A fasting plasma glucose ≥100 mg/dl (5.6 mmol/l) or previously diagnosed type 2 diabetes are important criteria in either of the two definitions used to diagnose the presence of the metabolic syndrome.

The presence of the metabolic syndrome raises the lifetime risk for ASCVD by about two fold, but this risk is significantly more in those people with the metabolic syndrome who already have T2DM.

Raised Fasting Plasma glucose

For patients with a fasting plasma glucose ≥100 mg/dl (5.6 mmol/l), the main goal is to delay the progression to type 2 diabetes mellitus. This progression to type 2 diabetes mellitus can be delayed or prevented by instituting lifestyle changes, especially weight reduction and increased physical activity. Drug therapies to reduce plasma glucose or insulin resistance are not recommended for such patients although recent trials have shown that they may be useful in some category of patients.

Diabetes

For type 2 diabetes, lifestyle therapy and pharmacotherapy, if necessary, should be used to achieve near-normal HbA1C (<7%).

Lifestyle Management

DIET should be the mainstay of all diabetes management!

In order to ensure compliance, the prescribed diet should be individualised. It must be realistic, flexible, and take into consideration the patient's likes and dislikes, to as large an extent as possible, and must suit the patient's life style. It is important to educate the patient about the basic requirements of the diet and judge compliance at regular intervals.

AVOID simple carbohydrates like sugar, sweets, jaggery, honey, etc., as they tend to cause a sharp rise in the blood glucose levels.

Many of these aspects have been discussed in detail in the section dealing with lifestyle changes.

The types of alternative sweeteners that are available are:

• a) Non-caloric sweeteners like saccharin, cyclamates, sucralose, acesulfame K.
• b) Aspartame; although this is usually classified as a noncaloric sweetener, it does have a caloric value of 4 calories per gm.
• c) Non-glucose carbohydrates like fructose, sorbitol, xylitol, lactose, isomalt, polydextrose, and maltodextrose. These contain calories and have varying effect on the blood glucose levels.

Most of the non-caloric sweeteners and aspartame are safe if taken in small amounts.

Many of other aspects have been discussed in detail in the section dealing with lifestyle changes.

A REGULAR EXERCISE PROGRAMME, TAILOR MADE FOR EVERY INDIVIDUAL AND UNDERTAKEN AFTER DUE FITNESS EVALUATION, WITH REGULAR MONITORING, IS AN ESSENTIAL PART OF MODERN DIABETES MANAGEMENT!

Increased daily routine physical activity and regular exercise is recommended as an important component of all lifestyle management regimens to prevent and manage the metabolic syndrome as well as all diabetes management regimens.

It confers benefits not only on glycemic control, but also on insulin sensitivity, lipid abnormalities, cardiovascular system, physical fitness, psychological well being, optimising body weight and disease prevention. It reduces overall ASCVD risk beyond that provided by weight reduction alone.

Many aspects have been discussed in detail in the section dealing with lifestyle changes.

If a patient is not optimally controlled by diet and exercise alone, oral hypoglycemic agents (OHA's) are usually the first line of drug therapy in the management of Type 2 diabetes.

Drug Of Choice

Type 2 diabetes is characterized by three basic abnormalities that contribute to the development of hyperglycemia:

• A) Impaired insulin secretion by the pancreas;
• B) Peripheral insulin resistance; and
• C) Excessive glucose production by the liver;

Type 2 patients would have a combination of these three mechanisms which cause the high blood glucose levels. The problem is that the extent and severity of each of these mechanisms varies in different individuals, and the oral agent which would be most optimal for any patient would depend on which of these three mechanism plays a major role in their hyperglycemia.

Although there is no hard and fast rule for this, it is widely accepted that in type 2 patients with low body weight, impaired insulin secretion is the predominant defect, while insulin resistance tends to be less severe than in the obese variety. Insulin resistance and hyperinsulinemia are the classic abnormalities of obese individuals with type 2 diabetes.

All the oral agents available do not have the same mechanism of action. Thus, one must know how a class of oral agent acts in order to choose the appropriate drug.

Oral Agents commonly used in the Treatment of Type 2 Diabetes

Incretin mimetics

OHA THERAPY in a RELATIVELY non-obese Type 2 Diabetes patient

Protocol

Recently, questions have been raised about cardiovascular safety of rosiglitazone and it should be used with added caution. Although, it is not clear whether this is a class effect of glitazones, it would appear prudent to be extra cautious even with the use of pioglitazone.

In view of this, metformin may the drug of choice as a sensitizer.

Managing the Overweight (Obese) Patient

Protocol

Recently, questions have been raised about cardiovascular safety of rosiglitazone and it should be used with added caution. Although, it is not clear whether this is a class effect of glitazones, it would appear prudent to be extra cautious even with the use of pioglitazone.

