolidinedio- gliptin, and linagliptin) are small molecules that en- nes and metformin.7 hance the effects of GLP-1 and glucose-dependent Recently, 2 new classes of antidiabetic drugs were insulinotropic peptide, increasing glucose-mediated in- marketed: glucagon-like peptide-1 (GLP-1) agonists sulin secretion and suppressing glucagon secre- and dypeptidil peptidase-4 (DPP-4) inhibitors. The tion.26,27 In clinical trials, DPP-4 inhibitors lower

GLP-1 agonists (exenatide and liraglutide) act as incre- HbA1c levels by 0.6 to 0.9 percentage points and are tin mimetics; they have structural similarity and bind weight neutral and relatively well tolerated.11,26,27 to the receptor for GLP-1, and they display a similar They do not cause hypoglycemia when used as mono- broad range of activities relevant to improving glyce- therapy. The potential for this class of compounds to mic control. They have a much longer half-life after interfere with immune function is of concern; an in- injection than does native GLP-1 due to the absence of crease in upper respiratory tract infections has been alanine at position 2, which is recognized by DPP-4, reported.28 and this characteristic makes them resistant to DPP-4 However, reaching an adequate HbA1c level is not cleavage. The GLP-1 agonists seem to lower HbA1c enough; in the past few years, in fact, epidemiologic levels by 0.5 to 1 percentage points, mainly by lower- studies have revealed that postprandial hyperglycemia ing postprandial blood glucose levels, and they reduce is a frequent phenomenon in patients with type 2 dia- body weight.6,20–23 Exenatide also suppresses gluca- betes mellitus receiving active treatment and can occur gon secretion and slows gastric motility. The GLP-1 even when metabolic control is apparently good; older agonists are not associated with hypoglycemia, but age, longer duration of diabetes, absence of obesity, they cause a relatively high frequency of gastrointesti- hypertension, and dyslipidemia are clinical features re- nal disturbances, with 30% to 45% of treated patients lated to exaggerated postprandial glucose (PPG) experiencing 1 or more episodes of nausea, vomiting, peaks.29 Postprandial hyperglycemia significantly con- or diarrhea. Despite their similar mechanism of action, tributes to high HbA1c concentrations and could be there are some differences between exenatide and lira- linked to the development of chronic diabetic compli- glutide. The Liraglutide Effect and Action in Diabetes 6 cations, particularly cardiovascular disease, and mi- (LEAD-6) study compared treatment with liraglutide, crovascular complications30 more than fasting hyper- 1.8 mg/d, and subcutaneous exenatide, 10 ␮g BID, and glycemia,31,32 even if this has never been proved in an

1224 Volume 34 Number 6 G. Derosa and P. Maffioli appropriately designed, defined-outcome, randomized prospective trial. The plasma glucose peak and in- Records identified by the search creased oxidative stress have been suggested as the (after duplicate filtration (n = 62) pathophysiologic mechanisms to explain this relation- ship.33 Patients treated with sulfonylureas had greater Not randomized controlled trials, animal postprandial blood glucose excursions than did those and basic research studies, review articles, studies clearly not fulfilling the inclusion not taking these medications, suggesting that sulfonyl- criteria based on title and abstract (n = 12) ureas cannot prevent PPG peaks.34 Several reviews have been reported in the literature on antidiabetic Full text retrieved (n = 50) drugs, including thiazolidinediones,15,17,35–39 GLP-1 agonists,22 and DPP-4 inhibitors27,40; however, little is The interventions assessed or the outcomes reported about acarbose. The aim of this review was to reported were not relevant to this review; assess whether treatment with acarbose can be effec- studies not fulfilling inclusion criteria (no tive and have a favorable safety profile in clinical prac- relevant comparison intervention) (n = 31) tice, alone and combined with other antidiabetic drugs, including the most important studies about acarbose in Included studies (n = 19) the past 15 years. Figure 2. Selection of various studies. MATERIALS AND METHODS A systematic search strategy was developed to identify randomized controlled trials in MEDLINE (National Li- group. Variations in fasting plasma glucose (FPG) level, brary of Medicine, Bethesda, Maryland; 1996 through homeostasis model assessment (HOMA) index, lipid pro- March 2011) and the Cochrane Register of Controlled file, insulin resistance, and inflammatory variables that Trials (The Cochrane Collaboration, Oxford, United occurred during various trials were secondary outcomes Kingdom). The terms acarbose, ␣-glucosidase inhibitors, of interest, as was the frequency of patients having 1 or type 2 diabetes, adverse events, combination therapy, and more adverse events, such as meteorism. The following postprandial glucose were incorporated into an elec- data were abstracted onto standardized case report tronic search strategy that included the Dickersin filter for forms: authors, year of publication, country of study, randomized controlled trials, a filter aimed at avoiding source of funding, study goal, means of randomization bias in the selection of trials for systematic reviews.41 The and blinding, duration of treatment, treatment character- bibliographies of all identified randomized trials and re- istics, participant sex, quantity of and reasons for study view articles were reviewed for additional studies of in- withdrawal, HbA1c levels and age characteristics of the terest. We reviewed all the citations retrieved from the treatment and control groups, outcomes, and adverse electronic search to identify potentially relevant articles event data. A validated 3-item scale was used to evaluate for this review. We subsequently reviewed the potential the overall reporting quality of the trials selected for in- trials to determine their eligibility. To qualify for inclu- clusion in the present review. This scale provided scoring sion, clinical trials were required to meet a series of pre- for randomization (0–2 points), double blinding (0–2 determined criteria regarding study design, study popula- points), and withdrawals (1 point). Scores ranged from 0 tion, interventions evaluated, and outcome measured. to 5, and scores Ն3 indicated a study of high quality.42 Studies were required to be randomized trials comparing Study selection was restricted to randomized controlled acarbose at any dosage with any other antidiabetic drug trials to ensure the inclusion of only high-quality in patients with type 2 diabetes mellitus or impaired glu- evidence. cose tolerance (IGT). Eligible trials had to present results on glycemic control or adverse events. Two outcomes RESULTS related to decreased glycemic control were of primary Comparison With the Efficacy and Safety Profile interest: (1) the proportion of individuals in each treat- of Other Drugs ment group achieving clinically significant HbA1c reduc- We identified 62 trials, but only 19 satisfied the quality tion and (2) the mean decrease (in milligrams per deciliter criteria and were included in this review (Figure 2). For a or millimoles per liter) in PPG levels in each treatment summary of the following studies, see Tables II and III.

