Prevention of Type 2 Diabetes || Decreasing Postprandial Plasma Glucose Using an α-Glucosidase...

167D. LeRoith (ed.), Prevention of Type 2 Diabetes: From Science to Therapy, DOI 10.1007/978-1-4614-3314-9_10, © Springer Science+Business Media New York 2012

Introduction

We are currently witnessing a worldwide explosion in the prevalence of type 2 diabetes mellitus [ 1 ] . Because of the high morbidity and the excess mortality associated with diabetes, it has major societal implications [ 2, 3 ] . Diabetes still remains the most common cause of blindness, end-stage renal disease and non-traumatic amputation and a major cause of cardiovascular disease (CVD) [ 4, 5 ] . Consequently, it has a strong impact on healthcare cost [ 6 ] . Given the magnitude of the problem, type 2 diabetes is one of the major challenges of the twenty- fi rst century. The only way that we can curtail this ever-growing problem is by developing and implementing pre-vention strategies.

The concept for the prevention of type 2 diabetes has grown from a better under-standing of the pathophysiology of the disease. Although a number of susceptibility genes are involved in the development of type 2 diabetes [ 7, 8 ] , it is usually precipi-tated by a number of environmental determinants such as sedentary lifestyle, nutri-tional over-indulgence and obesity [ 9– 11 ] . All these factors contribute to the development of insulin resistance, one of the major metabolic impairments leading to diabetes [ 12, 13 ] . Normal glucose tolerance will be maintained as long as the b cells can compensate for insulin resistance; however, glucose intolerance will

J.-L. Chiasson, MD (*) Department of Medicine , Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal , 3850 St. Urbain Street, Room 8-202 , Montréal , QC , Canada H2W 1T8 e-mail: [email protected]

M. Laakso, MD, PhD Department of Medicine , University of Eastern Finland , Kuopio , Finland

M. Hanefeld, MD, PhD Centre for Clinical Studies , Dresden , Germany

Chapter 10 Decreasing Postprandial Plasma Glucose Using an a -Glucosidase Inhibitor in Subjects with IGT for the Prevention of Type 2 Diabetes Mellitus: The STOP-NIDDM Trial

Jean-Louis Chiasson , Markku Laakso , and Markolf Hanefeld

168 J.-L. Chiasson et al.

appear when the b cells fail to fully compensate for insulin resistance [ 13, 14 ] . It will generally manifest itself at fi rst as impaired glucose tolerance (IGT) characterized by postprandial hyperglycaemia and/or impaired fasting glucose (IFG), which are now recognized as prediabetic states [ 15 ] . Although prediabetes is generally not associated with diabetes-speci fi c complications, the DPP showed in a random sam-ple of their study population that retinopathy was detected in 12.6% of those who converted to diabetes and in 7.9% of those who remained IGT [ 16, 17 ] . However, it is generally recognized that prediabetes, particularly IGT, is associated with an increased risk of CVD [ 18– 20 ] .

Postprandial Hyperglycaemia as a Risk Factor for Diabetes and CVD

The relatively mild postprandial hyperglycaemia characterizing IGT is believed to be suf fi cient to induce glucotoxicity and further decrease insulin action and insulin response to a glucose challenge, thus accelerating the progression of IGT to diabe-tes [ 21 ] . We do recognize that the concept of glucotoxicity is based more on animal than on human data. However, the observation that tight metabolic control in human diabetics, independent of the method by which it is achieved, leads to improvement in both insulin secretion and insulin sensitivity supports this hypothesis [ 22– 26 ] .

Most of the animal data is derived from the 90% pancreatectomy rat model. The advantages of this model are that the b cells in the remaining 10% of the pancreas are known to be normal and that the resulting hyperglycaemia is relatively mild [ 27 ] . Using this model, Rossetti et al. [ 28 ] have shown that partial pancreatectomy resulted in moderate glucose intolerance that was associated with a signi fi cant reduction in insulin sensitivity. Furthermore, correction of hyperglycaemia with phlorizin normalized tissue sensitivity to insulin. Using the same model, a number of studies have shown that chronic hyperglycaemia resulted in impaired insulin response to a hyperglycaemic clamp, and normalization of plasma glucose com-pletely corrected the insulin secretion defect [ 27, 29, 30 ] .