In view of this, metformin may the drug of choice to initiate therapy

Many trials have shown that a 20 mg dose of rimonabant, which is used in the management of obese diabetics, can lead to an average weight loss of approximately 6 kg over a year when accompanied with lifestyle therapies. Importantly, it leads to a decrease in abdominal obesity and improves cardiovascular risk factors. The most common reported side effects include depression, anxiety, and nausea and should not be used in patients on anti-depressives. It is NOT accepted for use by the U.S. FDA.

Theoretically, most Type 2 patients should be given a trial with diet and exercise for an adequate period (usually 4-6 weeks) before using oral hypoglycemic agents. But practically speaking, patients with fasting blood glucose levels more than 200 mg%, or in patients with significant symptoms, OHA therapy can be started along with diet and exercise. This will allow a more rapid relief of symptoms.

Sulfonylureas are the drugs of choice in the management of Type 2 diabetics who are not overweight.

Sulfonylureas, especially the short acting ones, are to be given 20-30 minutes before food intake, although this needs to be individualised.

Long acting sulfonylureas such as glibenclamide and glimepiride can be given as a single daily dose.

Meglitinides are much milder in their efficacy, but may be useful in patients with erratic meal timings in that they allow for flexible timing and missed meals.

Biguanides are considered the drugs of choice in those overweight Type 2 diabetics. They may be used in lean patients, but care should be taken that patients using biguanides maintain their ideal weight and do not become underweight.

Glitazones can be used in obese patients in whom a significant degree of insulin resistance would be expected, but have a significant time lag before showing their full activity. Recently, questions have been raised about cardiovascular safety of rosiglitazone and it should be used with added caution. It should not be used in patients with established cardiovascular disease, elderly patients and along with insulin. Although, it is not clear whether this is a class effect of glitazones, it would appear prudent to be extra cautious even with the use of pioglitazone. If pioglitazone is used along with insulin, the dose should not exceed 30mg/day.

If the patient shows a relatively high postprandial levels, then addition of an alpha-glucosidase inhibitors or the newly available DPP-IV inhibitors may be of help.

The starting dose should be small, starting with a small dose and giving with meals, if necessary, will help to avoid the gastrointestinal side effects.

OHA increments must be made in small amounts (half to one tablet at one time) and gradually (every 1-2 weeks), till optimal control is reached.

In many patients, there will be a need to combine two or more oral agents or even insulin therapy with possibly insulin sensitizers.

Potential combinations of OHAs for the treatment of type 2 diabetes

Combinations of submaximal doses of different classes of OHAs may be equally effective as or more effective than maximum dose of monotherapy in improving glucose control with fewer adverse effects.

Once Optimal Control Is Achieved

Re-enforce importance of diet and exercise;

Efforts must be made to reduce the dose slightly to see if the control is maintained; the rationale for this is to try and obtain the optimal target level for the individual with the smallest possible dose.

Emphasize need or regular follow-ups.

DIRECT EFFECTS OF ORAL ANTIHYPERGLYCEMIC AGENTS ON CARDIOVASCULAR RISK FACTORS IN TYPE 2 DM PATIENTS

A JUDICIOUS USE OF INSULIN THERAPY MAY BE NECESSARY FOR OPTIMAL MANAGEMENT IN MANY PEOPLE WITH TYPE 2 DIABETES!

Non dependence does NOT imply that Type 2's may never require insulin in order to obtain optimal control.

At the same time, unnecessary insulin therapy should be avoided as there is some evidence that high insulin levels in the blood may contribute to some aspects of the Metabolic Syndrome.

In view of this, THE DECISION TO USE INSULIN IN Type 2 patients SHOULD BE TAKEN AFTER CAREFUL, JUDICIOUS CONSIDERATION.

DIABETES PATIENTS WHO SHOULD RECEIVE INSULIN

Patients not optimally controlled with OHA use.

Insulin should be considered in diabetics with significant complications like ischemic heart disease, CVA, peripheral artery disease, significant retinopathy, nephropathy and neuropathy, hepatic complications such as viral hepatitis."

Any patient with an acute problem like several infection, injury, any metabolic catastrophe, etc., should receive insulin.

Patients with tuberculosis often do better with insulin.

Any Type 2 patient who manifests ketosis for whatever reason.

Diabetes patients undergoing most surgical procedures, especially those requiring general anesthesia, and where the patient will be on intravenous fluids for any significant period of time should be stabilized on insulin.

Pregnant women with diabetes, if not "tightly" controlled with diet alone, must be managed with insulin.