June 2012 1225 Clinical Therapeutics

Table II. Summary of the studies cited in the review where acarbose is used as a first-line drug.

Study Duration, mo Drugs Involved Aim Results

Derosa et al43,44 7 Acarbose, 100 mg TID, To evaluate the effects Acarbose use was more vs placebo of acarbose therapy on effective than was inflammatory placebo use in biomarkers and insulin improving glycemic resistance in diabetic control, HOMA-IR, and patients before and the lipid profile and in after a standardized reducing the post-OFL OFL peaks of the various variables, including inflammatory and insulin-resistance markers Koyasu et al45 12 Acarbose, 150 mg/d, To examine the effect of Acarbose use was vs placebo acarbose therapy on associated with a carotid IMT in patients beneficial effect in with established terms of preventing the coronary artery disease progression of carotid and newly diagnosed IMT compared with impaired glucose control, although it was tolerance or mild type 2 not associated with a diabetes mellitus significant decrease in IMT from baseline Essen Study46 6 Acarbose, 100 mg TID; To compare acarbose Acarbose and glibenclamide, mean and glibenclamide or glibenclamide use were dose of 4.3 mg/d; or placebo as first-line effective as placebo treatment in type 2 monotherapy when diet diabetic patients with alone failed; acarbose dietary failure use lowers the postprandial insulin increase and for this reason may be superior to glibenclamide use Essen-II Study47 6 Acarbose, 100 mg TID; To compare acarbose Acarbose and metformin, 850 mg and metformin or metformin use were BID; or placebo placebo as first-line effective as treatment in type 2 monotherapy for type 2 diabetic patients with diabetes; acarbose use dietary failure also improved the lipid profile and for this reason may be superior to metformin therapy Pan et al48 6 Acarbose, 100 mg TID, To compare the efficacy Monotherapy with or vildagliptin, 50 mg and tolerability of vildagliptin or acarbose BID vildagliptin or acarbose similarly decreased treatment in drug-naive glycated hemoglobin patients with type 2 and FPG levels, but diabetes acarbose use decreased body weight more

FPG ϭ fasting plasma glucose; HOMA-IR ϭ homeostasis model assessment insulin resistance; IMT ϭ intima-media thickness; OFL ϭ oral fat load.

1226 Volume 34 Number 6 G. Derosa and P. Maffioli

Table III. Summary of the studies cited in the review where acarbose is used as add-on therapy.

Study Duration, mo Drugs Involved Aim Results

49 Halimi et al 6 Acarbose, 100 mg TID, To investigate the potential of acarbose Acarbose use decreased HbA1c, FPG, or placebo added to add-on therapy for improving the and PPG levels compared with previously taken glycemic control of overweight patients placebo use and has potential clinical metformin, 850 mg BID with type 2 diabetes inadequately utility for improving glycemic control or TID controlled with metformin monotherapy in overweight patients with type 2 diabetes inadequately controlled with metformin Willms and Ruge50 3 Acarbose, 100 mg TID; To compare the efficacy and safety of Acarbose and metformin use were metformin, 850 mg acarbose and metformin added to effective in improving metabolic TID; or placebo in sulfonylurea therapy in diabetic patients control in patients insufficiently addition to previously insufficiently controlled with controlled with diet and taken sulfonylurea sulfonylureas alone sulfonylureas; reductions in body weight were greatest in the acarbose group Derosa et al51 4 Acarbose, 100 mg TID, To evaluate which add-on treatment In addition to having a similar effect or repaglinide, 2 mg between acarbose and repaglinide is as repaglinide use on PPG levels, TID, in addition to more efficacious in reducing PPG levels acarbose use seemed to have a more previously taken and which of these 2 treatments is more comprehensive positive effect on metformin ϩ efficacious in the global management of glucose metabolism compared with sulfonylurea glucose homeostasis repaglinide use, decreasing FPI levels and the HOMA index when used as add-on therapy to sulfonylureas and metformin Josse52 12 Acarbose, 50 mg TID, To evaluate the long-term efficacy of Acarbose therapy is effective in or placebo added to acarbose use in improving the glycemic improving glycemic control on a long- previously taken control of patients with type 2 diabetes term basis in patients with type 2 sulfonylurea, who were suboptimally controlled with diabetes, independent of metformin, or insulin either diet alone or diet plus concomitant antidiabetic medication sulfonylurea, metformin, or insulin use Kim et al56 2.5 Nateglinide, 120 mg To evaluate the effects of acarbose on Nateglinide and acarbose use are TID, or acarbose, 100 glucose fluctuations in patients with equally effective in type 2 diabetes for mg TID, added to type 2 diabetes using continuous postprandial glucose excursions previously taken basal glucose monitoring during basal insulin treatment insulin Derosa et al57,58 6 Acarbose, 300 or 45 To compare the effects of acarbose and Pioglitazone use was better than mg/d, added to pioglitazone on the modulation of acarbose use in improving insulin previously taken adipokines and vascular remodeling resistance and inflammatory variables sulfonylureas and markers during an OGTT after an OGTT; pioglitazone use gave metformin a significant BMI and body weight increase not observed with acarbose use STOP-NIDDM60,61 39 Acarbose, 100 mg TID, To assess the effect of acarbose use in Acarbose use significantly increased or placebo preventing or delaying conversion of reversion of impaired glucose impaired glucose tolerance to type 2 tolerance to normal glucose diabetes tolerance; acarbose use also reduced by 49% the development of cardiovascular events

ϭ ϭ ϭ ϭ ϭ ϭ BMI body mass index; FPG fasting plasma glucose; FPI fasting plasma insulin; HbA1c glycated hemoglobin; OGTT oral glucose tolerance test; PPG postprandial glucose; STOP-NIDDM ϭ Study to Prevent Non Insulin Dependent Diabetes Mellitus.