The mechanism(s) through which postprandial hyperglycaemia can exert its toxic effects is still controversial. However, much data have accumulated suggest-ing that it may be related to the production of reactive oxygen species (ROS) induced by hyperglycaemia, particularly the rise in plasma glucose following a meal containing carbohydrates [ 31 ] . It has been well documented that markers of oxidative stress were increased in correlation with plasma glucose in diabetic sub-jects, and that these markers improved under intensive glycaemic treatment [ 32, 33 ] . Furthermore, a hyperglycaemic response to an oral glucose tolerance test (OGTT) was shown to be associated with a reduction in anti-oxidant capacity in both healthy and type 2 diabetic subjects [ 34 ] . Also in healthy subjects, a 2-h hyperglycaemic clamp was associated with a 2.5-fold increase over baseline in nitrotyrosine, a marker of oxidative stress [ 35 ] . Ceriello et al. [ 36 ] have shown

16910 Decreasing Postprandial Plasma Glucose Using an a-Glucosidase Inhibitor...

that both a high carbohydrate load (75 g glucose) and a high fat load induced a rise in nitrotyrosine, and that a mixed meal containing both carbohydrate and fat resulted in a cumulative effect on the postprandial rise in the production of oxida-tive stress markers.

It is known that in sedentary obese non-diabetic subjects, the associated elevated FFA levels contribute to the impairment in insulin secretion [ 24, 37– 39 ] and insulin action [ 40, 41 ] , major defects leading to the development of type 2 diabetes. It can therefore be postulated that in genetically predisposed subjects, the oxidative stress induced by hyperlipidemia could lead to decreased insulin secretion and action, resulting in the development of IGT characterized by postprandial hyperglycaemia. This moderate postprandial hyperglycaemia will then exacerbate the resulting ROS production and further contribute to the deterioration of insulin secretion and action, thus accelerating the progression to diabetes [ 42– 46 ] .

There is also evidence that postprandial hyperglycaemia and hyperlipidemia are involved in the development of atherosclerosis in both diabetic and non-diabetic subjects [ 47 ] . A number of prospective observational studies and meta-analyses have con fi rmed the relationship between postprandial hyperglycaemia and cardio-vascular events and mortality [ 48– 51 ] . LDL cholesterol oxidation increases after meals and has been shown to be directly related to the degree of postprandial hyper-glycaemia [ 52 ] . The postprandial state is also associated with subclinical in fl ammation, augmented coagulation activity, increased expression of adhesion molecules and endothelial dysfunction [ 53– 56 ] . Endothelial dysfunction observed in subjects with IGT in response to a 75 g OGTT is an early step in atherosclerosis. This is further supported by the observation that the 2-h plasma glucose during an OGTT is an independent predictor of the intima media thickness (IMT) in non-diabetic subjects, an accepted surrogate marker of atherosclerosis [ 57 ] .

Acarbose for the Treatment of Postprandial Hyperglycaemia

Acarbose is a competitive inhibitor of the a -glucosidases of the brush border of the small intestine, enzymes that are necessary for the hydrolysis of the disaccha-rides, oligosaccharides and polysaccharides to monosaccharides for absorption [ 58 ] . Acarbose is a pseudo-tetrasaccharide of microbial origin. Its chemical struc-ture closely resembles that of an oligosaccharide obtained by digestion of starch. The active part of the molecule is an acarvosine unit linked to a maltose unit. This nitrogen link of the acarvosine unit confers to the compound its high af fi nity for the glucosyl site of the different a -glucosidases, which is more than 10,000–100,000 times that of the common oligosaccharides from carbohydrates inges-tion. Because of this nitrogen link, acarbose cannot be hydrolyzed by the enzyme. However, its high af fi nity binding is reversible and has the kinetics of a competi-tive inhibitor [ 58 ] .

Carbohydrates are usually absorbed rapidly in the proximal portion of the small intestine. The use of acarbose with meal will therefore slow the digestion and the


absorption of carbohydrates such that they will be hydrolyzed and absorbed throughout the whole length of the small intestine. This will attenuate the rise in postprandial plasma glucose in a dose-dependent manner, and consequently moderate the rise in postprandial plasma insulin [ 59 ] .

