**7. Antihyperglycemic medications**

**5. Use of statin and antiplatelet therapy**

syndrome [25, 32].

182 Diabetes and Its Complications

**for the respective populations**

with cardiovascular events need to be studied.

studies on Europids, indicated BMI of 18.5–24.9 kg/m<sup>2</sup>

ing WHO 1998 cut-off point for overweight (>24.9 kg/m<sup>2</sup>

of cut-off point of normal BMI for Asian people as 22.9 kg/m<sup>2</sup>

studies, including those conducted in the Westernized ones.

tion. The adult mean BMI levels of 20–23 kg/m<sup>2</sup>

mum population range (21–23 kg/m2

of a BMI of 20–22 kg/m<sup>2</sup>

BMI above 21 kg/m<sup>2</sup>

the population.

in Africa and Asia, whereas levels of 25–27 kg/m2

The use of statin is the other core element to prevent the premature death and disability in diabetes. The mechanisms of beneficial effects of statins in CVD are not completely understood. Some beneficial effects appear to occur independently of lowering of LDL cholesterol. Thus, most trials of statins and CVD outcomes tested specific doses of statins against placebo or other statins rather than aiming for specific LDL cholesterol goals, suggesting that the initiation and intensification of statin therapy should be based on risk profile [25, 32]. Before starting statin, lipid profile should be required at least once; a fasting sample is not routinely needed [32]. Antiplatelet therapy in diabetes is generally recommended for those with history of CVD and dual antiplatelet therapy is reasonable for up to 1 year after an acute coronary

**6. Body weight as per the recommended body mass index (BMI)** 

The WHO 1998 Consultation on Obesity, based on classifications used in a number of past

**Research perspectives:** Studies indicate that lower statin doses achieve lipid improvements in Chinese, Japanese and Koreans patients comparable with those observed with higher doses in Caucasians [33]. However as the mechanism of action of statins may not be just related to the lowering of LDL cholesterol, the relation of such observation

sultation on BMI for Asian populations concluded that Asians generally have a higher percentage of body fat than white people of the same age, sex and BMI and that the proportion of Asian people with a high risk of diabetes and CVD is substantial at BMIs lower than the exist-

Diabetes Federation and American Diabetes Association have recommended the upper limit

recommendations for different non-Caucasian populations have been made in various other

These recommendations are in agreement with the actual body mass index of the popula-

2002 [10]. The WHO consultation on BMI for Asian populations identified further potential public health action points along the continuum of BMI and indicated that the earlier opti-

[36]. The risk of insulin resistance and diabetes in adult increases progressively upwards

middle-income countries and nearly two thirds of diabetes globally are attributable to

appears to increase once BMI starts rising above the middle of the recommended BMI for

as normal [34, 35]. A WHO expert con-

) [36]. The WHO [35], International

are found among the general population

) gives some intuitive consistency for policy makers

[10]. More than 80% of the people with diabetes live in low- and

[10]. In general, the risk of insulin resistance and glucose intolerance

across North America and Europe in

[25, 35, 37]. Similar and variables

Type 2 diabetes is a chronic metabolic condition characterized by insulin resistance and insufficient pancreatic insulin production from beta-cell, resulting in high blood glucose levels [39]. Difficulty in utilizing the available insulin increases the workload of beta-cell. While using antihyperglycemic medications, the issues that need to be considered are shown in **Figure 3**. A few pertinent points are further discussed below.

#### **7.1. Reduction of insulin resistance and beta-cell workload**

Beta-cell failure is central to the ultimate development and progression of type 2 diabetes and it antedates and predicts diabetes onset and progression [40]. Subjects with normal glucose tolerance with 2-hour plasma glucose 120–139 mg/dL may have already lost 50% of beta-cell function, whereas subjects with impaired glucose tolerance with 2-hour plasma glucose 180– 199 mg/dL have lost up to 80% of beta-cell function. Thus, when the diagnosis of diabetes is made, the patient may have already lost 80% of their beta-cell function [41, 42]. The available clinical studies with appropriate protocols, however, indicate that existing therapy may not reverse or arrest progression of beta-cell dysfunction in type 2 diabetes [40]. Weight loss reduces insulin resistance and beta-cell workload and physical activity increases insulin utilization and also helps to reduce beta-cell workload and bodyweight. Both help to normalize the blood glucose and are also useful for cardiovascular health. Promotion of physical activity and exercise and loss of excess bodyweight for as long as possible are the cornerstones of management in type 2 diabetes. Medications favoring these two aspects are preferred for as long as possible.