Acarbose as First-Line Therapy in addition to diet and physical activity, acarbose (50 Acarbose Versus Placebo mg TID) or placebo; after the first month, acarbose was In 2 studies by Derosa et al,43,44 the authors evalu- titrated to 100 mg TID. Treatment with acarbose was ated the effect of acarbose treatment compared with more effective than was placebo use in improving Ͻ Ͻ placebo use on glycemic control, lipid profile, insulin HbA1c levels (P 0.05 and P 0.01, respectively) and resistance, and inflammatory variables in diabetic pa- in reducing FPG (P Ͻ 0.05) and PPG (P Ͻ 0.05) levels tients before and after a standardized oral fat load. One after 7 months of therapy. Regarding the lipid profile, hundred eighty-eight patients were assigned to receive, acarbose therapy reduced total cholesterol (TC), tri-

June 2012 1227 Clinical Therapeutics glyceride (Tg), and low-density lipoprotein cholesterol 0.003). Only the control group had significant in- (LDL-C) levels after 7 months compared with the con- creases in mean (SD) fasting immunoreactive insulin trol group (both, P Ͻ 0.05). levels (from 7.17 [5.18] ␮U/mL to 8.58 [6.70] ␮U/mL; Compared with placebo use, treatment with acar- mean change, 1.30 [3.70] ␮U/mL; P ϭ 0.02) and bose reduced HOMA insulin resistance (P Ͻ 0.05); in HOMA insulin resistance (from 2.02 [1.67] to 2.04 this study, tumor necrosis factor-␣, resistin, adiponec- [1.95]; mean change, 0.35 [1.23], P ϭ 0.012). In this tin (ADN), retinol binding protein-4, soluble intercel- study, in patients with established coronary artery dis- lular adhesion molecule-1, interleukin-6, high-sensitiv- ease who had newly diagnosed IGT or mild type 2 ity C-reactive protein, soluble vascular cell adhesion diabetes, 12 months of acarbose treatment had a ben- molecule-1, and soluble E-selectin were also evaluated. eficial effect compared with control in terms of pre- Treatment with acarbose seemed to improve ADN and venting the progression of carotid IMT. However, ac- retinol binding protein-4 levels compared with placebo arbose treatment was not associated with a significant use (P Ͻ 0.05), whereas no differences between pla- decrease in carotid IMT from baseline. cebo and acarbose treatment were recorded regarding the other variables. Regarding the variation after an Acarbose Versus Glibenclamide or Placebo oral fat load, treatment with acarbose seemed to be In the Essen Study,46 96 patients with type 2 dia- more effective in reducing the post–oral fat load peaks betes mellitus insufficiently treated with diet alone of the various variables, including insulin resistance (HbA1c level, 7%–9%) were randomized into 3 and the inflammatory markers, after 7 months of groups and treated for 24 weeks with acarbose, 100 mg therapy. TID; glibenclamide, 3.5-mg tablets dosed 1-0-0 or In a 1-year, prospective, randomized, open-label, 1-0-1 (mean dose, 4.3 mg/d); or placebo. Compared parallel-group study conducted by Koyasu et al,45 90 with placebo, both drugs had the same mean efficacy patients with established coronary artery disease on FPG levels (Ϫ1.4 mM with acarbose and Ϫ1.6 mM (ϳ50% stenosis on quantitative coronary angiogra- with glibenclamide), 1-hour PPG levels (Ϫ2.2 mM phy) who were newly diagnosed as having IGT or mild with acarbose and Ϫ1.9 mM with glibenclamide), and Ϫ Ϫ type 2 diabetes were randomly allocated to receive ei- HbA1c levels ( 1.1% with acarbose and 0.9% with ther acarbose, 150 mg/d, or placebo. The primary end glibenclamide), but a marked difference in 1-hour point was the absolute change from baseline to 12 postprandial insulin (PPI) values (Ϫ80.7 pM with ac- months in the largest measured intima-media thickness arbose and 96.7 pM with glibenclamide). The mean (IMT) value in the right and left common carotid ar- relative insulin increase (1 hour postprandial) was 1.5 teries. Secondary end points included the change from in the placebo group, 1.1 in the acarbose group, and baseline to 12 months in glucose profiles, HbA1c levels, 2.5 in the glibenclamide group. No changes in body and lipid profiles. After 12 months, IMT increased weight were observed. Regarding adverse events, acar- from a mean (SD) of 1.28 (0.53) mm to 1.30 (0.52) mm bose therapy led to mild or moderate intestinal symp- (mean [SD] change, 0.02 [0.29] mm; P ϭ NS) in the toms in 38% of patients, whereas glibenclamide use led acarbose group, whereas it increased from a mean (SD) to hypoglycemia, which could be solved by dose reduc- of 1.15 (0.37) mm to 1.32 (0.046) mm (mean [SD] tion, in 6% of patients. change, 0.17 [0.25] mm; P Ͻ 0.001) in the control group. The difference between the acarbose and con- Acarbose Versus Metformin or Placebo trol groups was significant (P ϭ 0.01) After 12 months, Hoffmann and Spengler47 randomized 96 patients only the acarbose group experienced significant mean with type 2 diabetes mellitus not controlled by diet (SD) reductions from baseline in mean 2-hour glucose alone into 3 groups and treated them for 24 weeks with concentrations on the 75-g oral glucose tolerance test acarbose, 100 mg TID; metformin, 850 mg BID; or