Because of its speci fi city for a -glucosidases, acarbose has no effect on the b -glucosidases such as lactase. The digestion and absorption of milk (lactose) is therefore not affected. More importantly, the intestinal absorption of monosaccha-rides such as glucose is not affected. The acarbose molecule is virtually non-absorbed (less than 1–2%) and can therefore exert its inhibiting effect throughout the small intestine up to the ileum. However, bacterial enzymes in the colon cleave it into a number of metabolites, of which 35% are found in the urine [ 58 ] .

Acarbose has to be present at the site of enzymatic activity at the same time as the carbohydrates to exert its competitive inhibitory activity on the disaccharides and oligosaccharides in the small intestine. Consequently, the drug has to be taken after the fi rst bite of the meal and not later than 15 min after the beginning of the meal [ 60 ] .

By delaying the digestion and the absorption of carbohydrates in the small intes-tine, acarbose can increase the amount of carbohydrates reaching the colon where they can be fermented and induce gastro-intestinal symptoms such as fl atulence and occasionally diarrhoea. These side effects can be prevented or minimized by starting at low dose and titrating very slowly to a maximal dose of 100 mg with each meal [ 61 ] .

Numerous studies including a Cochrane meta-analysis have shown that acarbose was effective in treating postprandial hyperglycaemia and in reducing HbA

1c in sub-

jects with type 2 diabetes, whether it was used as monotherapy or in combination with other antidiabetic medications [ 62– 66 ] . In fact, even when other oral hypogly-caemic agents have failed, acarbose is still effective in improving glycaemic con-trol. Therefore, acarbose is an effective drug in reducing postprandial hyperglycaemia and postprandial hyperinsulinemia, resulting in improved glycaemic control [ 58 ] . By its mechanism of action, acarbose decreases the glucose stress on b cells. By reducing postprandial hyperglycaemia, it decreases glucose toxicity and improves insulin sensitivity in subjects with IGT and diabetes [ 67, 68 ] . Furthermore, acarbose has been shown to reduce postprandial rise in markers of oxidative stress, of in fl ammation, of activated coagulation and to reduce postprandial endothelial dys-function in animal models as well as in human subjects with IGT or diabetes [ 69– 73 ] . Some studies have reported that acarbose given with a carbohydrate-rich meal was associated with an increase in GLP-1 [ 74, 75 ] . Acarbose has also been shown to increase adiponectin in subjects with type 2 diabetes and to reduce the size of myocardial infarctions in animal models [ 72, 76, 77 ] . In some studies with type 2 diabetes, acarbose treatment has been shown to be associated with a reduction in postprandial hypertriglyceridemia, systolic blood pressure and body weight [ 78– 82 ] . Thus, it has bene fi cial effects on major components of metabolic syndrome. All these observations support a potential role for acarbose in the prevention of type 2 diabetes mellitus and CVD.


The STOP-NIDDM Trial: The Study Design

The STOP-NIDDM Trial was an international study including Austria, Canada, Denmark, Finland, Germany, Israel, Norway, Spain and Sweden. Subjects with IGT were recruited from a high-risk population based on fasting plasma glucose between 5.6 and 7.8 mmol/L and a 2-h plasma glucose post-75 g glucose between 7.8 and 11.0 mmol/L inclusively. During the study, the fasting plasma glucose criterion for the diagnosis of diabetes was lowered to 7.0 mmol/L, such that 10% of our popula-tion would have been considered diabetic based on that single measurement. Overall, 1,429 subjects with IGT were randomized in a double-blind fashion to either pla-cebo or acarbose starting at 50 mg once a day and titrated gradually to 100 mg three times a day with meals. At entry, all subjects were advised on a weight maintaining or reducing diet and were encouraged to exercise regularly.

The primary objective was to determine the frequency of the development of diabetes based on a single 75 g OGTT performed yearly; however, at the 3-month visits, fasting plasma glucose was performed and if the level was ³ 7.0 mmol/L, the subject was scheduled for an OGTT. Secondary objectives included conversion of IGT to normal glucose tolerance, and quantify new cases of hypertension and car-diovascular events as well as changes in anthropometric measurements, blood pres-sure, lipid pro fi le and HbA

1c . Blood pressure and dyslipidemia were treated

according to local guidelines. The required sample size was calculated using a two-tailed a of 0.05 and a 1- b

of 90% assuming an annual conversion rate of 7%, a 36% reduction in the acarbose-treated group and a 10% dropout rate. It was calculated that 600 subjects needed to be randomized per treatment group. Analysis on the intent-to-treat population was done using the Cox proportional hazards model including covariates such as treat-ment and any baseline variable that could in fl uence outcome. Interim analysis was done every 6 months after the fi rst year of follow-up by an independent Data Safety and Quality Review Committee. ECG readings and evaluation of cardiovascular events were done by independent cardiologists blinded to treatment.