#### **7.2. Risk of hypoglycemia**

Hypoglycemia can manifest in different ways (**Figure 4**). Insulin is a known cause of hypoglycemia. The risk of hypoglycemia associated with the use of other antihyperglycemic medications is given below [21]:

**Figure 3.** Factors to consider while prescribing antihyperglycemic medications in type 2 diabetes.

**7.3. Acarbose**

decrease over time [45].

Acarbose is an effective drug with relatively long safety profile having various cardiovascular and metabolic beneficial effects, it is not associated with hypoglycemia and it promotes weight loss [43–48]. Different meta-analysis, review articles and more than 350 studies have reported its efficacy (when used alone or in combination with other antihyperglycemic medications, including metformin), safety profile, cardiovascular, weight reduction, metabolic and other benefits [43–48]. Metformin or acarbose is recommended by International Diabetes Federation and American Association of Clinical Endocrinologist when the lifestyle modification strategy is not enough for prevention of type 2 diabetes [21, 49]. Acarbose can also be

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185

Gastrointestinal side effects have been an issue with acarbose. The predominant gastrointestinal symptom associated with acarbose is flatulence; however, loose stools and/or abdominal discomfort have also been reported. The side effects occur maximally during the first 2 weeks of therapy and start decreasing. By 12 weeks, 13.7% report flatulence and 2.2% diarrhea, and a 5-year surveillance study of about 2000 patients with diabetes found that gastrointestinal side effects associated with acarbose were reported by only 3.9% of patients [45]. For administration and dose adjustment and for understanding its metabolic benefits, its unique mode of

• The effect of acarbose is to delay the digestion of starch and oligosaccharides in the small intestine so that the release and absorption of glucose takes place over a longer time across the length of the small intestine. In many individuals, alpha-glucosidases are most active in the upper small intestine, and as acarbose treatment continues, there is a compensatory increase in enzyme activity in the lower small intestine and gastrointestinal side effects

• Furthermore, exposure of the lower small intestine to undigested carbohydrate leads to an increased quantity and duration of glucagon-like peptide-1 (GLP-1) release [45]. Acarbose

• Low glycemic foods are preferred in type 2 diabetes. Low glycemic index foods are created by different processing methods; alpha-glucosidase inhibitors mimic these compounds in that they decrease the glycemic index (as well as the glycemic load) of carbohydrate-rich foods [46].

• Acarbose acts by competitive inhibition of alpha-glucosidase, so it is given at the same time as the ingested carbohydrate [45]. When taken as a tablet, the usual available form, it is less effective than when consumed in powdered form; so it is better to chew the tablet with food

• Acarbose blocks and slows the digestion of complex carbohydrate, like starch, and sucrose (table sugar) without affecting the absorption of monosaccharides like glucose and fructose (present in fruits) and disaccharide lactose (present in milk products), which is digested by beta-glucosidase [44–47]. Trials in some countries report a higher incidence of gastrointestinal symptoms when initiating the dose of acarbose [46]. It may be due to the dietary habit of the population using sugar-rich food or soft drinks with or after meals. In any case, while initiating

also potentiates the reduction of ghrelin [46], thus may help to increase satiety.

considered to be used as a first-line antihyperglycemic agent [46, 48].

action, not just alpha-glucosidase inhibition, need to be considered.

than to swallow at the beginning of a meal [47].

**Figure 4.** Manifestations of hypoglycemia. *Note:* The patient may not volunteer the information; the healthcare professionals have to ask the leading questions so that the dose of the medications likely to cause hypoglycemia, viz. insulin, sulfonylurea and repaglinides, can be appropriately reduced.


The patients only on antihyperglycemic treatment unlikely to cause hypoglycemia can check their glycemic control with blood glucose fasting, 2-hour postprandial glucose and HbA1c estimation. If the patients are also on medications, like sulfonylurea, repaglinide and insulin, which can cause hypoglycemia, they need to check their blood glucose also at other time (e.g. before meals and exercise or later in the day or at night) considering the hypoglycemic symptoms and the maximum onset and duration of action of the drugs likely to cause hypoglycemia.