(OGTT) (from 192.8 [35.9] mg/dL to 168.6 [51.0] placebo. Regarding HbA1c, a slight increase in the pla- mg/dL; mean change, Ϫ24.8 [45.2] mg/dL; P ϭ 0.001), cebo group and a pronounced decrease in the acarbose fasting TC (from 178.0 [28.3] mg/dL to 165.5 [22.9] and metformin groups were seen. Treatments with ac- mg/dL; mean change, Ϫ11.26 [26.1] mg/dL; P ϭ arbose and metformin were more effective in improv- Ͻ 0.009), and Tg (from 146.8 [79.5] mg/dL to 112.8 ing HbA1c levels compared with placebo use (P [55.7] mg/dL; mean change, Ϫ30.4 [62.7] mg/dL; P ϭ 0.0001), but no significant difference between acar-

1228 Volume 34 Number 6 G. Derosa and P. Maffioli bose and metformin treatment was recorded. Regard- gliptin therapy in reducing body weight: vildagliptin ing FPG and PPG levels, no changes were observed therapy reduced body weight a mean (SD) of Ϫ0.4 during 24 weeks of placebo treatment, whereas a (0.1) kg, whereas acarbose reduced body weight a marked decrease could be seen in FPG and PPG levels mean (SD) of Ϫ1.7 (0.2) kg; the mean (SD) between- with acarbose and metformin treatment (P Ͻ 0.0001 treatment difference was 1.3 (0.2) kg (P Ͻ 0.001). vs placebo for both, without a difference between ac- arbose and metformin treatment). Regarding lipid profiles, during the 24 weeks of Acarbose as Add-On Therapy treatment, mean Tg fell by 8.8% in the placebo group, Acarbose Versus Placebo in Addition to Metformin This 6-month, double-blind, placebo-controlled, by 26.8% in the acarbose group, and by 9.2% in the randomized, parallel-group study investigated the po- metformin group. The mean values for TC decreased tential of acarbose add-on therapy for improving the by 1.2% with placebo use and by 14.1% with acarbose use and rose by 1.6% with metformin therapy; how- glycemic control of overweight patients with type 2 ever, the differences were not statistically significant. diabetes inadequately controlled with metformin 49 The LDL-C level was slightly elevated with placebo use monotherapy. Seventy-four patients were random- (5.0%), fell by 21.8% with acarbose therapy, and was ized to receive acarbose titrated up to 100 mg TID, and not affected by metformin treatment. This time, there 78 were randomized to receive placebo. All the patients was a significant difference between acarbose and pla- were receiving metformin, 850 mg BID or TID, before cebo use (P ϭ 0.0065) and between acarbose and met- the study and continued to receive this dose through- formin use (P ϭ 0.0134). High-density lipoprotein out the study. The mean (SD) difference in HbA1c val- cholesterol (HDL-C) levels fell by 9.7% with placebo ues from baseline to the end point was Ϫ0.79% (1.2%) use, but increased by 16.2% with acarbose treatment in the acarbose intention-to-treat (ITT) group and and did not change with metformin use. Treatment 0.29% (1.3%) in the placebo ITT group (P ϭ 0.0001). differences reached significance for acarbose versus This significant difference was confirmed in the per- placebo use (P ϭ 0.0162), but not for metformin versus protocol population (mean [SD]: Ϫ0.79 [1.2] vs placebo use or metformin versus acarbose use. Calcu- 0.29% [1.4%]; P ϭ 0.0031). A patient was classified as lation of the LDL-C:HDL-C ratio (atherogenic index) a “responder” if the HbA1c value at the end of treat- increased 14.4% with placebo use, did not change with ment was Ͻ7.0% or had decreased Ͻ15% relative to metformin use, and decreased 26.7% with acarbose baseline. In the ITT population, 42% of patients in the use. The results were significant for acarbose versus acarbose group and 17% in the placebo group were placebo use (P ϭ 0.0013) and acarbose versus met- responders (P ϭ 0.002). In the per-protocol popula- formin use (P ϭ 0.0311). tion, 16% of patients in the acarbose group were re- The mean body weight was unchanged with placebo sponders compared with 39% in the placebo group treatment and was slightly reduced in the acarbose (0.8 (P ϭ 0.015). The mean (SD) difference in FPG levels kg) and metformin (0.5 kg) groups. from baseline to the end point was Ϫ1.09 (2.8) mM in the acarbose ITT group compared with 1.39 (2.8) mM ϭ Acarbose Versus Vildagliptin in the placebo ITT group (P 0.0001). The mean (SD) Pan et al48 compared the efficacy and tolerability of difference in 2-hour PPG levels from baseline to the end Ϫ vildagliptin, 100 mg/d given as 50 mg BID, and acar- point was 1.49 (3.8) mM in the acarbose ITT group bose, up to 300 mg/d given as 3 equally divided doses, compared with 1.19 (3.5) mM in the placebo ITT in a 24-week treatment in 661 drug-naive patients with group (P ϭ 0.0001). A statistically significant differ- type 2 diabetes. Monotherapy with vildagliptin or ac- ence in favor of acarbose compared with placebo was arbose decreased HbA1c levels similarly (mean [SD]: confirmed in the per-protocol analysis. There were no Ϫ1.4% [0.1%] in patients receiving vildagliptin and statistically significant differences between the acar- Ϫ1.3% [0.1%] in those receiving acarbose). A similar bose and placebo groups regarding fasting plasma in- trend was observed for FPG levels, which decreased a sulin (FPI) or PPI levels or Tg levels. In all, 60% of mean (SD) of Ϫ1.2 (0.1) mM with vildagliptin treat- patients in the acarbose group and 33% in the placebo ment and Ϫ1.5 (0.2) mM with acarbose treatment. group had an adverse event, generally mild and con- However, acarbose therapy seemed better than vilda- fined to the digestive system, considered to be possibly