The subjects were seen every 3 months by the coordinating nurse and every 6 months by the investigator for a median follow-up of 3.3 years. At the end of the treatment period, all subjects who had not converted to diabetes were put on placebo in a single-blind fashion for a 3-month washout period at the end of which the out-come measures were repeated.

The STOP-NIDDM Trial: The Prevention of Diabetes

Overall, 1,429 subjects were randomized to acarbose ( n = 714) or placebo ( n = 715) [ 83 ] . We excluded 17 subjects (8 on acarbose and 9 on placebo) because they did not meet the criteria for IGT and another 44 because they had no valid post-random-ization data, leaving 1,368 subjects (682 on acarbose and 686 on placebo) for analy-sis (Fig. 10.1 ). Altogether, 24.6% discontinued treatment prematurely, but these were maintained in the intent to treat population.


The baseline characteristics of the intent to treat population are listed in Table 10.1 . Men and women were equally represented (49 and 51% respectively) with a mean age of 54.5 years, a mean BMI of 31 kg/m 2 and a mean waist circum-ference of 102.2 cm. The mean fasting plasma glucose was 6.24 mmol/L and the mean 2-h plasma glucose 9.26 mmol/L. One hundred and thirty- fi ve subjects (9.7%) had a fasting plasma glucose ³ 7.0 mmol/L but <7.8 mmol/L. Forty-six per cent had hypertension, 58% dyslipidemia and 61% had metabolic syndrome according to the NCEP-ATP III de fi nition [ 84 ] . These patients were thus at very high risk of developing diabetes and CVD.

Based on a single OGTT, the cumulative incidence of diabetes over 3.3 years was 221 (32.4%) in the acarbose-treated group compared to 285 (41.2%) in the placebo group. Figure 10.2 illustrates the effect of acarbose vs. placebo on the probability of remaining free of diabetes over time. Decreasing postprandial glucose with acar-bose therefore resulted in a relative reduction of 25% and an absolute reduction of 8.8% in the risk of progressing to diabetes ( p = 0.0015). These results suggest that 11 patients with IGT would have to be treated (NNT) for 3.3 years to prevent one case of diabetes. Two years after the beginning of the study, the diagnostic criteria

Fig. 10.1 Trial pro fi le of the STOP-NIDDM trial (from Chiasson et al. [ 83 ] , with permission)


Table 10.1 Baseline characteristics of intent-to-treat population

Acarbose ( n = 682) Placebo ( n = 686)

Gender Male 329 (48%) 344 (50%) Female 353 (52%) 342 (50%)

Age (years) 54.3 (7.9) 54.6 (7.9) White 664 (97%) 670 (98%) Weight (kg) 87.6 (15.3) 87.1 (14.1) Body mass index (kg/m 2 ) 31.0 (4.3) 30.9 (4.2) Waist circumference (cm) 102.1 (11.7) 102.2 (11.2) Plasma glucose (mmol/L)

Fasting 6.23 (0.50) 6.24 (0.53) 2-h 9.26 (1.06) 9.25 (1.01)

Plasma insulin (pmol/L) Fasting 99.34 (57.64) 98.13 (56.78) 2-h 606.37 (437.46) 597.99 (414.38)

Serum lipids (mmol/L) Total cholesterol 5.76 (1.04) 5.61 (0.99) HDL-cholesterol 1.19 (0.32) 1.17 (0.33) LDL-cholesterol 3.66 (0.91) 3.54 (0.90) Triglycerides 2.07 (1.10) 2.07 (1.17)

Blood pressure (mmHg) Systolic 131.4 (16.3) 130.9 (16.2) Diastolic 82.8 (9.4) 82.0 (9.3)

Smoking (%) 79 (12%) 99 (14%)

Data are mean (SD) or number (%)