The popular guidelines cover detail aspects of different medications including the monitoring of glucose [21, 25, 39]. As acarbose, an alpha-glucosidase inhibitor, is increasingly used and has relatively longer safety profile, efficacy and other benefits, it can also be considered in the early phase of therapy in glucose intolerance. Four alpha-glucosidase inhibitors currently exist: acarbose, miglitol, voglibose and emiglitate [43]. Acarbose inhibits both alpha-amylase (which breaks down starch to disaccharides) and other alpha-glucosidase (which digests disaccharides), where as voglibose and miglitol inhibit the disaccharide-digesting enzymes well, but have no effect on the starch digesting enzyme alpha-amylase [44]. Acarbose and voglibose are minimally absorbed from the intestine and have very low bioavailability [44] with acarbose having less than 2% systemic availability [45]. Miglitol is almost completely absorbed from the upper part of the intestine [44]. Acarbose was first developed. Among the alpha-glucosidase inhibitors, acarbose is the most prescribed drug and most data and bestoutcomes are obtained for it [43].

#### **7.3. Acarbose**

• Metformin, acarbose and other alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibi-

**Figure 4.** Manifestations of hypoglycemia. *Note:* The patient may not volunteer the information; the healthcare professionals have to ask the leading questions so that the dose of the medications likely to cause hypoglycemia, viz.

• Sulfonylurea is associated with moderate-to-severe risk and repaglinide moderate risk of

The patients only on antihyperglycemic treatment unlikely to cause hypoglycemia can check their glycemic control with blood glucose fasting, 2-hour postprandial glucose and HbA1c estimation. If the patients are also on medications, like sulfonylurea, repaglinide and insulin, which can cause hypoglycemia, they need to check their blood glucose also at other time (e.g. before meals and exercise or later in the day or at night) considering the hypoglycemic symptoms and the maximum onset and duration of action of the drugs likely to cause

The popular guidelines cover detail aspects of different medications including the monitoring of glucose [21, 25, 39]. As acarbose, an alpha-glucosidase inhibitor, is increasingly used and has relatively longer safety profile, efficacy and other benefits, it can also be considered in the early phase of therapy in glucose intolerance. Four alpha-glucosidase inhibitors currently exist: acarbose, miglitol, voglibose and emiglitate [43]. Acarbose inhibits both alpha-amylase (which breaks down starch to disaccharides) and other alpha-glucosidase (which digests disaccharides), where as voglibose and miglitol inhibit the disaccharide-digesting enzymes well, but have no effect on the starch digesting enzyme alpha-amylase [44]. Acarbose and voglibose are minimally absorbed from the intestine and have very low bioavailability [44] with acarbose having less than 2% systemic availability [45]. Miglitol is almost completely absorbed from the upper part of the intestine [44]. Acarbose was first developed. Among the alpha-glucosidase inhibitors, acarbose is the most prescribed drug and most data and best-

tors are associated with neutral risk of hypoglycemia.

insulin, sulfonylurea and repaglinides, can be appropriately reduced.

hypoglycemia [21].

184 Diabetes and Its Complications

outcomes are obtained for it [43].

hypoglycemia.

Acarbose is an effective drug with relatively long safety profile having various cardiovascular and metabolic beneficial effects, it is not associated with hypoglycemia and it promotes weight loss [43–48]. Different meta-analysis, review articles and more than 350 studies have reported its efficacy (when used alone or in combination with other antihyperglycemic medications, including metformin), safety profile, cardiovascular, weight reduction, metabolic and other benefits [43–48]. Metformin or acarbose is recommended by International Diabetes Federation and American Association of Clinical Endocrinologist when the lifestyle modification strategy is not enough for prevention of type 2 diabetes [21, 49]. Acarbose can also be considered to be used as a first-line antihyperglycemic agent [46, 48].