June 2012 1229 Clinical Therapeutics or probably related to drug therapy and leading to The treatment was then crossed-over for another 12 withdrawal by 15% and 3%, respectively. weeks until week 27. After 15 weeks of therapy, the repaglinide-treated patients experienced a significant Ϫ Ϫ Acarbose Versus Metformin in Addition to decrease in HbA1c ( 1.1%), FPG ( 9.5%), and PPG Sulfonylurea (Ϫ14.9%) levels compared with baseline values (all, 50 Willms and Ruge compared the efficacy and tol- P Ͻ 0.05). However, the same treatment was associ- erability of acarbose and metformin use when added to ated with a significant increase in body weight (2.3%), sulfonylurea therapy in diabetic patients insufficiently body mass index (3.3%), and FPI levels (22.5%) (all, controlled with sulfonylurea treatment alone. In this P Ͻ 0.05); the increase was reversed during the cross- 12-week, single-center, placebo-controlled study, 89 over phase. After 15 weeks of therapy, the acarbose- patients were randomized to receive acarbose (100 mg treated patients experienced a significant decrease in TID), metformin (850 mg BID), or placebo in addition Ϫ Ϫ HbA1c levels ( 1.4%), FPG levels ( 10.7%), PPG lev- to sulfonylurea therapy. The primary end point, HbA1c els (Ϫ16.2%), body weight (Ϫ1.9%), body mass index level, decreased from baseline in all 3 groups after 12 (Ϫ4.1%), FPI levels (Ϫ16.1%), PPI levels (Ϫ26.9%), weeks. The mean (SD) decrease was greater in the 2 and HOMA index (Ϫ30.1%) compared with baseline groups receiving active therapy compared with in those values (all, P Ͻ 0.05). All these changes were reversed Ϫ receiving placebo (acarbose, 2.3% [0.32%]; met- during the crossover study phase, except those relating formin, Ϫ2.5% [0.16%]; and placebo, Ϫ1.3% to HbA1c, FPG, and PPG levels. The only changes that [0.34%]). There was no significant difference between significantly differed when directly comparing acar- ϭ the acarbose and metformin groups (P 0.65), bose- and repaglinide-treated patients were those relat- whereas differences between both active therapies and ing to FPI levels (Ϫ16.1% vs 22.5%, respectively) and Յ placebo were significant (P 0.01 for acarbose use the HOMA index (Ϫ30.1% vs 2.7%) (both, P Ͻ 0.05). and P Յ 0.004 for metformin use). Similar results were obtained for PPG values (mean [SD]: Ϫ2.6 [0.8] mM for acarbose, Ϫ2.6 [0.8] mM for metformin, and Ϫ2.0 Acarbose Versus Placebo in Addition to Metformin or [0.9] mM for placebo). Regarding lipid profiles, acar- Sulfonylurea or Insulin Therapy 52 bose and metformin treatments had similar effects on In a Canadian trial by Josse, 354 patients with TC levels (Ϫ0.23 mM for both), but acarbose had a type 2 diabetes mellitus were studied: 77 were treated greater effect on Tg (Ϫ0.41 mM for acarbose, Ϫ0.27 with diet alone, 83 with metformin, 103 with sulfonyl- mM for metformin, and Ϫ0.3 mM for placebo). Re- urea, and 91 with insulin. Patients in each treatment ductions in body weight over the treatment period stratum were randomized, double-blind, to receive ei- were seen in all 3 groups and were greater in the acar- ther acarbose, 50 mg TID, or placebo for 1 year; con- bose group (3.5 kg with acarbose use, 1.0 kg with current antidiabetic medication could not be increased metformin use, and 1.4 kg with placebo use). There during the study period. The aim was to evaluate the were no significant differences in the incidence of gas- long-term efficacy of acarbose in improving the glyce- trointestinal adverse effects among the 3 groups, and mic control of patients with type 2 diabetes who were all the regimens were generally well tolerated. suboptimally controlled with either diet alone or diet plus sulfonylurea, metformin, or insulin. Acarbose Versus Repaglinide in Addition to At the end of the 12-month study period, treatment Metformin and Sulfonylurea with acarbose produced significant decreases in HbAlc 51 In a study by Derosa et al, the effects of acarbose levels in all but the insulin group. The mean HbAlc and repaglinide treatment were compared in type 2 value decreased 0.8% to 0.9% for all groups other diabetic patients treated with sulfonylurea-metformin than the insulin-treated group, where it decreased combination therapy. After a 4-week run-in period 0.4%. The maximum decline in HbAlc levels was evi- with a sulfonylurea-metformin combination, 103 pa- dent at 6 months and was maintained thereafter. Re- tients were randomized to receive in addition either garding PPG levels, acarbose treatment resulted in a repaglinide, up to 6 mg/d (2 mg TID), or acarbose, up decrease in mean (SD) PPG levels in all 4 strata, from to 300 mg/d (100 mg TID), with forced titration (inde- 19 (0.8) to 15.3 (0.7) mmol/L (P Ͻ 0.001), compared pendently of their glycemic control, unless adverse ef- with placebo use. In total, 52% of acarbose-treated fects developed due to the drug dosage) for 15 weeks. patients responded with a 15% decrease in HbAlc con-