Fig. 10.2 Effect of acarbose and placebo on the cumulative probability of remaining free of diabetes over time in subjects with impaired glucose tolerance (IGT) (from Chiasson et al. [ 83 ] , with permission)


for the diagnosis of diabetes changed: the fasting plasma glucose was lowered to 7.0 mmol/L, and whichever criterion was used had to be con fi rmed on a separate day. Accordingly, if we use a fasting plasma glucose ³ 7.0 mmol/L on two consecu-tive visits as the criterion, 117 (17%) patients developed diabetes in the acarbose group compared to 178 (26%) in the placebo group resulting in an absolute reduc-tion of 8.7% and a relative reduction of 32.4% ( p = 0.001). Similarly, if we used two positive OGTTs, 105 (15%) patients converted to diabetes in the acarbose group and 165 (24%) in the placebo group for an absolute reduction of 8.7% and a relative reduction of 36.4% ( p = 0.0003). No matter which criteria were used for the diagno-sis, the absolute risk reduction was essentially the same, 8.7%.

Figure 10.3 illustrates the analysis using the Cox proportional-hazards model adjusted for age, gender and BMI. Interestingly, acarbose was still effective in reducing the risk of diabetes whether the subjects were older or younger, male or female, or had a higher or lower BMI. However, it was particularly effective in the elderly, in moderately overweight subjects and in women. Furthermore, acarbose treatment was associated with an increase in the conversion of IGT to normal glu-cose tolerance [hazard ratio 1.42 (95% CI: 1.24–1.62); p = 0.0001].

At the end of the treatment period, all subjects were put on placebo in a single-blind fashion for another 3-month period after which all outcome variables were measured. During this short period, the bene fi t of acarbose on the conversion of IGT to diabetes totally disappeared. It is obvious that any intervention for the prevention of diabetes has to be maintained inde fi nitely to remain effective [ 83, 85, 86 ] .

The most common side effects to acarbose treatment were gastrointestinal symp-toms, mainly fl atulence and diarrhoea. But these were judged to be mild to moderate in severity and mostly disappeared over time.

In a secondary analysis, we evaluated the impact of single traits and overall meta-bolic syndrome on the conversion of IGT to diabetes [ 87 ] . The prevalence of meta-bolic syndrome in the STOP-NIDDM population was 61% based on the NCEP-ATP III de fi nition [ 84 ] . Multivariate analysis revealed that the treatment group, 2-h plasma glucose, triglycerides and leukocyte counts were all independent predictors

Fig. 10.3 Effect of acarbose on the development of diabetes in subjects with IGT according to age, gender and BMI (from Chiasson et al. [ 83 ] , with permission)


of diabetes. In the placebo group, the annual incidence of diabetes was 18.7% vs. 11.2% in subjects with and without metabolic syndrome respectively. In the acar-bose-treated group, the corresponding incidence rates were 13.5% vs. 9.4% respec-tively. Subjects with metabolic syndrome treated with acarbose had the same risk for diabetes as those on placebo without metabolic syndrome (Fig. 10.4 ). Interestingly, the number needed to treat to prevent one new case of diabetes was 5.8 in patients with metabolic syndrome compared to 16.5 in those without the metabolic syn-drome [ 87 ] . The absolute ef fi cacy of acarbose in patients with metabolic syndrome was similar to that found in prevention trials using lifestyle intervention [ 88, 89 ] .

We also looked at the effects of a number of candidate gene polymorphisms on the incidence of diabetes in a sub-group ( n = 770) of the STOP-NIDDM population (Table 10.2 ) [ 90– 94 ] . With the exception of the 3 ¢ UTR polymorphism of the leptin receptor gene and the Pro12Ala of the PPAR g gene, all other single nucleotide poly-morphisms (SNPs) studied increased the risk for diabetes. Three of the polymor-phisms were associated with gender differences; women carrying the combination of the G-allele of SNP +45 and the T-allele of SNP +276 of the adiponectin gene had an especially high risk of developing diabetes (odds ratio 22.2%, 95% CI 2.7–183.3) [ 90 ] . Interestingly, acarbose treatment completely neutralized the effect of

Fig. 10.4 The effects of acarbose on the probability of remaining free of diabetes in subjects with IGT and its modulation by the presence of the metabolic syndrome (from Hanefeld et al. [ 87 ] , with permission)


risk genotypes of the adiponectin gene on the risk of type 2 diabetes. Three other genotypes were associated with an increase in the effect of acarbose on the preven-tion of diabetes: SNPs of the PPAR d , Gly482Ser of the PGC-1 a and Pro12Ala of the PPAR g gene [ 92 ] . Two of the SNPs, 3 ¢ UTR of the leptin receptor gene and the combination SNP +45 and SNP +276 of the adiponectin gene, were associated with increased weight loss [ 90, 94 ] . Finally, the Gly250Ala polymorphism of the hepatic lipase gene was associated with an increased risk of diabetes and a reduction in the conversion of IGT to normal glucose tolerance [ 91 ] . Many polymorphisms are asso-ciated with an increased risk of conversion of IGT to diabetes and some modulate the effect of acarbose on the prevention of diabetes.