Any patient, even if optimally controlled with OHA's who shows evidence that may contraindicate the use of these oral agents, must be shifted to insulin.

Many underweight patients and those with significant symptoms would do better with insulin therapy, possibly in combination with small doses of sensitisers;

Patients with INSULIN-REQUIRING diabetes, even though they are not prone to ketosis, should be identified and their management supplemented with insulin to get the best possible control;

Types of insulins available for clinical use:

Although animal insulins made from beef and pig pancreas may still be found, the vast majority of the insulins used now are of the "human" variety. Recently there has been an increasing emphasis on the use of the newly available insulin analogs and the clinical question is to place them correctly in the therapeutic armamentarium.

It would not be correct to totally replace the use of human insulins with analogs in routine therapy, especially as one has to factor in the costs to the patient and in many cases the use of human insulins would offer good control.

Table Showing Commonly used Insulin Preparations:

Long acting analogs

They exhibit a relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing, although some patients may do better with a twice daily dose of levemir insulin. Clinically, its potency is approximately the same as human insulin and it does not lead to a better glycemic control.

Rapid acting analogs

Their use in place of the human insulins does not always lead to a better control, but their rapid onset and short duration of action make them of particular use in some clinical situations.

Rapid acting analogs

Their use in place of the human insulins does not always lead to a better control, but their rapid onset and short duration of action make them of particular use in some clinical situations:

• Patients exhibiting high postprandial glycemia with late hypoglycemia.
• Brittle diabetes.
• In the elderly and in children.
• In those with erratic eating habits.
• Perioperative period.
• Sick day therapy.
• Renal and hepatic dysfunction where one sees low fasting blood glucose levels with high postprandial blood glucose values and the fear of late hypoglycemia.
• People on RT and other tube feeds.
• Significant variations in bioavailability in the same patient on a day to day basis.

Long acting analogs

These are indicated for the treatment of hyperglycemia in adult and pediatric patients 6 years of age and older with Type 1 or Type 2 diabetes mellitus.

It exhibits a relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing, although some patients on levemir may do better with twice daily injections. Clinically, its potency is approximately the same as human insulin and it does not lead to a better glycemic control.

But it may have a special role to play in those clinical situations where a steady basal level of insulin is required.

However, each person responds to insulin in his or her own way. That is why onset, peak time, and duration are given as ranges.

It is important to have an understanding of the time-activity characteristics of the available insulins. When blood glucose levels are not well controlled at certain times during the day, or if hypoglycemic reactions are occurring, the knowledge of the action and characteristics of each insulin being taken will help to determine where changes need to be made.

Fortunately, the picture becomes much more clear, if it is realised that from a practical and clinical viewpoint, human insulins can be divided into two main groups, depending on their time course of action. These are the "short-acting (SAI)" and the "intermediate acting (IAI)" insulins.

* Rosiglitazone should not be used along with insulin and the dose of pioglitazone should not exceed 30mg/day.

In most patients with a significant degree of symptoms, or in whom the fasting blood glucose values are higher than 250-300mg%, insulin therapy, if indicated in a particular patient, may be started along with the diet and exercise prescription.

Start with a small dose and gradually titrate upwards depending on the time characteristics of the insulins used as well as the individual response of a patient.

With increasing use, it would be possible to cut out some of the steps outlined above and start with a twice daily mixture of SAI and IAI insulins, especially in insulin requiring patients.

The most commonly used regimen is the Premixed regimen:

It is the most convenient and effective insulin regimen for initiation of insulin therapy. In this there is dual coverage as it is a combination of short acting and intermediate acting insulin preparations in fixed ratio like 30:70 or 50:50 respectively (options for different food habits). So the same preparation is able to give both basal and meal related coverage and helps to mimic physiology to a great extent. There for these are considered as the effective and compliant insulin preparations for initiation as well as intensification of insulin therapy.

Rosiglitazone should not be used along with insulin and the dose of pioglitazone should not exceed 30mg/day.

Basal Only Regimen

In this patients on OHAs who are not optimally managed are supplemented with just basal insulin. This is done with the help of NPH or the modern insulins. With NPH patients usually require 2 doses per day where as with insulin analogues with one injection per day you can achieve the desired targets in most of the patients, if chosen appropriately.

Basal Bolus Regimen

Very rarely required for T2DM patients, but may be necessary in certain clinical scenarios. In this a basal insulin supplementation given with the help of long acting insulins either two or one (with insulin analogues) injections and then three meal related short acting insulin injections.

The sites where the injections can be given. Efforts must be made to rotate the site of the injection throughout the permissible areas and not inject only into one region.

Hypoglycemia

Edema

Allergy

Lipodystrophy and scar formation