1230 Volume 34 Number 6 G. Derosa and P. Maffioli

centration or a posttreatment HbAlc concentration were used to assess intraday and interday glycemic Ͻ7%, whereas only 26% of placebo-treated patients variability. Hypoglycemia was defined as a glucose so responded. No serious adverse events were reported level Ͻ3.9 mM for at least 15 minutes in CGM. Ac- during the study; the only adverse events related to cording to reference values of MAGE, patients with acarbose therapy were gastrointestinal (flatulence, di- type 2 diabetes mellitus were classified into 2 groups: arrhea, and abdominal cramps or distention) and were the low-MAGE group, with MAGE Ͻ3.4 mM not reported with placebo use. In addition, reported (L-MAGE), and the high-MAGE group, with MAGE adverse effects were classified as mild and tended to Ն3.4 mM (H-MAGE). The H-MAGE group received decrease over time. further treatment with acarbose for 2 weeks and was monitored a second time using the CGM system. After Acarbose in Addition to Insulin first CGM, the L-MAGE group had 41 cases and the Mori et al53 evaluated the effects of acarbose treat- H-MAGE group had 45 cases. The MAGE and the ment on glucose fluctuations in patients with type 2 mean of daily differences of the type 2 diabetes mellitus diabetes mellitus receiving insulin using continuous group were all higher than those of individuals with glucose monitoring (CGM). Five patients were ran- normal glucose regulation (P Ͻ 0.01). Twenty-four domized to receive acarbose, 300 mg/d, on days 1 and percent of patients in the H-MAGE group had 13 hy- 2 but not on days 3 and 4; the remaining 5 patients poglycemic events (10 of the 13 events occurred at were not administered acarbose on days 1 and 2 but night), and 5% of patients in the L-MAGE group had 2 were given 300 mg/d on days 3 and 4. During CGM, hypoglycemic events, which also occurred at night insulin was administered at the same time and the same (P Ͻ 0.01). The MAGE value was correlated with the dose. When acarbose was administered, the average hypoglycemia value and the 2-hour PPG value (r ϭ CGM profile was decreased in almost all the patients Ϫ0.32 and 0.26, respectively; P Ͻ 0.05). After further regardless of the current insulin regimen. The 24-hour acarbose therapy and second CGM, the MAGE and mean (SD) blood glucose level when acarbose was not mean of daily differences values in the H-MAGE group administered was 158.03 (32.78) mg/dL, the 24-hour were significantly decreased (40% [P Ͻ 0.01] and 15% blood glucose fluctuation was 677.05 mg·h/dL, and the [P Ͻ 0.05], respectively), but remained higher than in mean amplitude of glycemic excursions (MAGE) was those with normal glucose regulation (P Ͻ 0.05); 2% 97.09 mM. The 24-hour mean (SD) blood glucose level had 1 hypoglycemic event, an incidence significantly when acarbose was administered was 131.19 (22.48) decreased (2% vs 24%, P Ͻ 0.01). The mean (SD) ϭ mg/dL (P 0.004), the 24-hour blood glucose fluctu- daily insulin dose also decreased, from 0.9 (0.4) U/kg ϭ ation was 453.27 mg·h/dL (P 0.002), and the MAGE to 0.7 (0.3) U/kg (P Ͻ 0.05). was 65.00 mM (P ϭ 0.010). The mean (SD) proportion of time spent in the hyperglycemic range (defined as Ն180 mg/dL) during CGM was 29.5% (24.4%) when Acarbose Versus Nateglinide in Addition to Insulin acarbose was not administered and 16.2% (25.4%) Based on the evidence that basal insulin treatment is 55 when it was administered. The mean (SD) proportion frequently unsuccessful in controlling PPG levels, 56 of time spent in the hyperglycemic range (defined as Kim et al conducted a study in which 58 type 2 dia- Ն140 mg/dL) during CGM was 58.7% (29.4%) and betic patients, after FPG levels were optimized by insu- 40.4% (36.3%), respectively. The mean (SD) propor- lin glargine therapy, were randomized to take nateglin- tion of time spent in the hypoglycemic range (defined as ide, 120 mg TID just before meals, or acarbose, 100 mg Ͻ70 mg/dL) during CGM was 0.31% (0.63%) when TID together with meals, and then were crossed over acarbose was not administered and 0.02% (0.5%) after the second washout period. Both drugs effectively when it was administered. reduced PPG levels compared with A similar study was conducted by Su et al54 in which monotherapy. No significant differences were found 86 type 2 diabetic patients who used premixed insulin between nateglinide and acarbose in terms of mean analogue ( 30) twice daily and had HbA1c glucose level, standard deviation of glucose levels, levels Ͻ6.5% and 20 controlled subjects with normal MAGE, and average daily risk range. There was no glucose regulation were monitored using the CGM sys- episode of severe hypoglycemia, and no serious adverse tem. The mean MAGE and mean of daily differences events were recorded.