The STOP-NIDDM Trial: The Prevention of Cardiovascular Disease

CVD remains the leading cause of death in type 2 diabetes mellitus, accounting for 40–50% of all deaths [ 95 ] . In these patients, there is a two- to tenfold increase in mortality risk from coronary heart disease, cerebrovascular disease and peripheral vascular disease [ 96– 98 ] . Though type 2 diabetes is generally associated with other cardiovascular risk factors such as hypertension and dyslipidemia [ 99, 100 ] , it is believed that hyperglycaemia per se, particularly postprandial hyperglycaemia, is an independent risk factor for CVD in both diabetic and non-diabetic subjects [ 48, 51, 100, 101 ] . It has been acknowledged that macrovascular disease starts years before the development of diabetes [ 102 ] . Many studies have now con fi rmed that prediabetes, particularly IGT, is associated with increased risk of CVD even after adjusting for other classical risk factors [ 19, 103– 106 ] . Even a moderate increase in postprandial plasma glucose was a strong predictor of atherosclerosis [ 57, 107– 111 ] .

Table 10.2 Impact of candidate gene polymorphisms on the conversion of IGT to diabetes and to normal glucose tolerance, on weight loss and on the effect of acarbose on the incidence of diabetes

Gene Polymorphisms IGT to diabetes

Acarbose effect

Weight lost IGT to NGT

PPAR g Pro12A1a – ↑♀ – – PGC-1 a Gly482Ser ↑ ×1.6 ↑ – – Hepatic lipase Ala250Ala ↑ ×2.74 – – ↓ Adiponectin SNP + 45G ↑ ×1.8 – – –

SNP +276T ↑ ×4.5 – – – + 45G +276T ↑ ×22.2 ↑ ↑ –

PPAR d Crs6902123 ↑ ×2.7 – – – + Gly482Ser ↑ ×2.5 ↑ – – + Pro12Pro ↑ ×3.9♀ – – –

HNF4 a Rs4810424 ↑ ×1.7♀ – – –

Leptin receptor gene 3 ¢ UTR – – ↑ – ♀Female


Evidence supports the hypothesis that postprandial hyperglycaemia may be linked to CVD through the generation of oxidative stress [ 31 ] .

In the STOP-NIDDM Trial, 47 subjects had at least one cardiovascular event; 15 were in the acarbose-treated group compared to 32 in the placebo group (Fig. 10.5 ) [ 112 ] . All the cardiovascular events were evaluated and con fi rmed by an indepen-dent committee of cardiologists blinded to treatment. Acarbose treatment was asso-ciated with a 49% reduction in any cardiovascular event with a hazard ratio of 0.51 (95% CI 0.28–0.95). Even myocardial infarction, despite the small number of events, was signi fi cantly reduced by acarbose with a hazard ratio of 0.09 (95% CI 0.01–0.72). Though all other cardiovascular events were not reduced signi fi cantly, they were all favourably affected by acarbose. Figure 10.6 shows the probability of developing CVD over time, with the two groups starting to separate after 1½ years in favour of acarbose ( p = 0.04 by log rank test and 0.03 by Cox proportional- hazards model). All subjects had an ECG done at randomization and at the end of the study. The reading of the ECGs by independent cardiologists blinded to treatment revealed 8 silent myocardial infarctions which had not been identi fi ed clinically, 1 was in the acarbose-treated group and 7 in the placebo group for a total of 2 myocardial infarc-tions under acarbose treatment and 19 under placebo ( p = 0.0002 by Chi square analysis) [ 113 ] . Furthermore, in a sub-group of patients from the STOP-NIDDM trial ( n = 132), the IMT of the carotids, an accepted surrogate of atherosclerosis, was measured by B-mode ultrasound before randomization and at the end of the study [ 114 ] . The mean annual IMT increase was 0.02 (SD 0.07) mm in the acarbose group vs. 0.05 (0.06) mm in the placebo group ( p = 0.027). The annual increase in IMT was therefore reduced by 50% with acarbose treatment compared to placebo. The STOP-NIDDM trial also showed that treating postprandial hyperglycaemia with

Fig. 10.5 Effect of acarbose on the development of cardiovascular events in subjects with IGT (from Chiasson et al. [ 112 ] , with permission)


acarbose over 3 years was associated with a reduction of other cardiovascular risk factors that are part of metabolic syndrome such as excess body weight, dyslipi-demia and hypertension.