Gastrointestinal side effects have been an issue with acarbose. The predominant gastrointestinal symptom associated with acarbose is flatulence; however, loose stools and/or abdominal discomfort have also been reported. The side effects occur maximally during the first 2 weeks of therapy and start decreasing. By 12 weeks, 13.7% report flatulence and 2.2% diarrhea, and a 5-year surveillance study of about 2000 patients with diabetes found that gastrointestinal side effects associated with acarbose were reported by only 3.9% of patients [45]. For administration and dose adjustment and for understanding its metabolic benefits, its unique mode of action, not just alpha-glucosidase inhibition, need to be considered.


therapy with acarbose, starting with low dose (e.g. 25 mg or in a few cases still lower, once a day after dinner) and with slow stepwise-increasing dose over weeks avoiding the sugar-rich food or soft drinks with or after meals may help the patient to tolerate acarbose. Cochrane review reports that acarbose dosages higher than 50 mg three times daily offer no additional effect on HbA1c but more adverse effects instead. However, the fasting and post-load glucose may benefit from higher dosages [43].

immobility of the patients or the initial stage of diagnosis, rapid control of high blood glucose may thus be required to be done as rescue therapy. However, sulfonylurea, repaglinide and insulin not only cause hypoglycemia but also prevent the patients to lose weight and may even cause weight gain. Normalizing blood glucose is important, but there are other factors to consider as well (**Figure 3** ). Moreover, even if sulfonylurea is continued to control the blood glucose, the glucose-lowering effect of sulfonylurea by beta-cell stimulation is not durable and wane over some years [41, 42]. DeFronzo has pointed out that such focus on simply HbA1c reduction with continuous use of sulfonylurea may lead to '*treat to fail*' approach and thus underlying pathophysiology also needs to be considered [41, 42]. The aim in the management of hyperglycemia in type 2 diabetes is to normalize it for as long as possible with the help of antihyperglycemic medications avoiding hypoglycemia and helping the patient to continue regular physical activity and exercise and to reduce excess bodyweight for as long

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**+ Regular use of antihyperglycemic medicines**

level

+ Gradually building up of metformin dose to the optimum

+ Addition of acarbose, pioglitazone, dipeptidyl peptidase-4 inhibitor, glucagonlike peptide-1 receptor agonist, sodium–glucose cotransporter

+ Repaglinide, sulfonylurea or basal insulin with other drugs

+ Combination insulin therapy with or without other drugs

2 inhibitors

Note: The medications are used if not contraindicated and as per their effectiveness, tolerance by patients and local guidelines. \*'*Dynamic dose adjustment of medications likely to cause hypoglycemia*' aims to taper off the dosage of the drugs like sulfonylurea to continue normalization of HbA1c for long time with diet, regular physical activity and exercise and possible loss of excess bodyweight for as long as possible and with other drugs not likely to cause hypoglycemia. †Even if HbA1c is well controlled, considering the long-term safety profile, mechanisms of action and negligible systemic absorption, acarbose can be added once the optimum dose of metformin is tolerated. Acarbose is started with low and slow stepwise-increasing dose over weeks or months to the optimum tolerable level. In patients only on antihyperglycemic drugs unlikely to cause hypoglycemia, they may have their major meals two times a day as per their convenience and custom. In such patients, the dose of acarbose can be gradually increased to the optimum tolerable level, e.g. 50–100 mg two times daily with the meals. Whatever the dose the patients tolerate, it is likely to be beneficial

‡Whether to add other new drug even if blood glucose is well controlled and which one to add as 3rd or 4th drug will

depend on various factors as discussed in the text and on the guidelines of the local regulatory bodies.

**± Temporary use of other antihyperglycemic drugs likely to cause hypoglycemia\***

± Short-term temporary use of sulfonylurea or insulin to control hyperglycemia immediately as rescue

± Short-term temporary use of sulfonylurea or insulin to control hyperglycemia immediately as rescue

± Short-term temporary use insulin to control hyperglycemia immediately

as rescue therapy

therapy

therapy

**Phases of therapy Diet, physical** 

2. Once the dose of metformin is optimum & tolerable, next phase of therapy with other 2nd to 4th drugs unlikely to cause hypoglycemia†,‡

3. Regular hypoglycemic

therapy

4. Long-term combination insulin therapy phase

1. Initiation of therapy Recommended diet,

**activity and exercise and weight plan**

reduction of excess body weight and regular physical activity and exercise

Continue above diet, physical activity and exercise and weight plan

Continue diet and physical activity and exercise plan

Continue diet and physical activity and exercise plan

considering its unique mode of action and long-term safety profile.

**Table 1.** A suggested algorithm of antihyperglycemic therapy in type 2 diabetes.

Thus considering the benefits and safety of acarbose, it can be used in the treatment of diabetes next after metformin even if HbA1c is well controlled. With judicious initiation of the drug, most patients may be able to tolerate the drug. As in the case of metformin, those who tolerate the drug will be benefitted.