June 2012 1231 Clinical Therapeutics

Acarbose Versus Pioglitazone Added to Sulfonylureas Acarbose Treatment and IGT and Metformin Treatment with acarbose seemed to have a favor- In 2 studies by Derosa et al,57,58 the authors com- able safety profile and to be effective in patients with pared the effects of treatment with acarbose and piogli- IGT; in the STOP-NIDDM (Study to Prevent Non tazone on the modulation of adipokines and vascular Insulin Dependent Diabetes Mellitus) trial,60 714 remodeling markers during an OGTT in 473 type 2 patients with IGT were randomized to receive acar- diabetic patients taking oral hypoglycemic agents. Ac- bose, 100 mg TID, and 715 to receive placebo. The arbose and pioglitazone were added to the current an- primary end point was development of diabetes on tidiabetic therapy with sulfonylureas and metformin, the basis of a yearly OGTT. Treatment with acar- and patients were treated until the maximum doses of bose significantly increased reversion of IGT to nor- Ͻ 300 and 45 mg, respectively, were reached. Pioglita- mal glucose tolerance (P 0.0001); the risk of pro- zone therapy was more effective than was acarbose use gression to diabetes over 3.3 years was reduced by 25%. At the end of the study, treatment with pla- in improving HbA1c values, FPI levels, and HOMA insulin resistance after 6 months of full treatment (P Ͻ cebo was associated with an increase in conversion 0.05), but treatment with acarbose decreased PPG lev- of IGT to diabetes. The most reported adverse effects of acarbose treatment were flatulence and diarrhea. els compared with baseline (P Ͻ 0.05), which was not Decreasing postprandial hyperglycemia with acar- observed with pioglitazone use. In this study, an bose use was associated with a 49% relative risk OGTT was performed after 3 and 6 months of therapy reduction in the development of cardiovascular to evaluate the effects of the 2 drugs on inflammatory events (P ϭ 0.03) and a 2.5% absolute risk reduc- and insulin-resistance variables, such as nitrites/ni- tion.61 Among cardiovascular events, the major re- trates, adenosine diphosphate, resistin, matrix metal- duction was in the risk of myocardial infarction (P ϭ loproteinases 2 and 9, soluble intercellular adhesion 0.02). Treatment with acarbose was associated with molecule-1, interleukin-6, high-sensitivity C-reactive a 34% relative risk reduction in the incidence of new protein, soluble vascular cell adhesion molecule-1, sol- cases of hypertension (P ϭ 0.006) and a 5.3% abso- ␣ uble E-selectin, and tumor necrosis factor- ; the data lute risk reduction. Even after adjusting for major evidenced a greater effect of pioglitazone treatment risk factors, the reduction in the risk of cardiovascu- compared with acarbose treatment in improving all lar events (P ϭ 0.02) and hypertension (P ϭ 0.004) inflammatory and insulin resistance variables after an associated with acarbose treatment was still statisti- OGTT. However, despite these favorable effects, pi- cally significant. oglitazone use resulted in a significant body mass index There is also an ongoing trial in China, the Acarbose and body weight increase not observed with acarbose Cardiovascular Evaluation Trial, that is currently in- use (P Ͻ 0.05). vestigating whether reducing PPG levels can reduce Also, Ochiai et al59 compared pioglitazone treat- cardiovascular-related morbidity in patients who have ment with acarbose treatment in 33 patients with type IGT and established coronary heart disease or acute 2 diabetes who had never been treated with insulin, coronary syndrome.62 pioglitazone, or acarbose. Patients were randomized to take acarbose, 300 mg/d, or pioglitazone, 15 mg/d, for DISCUSSION 3 months. During the study, all drugs other than insu- From the studies reported herein, treatment with acar- lin, pioglitazone, and acarbose were continued and bose seems to be more effective than placebo, both as kept unchanged. Treatment with acarbose and piogli- first-line and add-on therapy, in improving HbA1c, tazone decreased HbA1c values by 0.49% and 0.63%, FPG, and PPG levels and the lipid profile. This action respectively. Pioglitazone use increased serum levels of on the lipid profile is interesting considering that not total ADN by 2.1-fold and its high-molecular-weight only postprandial hyperglycemia, but also postpran- isoform by 3.6-fold. Treatment with acarbose caused a dial hyperlipidemia are strong independent risk factors small, but significant increase in serum concentrations for cardiovascular disease63 and that we live most of of total ADN. However, in contrast to pioglitazone our time in a postprandial condition regarding lipid therapy, no appreciable changes were observed in the metabolism.64 In the studies by Derosa et al,43,44 treat- levels of high-molecular-weight ADN. ment with acarbose seemed to be effective in reducing