Anthropometric measurements were all favourably affected by acarbose treat-ment. Over 3 years, body weight decreased by 1.2 kg under acarbose compared to an increase of 0.3 under placebo; the 1.4 kg difference was signi fi cant at p < 0.001 [ 112 ] . Acarbose was associated with a reduction in body mass index of 0.60 kg/m 2 compared to 0.12 kg/m 2 under placebo ( p < 0.001). Finally, waist circumference decreased by 0.6 cm under acarbose treatment vs. a reduction of 0.2 under placebo ( p = 0.001). The lipid pro fi le was also affected favourably by acarbose treatment. Triglycerides decreased by 0.18 mg/dL in the acarbose treatment group compared to 0.04 mg/dL in the placebo group ( p = 0.01). Acarbose signi fi cantly reduced the mean systolic (−0.92 mmHg) and diastolic (−1.4 mmHg) blood pressure compared to placebo ( p < 0.001). But more importantly, acarbose signi fi cantly reduced the incidence of new cases of hypertension. In subjects normotensive at baseline ( n = 666), 96 developed hypertension based on the most recent criteria ( ³ 140/90 mmHg). Acarbose treatment in subjects with IGT resulted in a relative reduction in the incidence of hypertension of 41% [ 115 ] (Fig. 10.7 ). The STOP-NIDDM trial is the fi rst prospective intervention study in subjects with IGT show-ing that an a -glucosidase inhibitor was associated with a signi fi cant reduction in cardiovascular events and in the incidence of hypertension. All these observations lend further support to the hypothesis that postprandial hyperglycaemia is an inde-pendent risk factor for CVD. However, its cardiovascular effects still have to be

Fig. 10.6 Effect of acarbose on the probability of developing cardiovascular disease (CVD) in subjects with IGT (from Chiasson et al. [ 112 ] , with permission)


con fi rmed in a well-designed and well-powered prospective study where the primary outcome will be CVD. The ongoing Acarbose Cardiovascular Evaluation (ACE) trial is such a study.

The STOP-NIDDM Trial: Cost-Effectiveness of Acarbose Treatment for the Prevention of Diabetes and CVD in Subjects with IGT

The high prevalence of prediabetes, IGT and IFG constitutes a huge population at high risk for the development of diabetes and CVD with a major impact on health-care costs. Consequently, there is an emerging body of cost-effectiveness literature in the management of prediabetes.

For acarbose, economic analyses have been done for Spain, Germany, Sweden and Canada within the STOP-NIDDM trial [ 116– 120 ] . Each of these within-trial analyses compared only the direct cost to the healthcare system in each country for acarbose vs. placebo, using the risk reduction in new cases of diabetes and cardiovas-cular events over the mean 3.3-year follow-up in the STOP-NIDDM Trial. Healthcare resource utilization data and unit costs were used to calculate the cost outcomes esti-mated by modelling techniques. The main economic outcome for all these analyses

Fig. 10.7 Effect of acarbose on the probability of remaining free of hypertension and its modulation by the presence of the metabolic syndrome (unpublished data)


was the incremental cost per cases of diabetes averted and, for the German and Swedish analyses, the incremental cost per subject free of cardiovascular events [ 118 , 119 ] . The incremental cost ratios were obtained for the total STOP-NIDDM population and in groups at high risk for diabetes, CVD or both. The high-risk groups were de fi ned as the upper quartiles of validated risk scores for type 2 diabetes and CVD applied to individual patient data from the STOP-NIDDM Trial [ 121, 122 ] .

