**8. Principles of planning of antihyperglycemic therapy**

Apart from various factors (**Figure 3**) to consider while prescribing antihyperglycemic medications, there are other principles to guide planning of antihyperglycemic therapy in type 2 diabetes.

#### **8.1. Possible loss of excess bodyweight for as long as possible and regular physical activity and exercise: The cornerstones of therapy of diabetes**

Loss of excess body weight and maintaining regular physical activity and exercise reduce insulin resistance and beta-cell workload and also benefit cardiovascular health and are thus the cornerstones of therapy of diabetes. The medications which support such aspects are preferred.

#### **8.2. Requirement of combination therapy**

Combination therapy, even in many newly diagnosed diabetic patients, is often required and it may also allow the use of submaximal doses of each antihyperglycemic medication resulting in fewer side effects [41, 42].

#### **8.3. Need of gradual building up of the doses of metformin and acarbose**

The doses of antihyperglycemic medications, particularly of metformin and acarbose having longer history of safety profile and other benefits, have to be built up slowly so that the patients tolerate the drugs; their maximum effect may take some time to be clinically evident.

#### **8.4. 'Dynamic dose management of medications likely to cause hypoglycemia'**

There is often need of controlling blood glucose immediately to prevent or treat acute complications [50]. Sulfonylurea and insulin act relatively fast. Insulin remains effective in all situations and it also helps to prevent ketosis. During the infection, other complications or 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

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

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

Apart from various factors (**Figure 3**) to consider while prescribing antihyperglycemic medications, there are other principles to guide planning of antihyperglycemic therapy in type 2

Loss of excess body weight and maintaining regular physical activity and exercise reduce insulin resistance and beta-cell workload and also benefit cardiovascular health and are thus the cornerstones of therapy of diabetes. The medications which support such aspects are

Combination therapy, even in many newly diagnosed diabetic patients, is often required and it may also allow the use of submaximal doses of each antihyperglycemic medication result-

The doses of antihyperglycemic medications, particularly of metformin and acarbose having longer history of safety profile and other benefits, have to be built up slowly so that the patients tolerate the drugs; their maximum effect may take some time to be clinically

There is often need of controlling blood glucose immediately to prevent or treat acute complications [50]. Sulfonylurea and insulin act relatively fast. Insulin remains effective in all situations and it also helps to prevent ketosis. During the infection, other complications or

**8.3. Need of gradual building up of the doses of metformin and acarbose**

**8.4. 'Dynamic dose management of medications likely to cause hypoglycemia'**

**8.1. Possible loss of excess bodyweight for as long as possible and regular physical** 

**8. Principles of planning of antihyperglycemic therapy**

**activity and exercise: The cornerstones of therapy of diabetes**

may benefit from higher dosages [43].

**8.2. Requirement of combination therapy**

ing in fewer side effects [41, 42].

tolerate the drug will be benefitted.

186 Diabetes and Its Complications

diabetes.

preferred.

evident.


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

‡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.

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

as possible. Physical activity and exercise increases glucose utilization and reduces blood glucose. Thus, there is need of continuous effort to reduce the dose of sulfonylurea, repaglinide and insulin to the lowest possible level as the '*Dynamic dose management of medications likely to cause hypoglycemia*' letting the healthy lifestyle and other non-hypoglycemic antihyperglycemic drugs to maintain the blood glucose [50]. Patient education and guidance from family physicians, diabetes educators and other health care workers will help to achieve such dynamic dose management.

**9. Avoiding unnecessary medicines and products**

**10. Education to the patient and training of educators**

Structured education is an integral part of diabetes care [39]. Lifestyle management is a fundamental aspect of diabetes care and includes diabetes self-management education, diabetes self-management support, nutrition therapy, physical activity, smoking cessation counseling and psychosocial care [25]. Nurses and other healthcare professionals requires adequate training and certification to work in the health system to fill the gap between medical professionals and patients and thus between the available scientific knowledge and effective appli-

**Public health perspectives:** For the training in the management and education of people with diabetes, the nurses and other healthcare professionals (with minimum of 2 years of professional practice experience) should have at least 1000 hours of practice experience in diabetes self-management education along with various educational activities [54]. In the non-industrialized countries, it may thus entail 1 year of working under the supervision of physicians (as a sort of residential training) in the daily diabetes and other outdoor and indoor services providing care and education to the patients fulfilling the other training requirements (like logbook recordings of case history records, procedure and academic activities, assignments and assessments) [50, 55]. To incorporate such trained personnel in the local health system, the terminology of certification of such training should match with the nomenclatures of other existing healthcare workers and with the various intervention programs being planned and/or implemented [55].

**Research perspectives:** State may develop some support system (e.g. by making available research funds or by involving pharmaceutical companies or other donor agencies) to study the local herbal, traditional or plant products and to identify and isolate the active the pharmacological ingredient of such possible crude products [52].

unnecessary medications.

cation by the patients [50].

There is no clear evidence that dietary supplementation with vitamins, minerals, herbs or spices can improve outcomes in people with diabetes who do not have underlying deficiencies, and there may be safety concerns regarding their long-term use [25]. Unnecessary medication or local herbal, traditional or plant products may increase the cost and/or number of tablets to be taken which can affect the adherence to the essential medicines. Any medications or various products are also some form of chemicals and can also cause side effects, affect different organ systems or interact with other medications [52]. It is a famous saying 'Everything under the sun, including the sun, can cause allergy or side-effects'. For example, peripheral edema may occur in up to 16% with pregabalin [53]; however, amlodipine, a useful and essential medicine for hypertension, may instead be inadvertently stopped due to its well-known association with peripheral edema. Symptoms like tingling, numbness or others may need to be investigated. However, if treatment does not change the course of the condition and if symptoms do not affect sleep or daily life of the patients, explanation and reassurance with the required follow-up may be preferred than using

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#### **8.5. Long-term safety profile**

Geoffrey Rose rightly highlighted 'Safety is paramount with long-term interventions' [9]. There is relatively longer history of safety profile with metformin and acarbose. They are preferred in the prevention and in the early phase of treatment of diabetes so that they can be safely continued for long time.

Based on such principles, a suggested approach of antihyperglycemic therapy is outlined in algorithm in **Table 1**.

Compared to the two agents prescribed separately, combination tablets reduce pill burden and help adherence of patients [49]. However due to the contrasting effect as well as the need of 'dynamic dose adjustment of medications likely to cause hypoglycemia' to the lowest possible dose and of gradual building of the dose of metformin for its continued maintenance at the optimum level, the formulation of fixed dose of combination of such drugs in a single tablet is irrational (**Table 2**) [50]. Availability of such fixed dose combination formulation in the market is likely to lead to the continued usage of sulfonylurea and suboptimal dosage of metformin even right from the time of diabetes diagnosis with all its effects in the patients.


\*Apart from the risk of effect of severe hypoglycemia on heart, it is also advised that use of the sulfonylurea types (glibenclamide, glipizide, glimepiride and others) that bind the sulfonylurea receptor-2 A and B should be avoided in high-risk patients suspected of having significant coronary artery disease [51]. † Sulfonylureas are often advised to be taken at least 15–20 minutes before a meal [51].

**Table 2.** The contrasting effect and uses of metformin and sulfonylurea and repaglinide making their fixed dose combination formulation irrational.