1232 Volume 34 Number 6 G. Derosa and P. Maffioli the post–oral fat load peaks of insulin resistance and diabetes and in patients where metabolic control is ap- inflammatory markers such as tumor necrosis factor-␣, parently good due to its positive effect on postprandial resistin, ADN, retinol binding protein-4, soluble inter- hyperglycemia. Postprandial hyperglycemia could sig- cellular adhesion molecule-1, soluble vascular cell ad- nificantly contribute to the development of chronic di- hesion molecule-1, interleukin-6, high-sensitivity C-re- abetic complications, particularly cardiovascular dis- active protein, and soluble E-selectin. Expression of ease, and microvascular complications of diabetes, cell adhesion molecules is increased in diabetes,65 and even more than fasting hyperglycemia; by flatting these molecules have been suggested to have a role in glycemic variability, acarbose use could contribute the microvascular complication of this disease. Similar to reducing diabetes complications. Treatment with to treatment with metformin66 and pioglitazone,67 ac- acarbose could be linked to some additive beneficial arbose therapy seems to have a beneficial effect com- effects, such as improving the lipid profile, reducing pared with placebo use in terms of preventing the pro- circulating levels of cell adhesion molecules, reduc- gression of carotid IMT in patients with established ing IMT progression, and reversing IGT to normal coronary artery disease who had newly diagnosed IGT glucose tolerance. Regarding adverse events, treat- or mild type 2 diabetes mellitus.45 Compared with the ment with acarbose is associated with a high inci- other drugs, acarbose monotherapy seemed to be as dence of gastrointestinal adverse effects, such as flat- effective as treatment with metformin,50 glibencl- ulence and diarrhea, due to its mechanism of action. amide,46 and vildagliptin48 for the control of type 2 For all the considerations reported herein, when cur- diabetes. However, glibenclamide treatment elevates rent therapy is not adequate to obtain glycemic con- PPI levels, which has been shown to be correlated with trol, this review suggests that acarbose could be an an increased risk of cardiovascular disease,46 whereas option as monotherapy and as an add-on to other treatment with acarbose seems to decrease PPI values. antidiabetic drug treatment, especially when post- Treatment with acarbose seemed to have also a posi- prandial hyperglycemia is the main concern. tive effect on the lipid profile, improving the LDL-C concentration, the LDL-C:HDL-C ratio, which is an ACKNOWLEDGMENT atherogenic index,47 and Tg.50 Compared with vilda- The authors have no relevant affiliations or financial gliptin use, treatment with acarbose decreased body involvement with any organization or entity with a weight more.48 In addition to insulin use, treatment financial interest in or financial conflict with the subject with acarbose seems to have a favorable safety profile, matter or materials discussed in the manuscript. This decreasing hypoglycemic events, flatting glycemic vari- includes employment, consultancies, honoraria, stock ability, and allowing reduced total insulin use per ownership or options, expert testimony, grants or pat- day.54 Treatment with acarbose was inferior to piogli- ents received or pending, or royalties. No writing as- tazone use in improving inflammatory and insulin re- sistance was utilized in the production of this manu- sistance variables after an OGTT57,58 and in a baseline script. Both Authors contributed equally to this review, condition.59 Regarding IGT, treatment with acarbose this includes literature search, figures creation, study seems to increase reversion of IGT to normal glucose design, data collection, data interpretation, writing. tolerance by 25%60 and to give a 49% relative risk reduction in the development of cardiovascular events in patients with IGT.61 CONFLICTS OF INTEREST A limitation of this review is that the studies in- The authors have indicated that they have no conflicts cluded are all short-term trials; long-term studies are of interest regarding the content of this article. needed to determine whether the effects observed with acarbose are maintained during the years. REFERENCES 1. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of CONCLUSIONS intensive glucose control in type 2 diabetes. N Engl J Med. Acarbose administration can be an option for the treat- 2008;359:1577–1589. ment of type 2 diabetes; it is effective and tolerated as 2. Action to Control Cardiovascular Risk in Diabetes Study monotherapy and as an add-on to other antidiabetic Group. Effects of intensive glucose lowering in type 2 drug treatment in patients with uncontrolled type 2 diabetes. N Engl J Med. 2008;358:2545–2559.

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missing link between diabetes and necessary? Control Clin Trials. 1996; cebo-controlled study. Diabet Med. cardiovascular events? Endocr Pract. 17:1–12. 1999;16:755–761. 2008;14:112–124. 43. Derosa G, Maffioli P, D’Angelo A, et 51. Derosa G, Salvadeo SA, D’Angelo A, 33. Ceriello A. Postprandial hyperglyce- al. Acarbose on insulin resistance et al. Metabolic effect of repaglinide mia and diabetes complications: is after an oral fat load: a double- or acarbose when added to a double it time to treat? Diabetes. 2005; blind, placebo controlled study. J oral antidiabetic treatment with sul- 54:1–7. Diabetes Complications. 2011;25:258– phonylureas and metformin: a 34. Wolffenbuttel BHR, Landgraf R; 266. double-blind, cross-over, clinical Dutch and German Repaglinide 44. Derosa G, Maffioli P, Ferrari I, et al. trial. Curr Med Res Opin. 2009;25: Study Group. A 1-year multicenter Acarbose actions on insulin resis- 607–615. randomized double-blind compari- tance and inflammatory parameters 52. 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Halimi S, Le Berre MA, Grangé V. 57. Derosa G, D’Angelo A, Salvadeo SA, erations and clinical utility of a fixed Efficacy and safety of acarbose et al. Modulation of adipokines and dose combination of saxagliptin/ add-on therapy in the treatment of vascular remodelling markers during metformin in the treatment of type 2 overweight patients with Type 2 dia- OGTT with acarbose or pioglita- diabetes. Diabetes Metab Syndr Obes. betes inadequately controlled with zone treatment. Biomed Pharmaco- 2011;4:263–271. metformin: a double-blind, placebo- ther. 2009;63:723–733. 41. Dickersin K, Scherer R, Lefebvre C. controlled study. Diabetes Res Clin 58. Derosa G, Mereu R, D’Angelo A, et Identifying relevant studies for sys- Pract. 2000;50:49–56. al. Effect of pioglitazone and acar- tematic reviews. BMJ. 1994;309: 50. Willms B, Ruge D. Comparison of bose on endothelial inflammation 1286–1291. acarbose and metformin in patients biomarkers during oral glucose toler- 42. 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59. Ochiai H, Ooka H, Shida C, et al. Acarbose treatment increases serum total adiponectin levels in patients with type 2 diabetes. Endocr J. 2008; 55:549–556. 60. Chiasson JL, Josse RG, Gomis R; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP- NIDDM randomised trial. Lancet. 2002;359:2072–2077. 61. Chiasson JL, Josse RG, Gomis R; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with im- paired glucose tolerance: the STOP- NIDDM trial. JAMA. 2003;290: 486–494. 62. Acarbose Cardiovascular Evalua- tion Trial (ACE). http://clinicaltrials. gov/ct2/show/NCT00829660. Ac- cessed May 3, 2011. 63. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308. 64. Karpe F, Steiner G, Uffelman K, et al. Postprandial lipoproteins and pro- gression of coronary atherosclero- sis. Atherosclerosis. 1994;106:83–97. 65. Matsumoto K, Sera Y, Abe Y, et al. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabe- tes Res Clin Prado. 2004;64:225–228. 66. Cominacini L, Fratta Pasini A, Garbin U, et al. Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control. Diabetologia. 1995;38:1122– 1124. 67. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone com- pared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA. 2006;296:2572–2581. Address correspondence to: Giuseppe Derosa, MD, PhD, Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, P.le C. Golgi, 2 - 27100 Pavia, Italy. E-mail: [email protected]

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