All these within-trial analyses in each country demonstrated favourable cost-effectiveness results for acarbose treatment in the prevention of diabetes. In Germany, acarbose treatment was cost-effective for the total population at 772€ (2004) per cases of diabetes averted. However, acarbose was the preferred strategy compared to placebo for all high-risk groups [ 119 ] . In Spain, where the analysis was done only for the total population, acarbose treatment was estimated to be both cost-savings and improved outcomes [ 120 ] . In Sweden, acarbose treatment was esti-mated to be the dominant strategy vs. placebo in subjects at high risk for CVD and combined high risk for diabetes and CVD. For the total population and for those at high risk for diabetes, the incremental cost-effectiveness ratios were approximately 3,000 and 825€ (2005) respectively [ 118 ] . In Canada, the analysis was done using the Markov model over a 10-year follow-up [ 117 ] . Acarbose treatment was superior to placebo in regard to cost per life year gained. All these within-trial cost-effectiveness analyses of the STOP-NIDDM trial population suggest that acarbose treatment for the prevention of diabetes would be cost-effective. Therefore, investing in the pre-vention of diabetes would be a good investment for the future.

The decision to invest in the prevention of diabetes implies that we have to invest in screening strategies. Screening everybody would not be cost-effective. However, there is general support for the screening of high-risk populations [ 123, 124 ] . A number of screening strategies based on opportunistic screening have been pro-posed based on fasting and/or OGTT [ 125, 126 ] . Strategies based on fasting plasma glucose only would miss 30–60% of subjects with IGT depending on the ethnic group, gender and age of the population [ 127– 129 ] . Although OGTT is the gold standard, it lacks reproducibility, is cumbersome, time-consuming and not without cost. More recently, a number of risk-score models have been developed and vali-dated in different populations. Two simple risk scores have been developed and validated from the STOP-NIDDM trial data to predict the development of diabetes and cardiovascular events in individuals with IGT, and these scores can also be used to estimate the risk reduction with acarbose [ 130 ] . Such a screening procedure is recommendable. It provides a simple, inexpensive and sensitive test for the screen-ing of subjects at high risk for diabetes.

Conclusion

Type 2 diabetes mellitus remains one of the major challenges of the twenty- fi rst century because of its high and growing prevalence, its high morbidity, its excess mortality and its impact on healthcare costs. Our only hope to curtail this


ever-growing problem is by developing and implementing prevention strategies. The STOP-NIDDM trial has addressed and validated the concept of postprandial plasma glucose as a risk factor for the development of diabetes and CVD. This international randomized controlled trial evaluated the effect of an a -glucosidase inhibitor, acarbose, on the incidence of diabetes and CVD in a high-risk population with IGT and a fasting plasma glucose ³ 5.6 mmol/L over a period of 3.3 years. Acarbose treatment resulted in a relative risk reduction of 25% when the diagnosis was based on a single OGTT and an absolute reduction of 8.8% ( p = 0.0015). The number needed to treat to prevent one case of diabetes was 11. When the diagnosis was based on two OGTTs as now required, the relative risk reduction was 36.4% with an absolute reduction of 8.7% ( p = 0.0003). Acarbose was even more effective in IGT subjects with metabolic syndrome where the NNT was 5.8 subjects to pre-vent the development of one case of diabetes. Acarbose also reduced most of the risk factors associated with metabolic syndrome: BMI, triglycerides and hyperten-sion. Furthermore, acarbose treatment was associated with a 49% relative risk reduction of any cardiovascular events and 41% reduction of newly diagnosed hypertension. The major effect was on the reduction in myocardial infarctions, both those diagnosed clinically as well as the silent myocardial infarctions diagnosed on ECG reading. It was also shown in a sub-group of the STOP-NIDDM population that acarbose resulted in a 50% reduction in the progression of the IMT of the carot-ids. These observations are now being tested in a well-powered prospective study, the ACE trial. The use of acarbose for the prevention of diabetes and CVD has been shown to be cost-saving or cost-effective in the perspective of the healthcare system of most developed countries. Opportunistic screening for high-risk individuals using a simple, inexpensive and validated tool such as the STOP-NIDDM risk-score would make it even more cost-effective.

The high and ever-growing prevalence of type 2 diabetes mellitus worldwide is exerting an enormous stress on the health of the populations and on the healthcare systems. We now know that type 2 diabetes can be prevented, or at least delayed. It is imperative that we implement prevention strategies to curtail this ever-growing problem. The STOP-NIDDM trial has shown that the use of acarbose was an effec-tive and cost-saving strategy that should be considered for the prevention of diabetes.

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