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IMPAIRED GLYCEMIA AND TYPE 2 DIABETES (T2DM)


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.

Management

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.

BASIC DIET ADVICE

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.

ALTERNATIVE SWEETENERS

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, xylitol, 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.

PHYSICAL ACTIVITY AND EXERCISE

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.


DRUG THERAPY

ORAL HYPOGLYCEMIC AGENTS (OHAs)

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.

MAIN GROUPS OF OHAs

Oral Agents commonly used in the Treatment of Type 2 Diabetes

Agent
Dose
Duration of action
Efficacy
Major side effects
Contraindications
Sulfonylureas
Increase insulin secretion by pancreas;
Metabolizedprimarily liver, excreted by kidney
   
   
Average decrease in FPG 60-80 mg%
Average decrease in HbA1c: 0.8- 2%
Hypoglycemia; abdominal discomfort, nausea in around 1% to 3% patients; hyperacidity, metallic taste or change in taste; weight gain;
Significant renal or hepatic dysfunction
Glipizide
2.5-20 mg/day
8-12 hours
   
Hypoglycemia risk 4-6%
   
Glibenclamide
2.5-20 mg/day
16-24 hours
   
Hypoglycemia risk 4-6%
   
Gliclazide
80-240mg/day
6-8 hours
   
Hypoglycemia risk < 2%
   
Glimepiride 1-8 mg/day 24 hours     Hypoglycemia risk < 2%    
Biguanides
Decreases hepatic glucose production
Not metabolized, eliminated by kidneys
   
   
Average decrease in FPG 65-75 mg%
Average decrease in HbA1c: 1 - 2%
Gastrointestinal discomfort, especially nausea; metallic taste in mouth, loss of appetite; vitamin B12 deficiency, rarely lactic acidosis; weight loss
DKA, alcoholism, renal or hepatic dysfunction; congestive heart failure; acute illness; cardiovascular collapse (shock); acute myocardial infarction;septicemia; acute or chronic metabolic acidosis; respiratory insufficiency;
Metformin
500-1500 mg/ per day with meals
8 hours
      
   
   
Alpha-glucosidase inhibitors
Delays absorption of complex carbohydrates in intestines
Not absorbed systemically
To be taken with first bite of the meal
   
Average decrease in FPG 25-30 mg%
Average decrease in HbA1c: 0.5 to1%
Abdominal discomfort, bloating, "gas" formation, nausea and diarrhea;
liver disease, bowel or intestinal disease, intestinal obstruction
Acarbose 25-100 mg with each meal 4 Hours            
Miglitol 50-100mg. with each meal 4 Hours            
Voglibose 200mg with each meal                
Meglitinides
Increases pancreatic insulin secretion
Metabolized in the liver
    Average decrease in FPG 30-40 mg%
Average decrease in HbA1c: 0.5 to 0.7%
Hypoglycemia; gastrointestinal upsets; muscle aches, URTI and flu-like symptoms; body ache; Type 1 DM; diabetic ketoacidosis, hepatic dysfuntion
Repaglinide 0.5-4 mg with each meal 3 hours            
Nateglinide
60-120 mg with each meal
3 hours
   
   
   
Glitazones
Reduces insulin resistance at cellular level;
Metabolized in the liver
Taken with or without food
   
Average decrease in FPG 70-80 mg%
Average decrease in HbA1c: 1.5 - 2.5 %
Weight gain, edema;URTI; toothaches; sore throat; body ache; headaches;
Hepatic dysfunction; CHF, increasing edema
Rosiglitazone
4-8 mg/day
12 hours
   
   
   
Pioglitazone 15-45 mg/day 24 hours            
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.

Incretin mimetics

Property
DPP-IV antagonists
GLP-1/agonists
Route of administration
Oral
Subcutaneous
Mode of action
Inhibit peptide hormone metabolism by DPP-IV enzyme, thus
a) enhance insulin secretion; b) inhibit glucagon secretion;
c) improve ß-cell function
Enhancement of endogenous incretin hormone effects, thus
a) enhance insulin secretion;
b) inhibit glucagon secretion;
c) improve ß-cell function
d) slow gastric emptying
e) induce satiety and weight loss
Sitagliptin
   
Exenatide
Dosing schedule
100mg/day can be taken with or without food.
Therapy initiated at 5 mcg per dose administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Not to be administered after a meal. Based on clinical response, the dose can be increased to 10 mcg twice daily after 1 month of therapy. Each dose should be administered as a SC injection in the thigh, abdomen, or upper arm.

The pen should be discarded 30 days after first use, even if some drug remains in the pen.
Glycemic control
More dominant effect on postprandial levels, although some effect on fasting levels also seen
Most dominant effect appears related to controlling postprandial hyperglycemia
Adverse effects
Diarrhea; gas; headache; indigestion; nausea; sore throat; stomach upset; stuffy or runny nose; vomiting; weakness.anorexia and early satiety are notable;
Nausea, vomiting, anorexia, thus not recommended in patients with severe gastrointestinal disease.

No hypoglycemia when used as monotherapy;
Contra-indications
Need for dosage adjustment based upon renal function;

Avoid if possible in patients using digoxin
Not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min)

Not recommended in patients with severe gastrointestinal disease.

 

Protocols for OHA THERAPY

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.

GENERAL ASPECTS IN OHA THERAPY

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


Sulfonylurea plus
ThiazolinedionesMetforminInsulina-Glucosidase inhibitor
Metformin plus
Sulfonylurea Non-sulfonylurea insulin secretagogue Thiazolidinedione a-Glucosidase inhibitor Insulin
Thiazolidinedione plus
Metformin Sulfonylurea Non-sulfonylurea insulin secretagogue Insulin not to be used rosiglitazone ( pioglitazone not more than 30mg/day should be used)a-Glucosidase inhibitor
a-Glucosidase inhibitor plus
Metformin Thiazolidinedione Sulfonylurea Non-sulfonylurea insulin secretagogue Insulin
Do not combine:
Sulfonylurea + non-sulfonylurea insulin secretagogue OR another sulfonylurea Insulin secretagogue + preprandial insulinInsulin + sulfonylureasInsulin with rosiglitazone ( with pioglitazone not more than 30mg/day should be used)
Sulfonylurea + non-sulfonylurea insulin secretagogue OR another sulfonylurea Insulin secretagogue + preprandial insulinInsulin + sulfonylureasInsulin with rosiglitazone ( with pioglitazone not more than 30mg/day should be used)

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

Agent Class
Insulin Resistance
Lipids
Body Weight
Lipoprotein (a)
Prothrombotic state ( PAI-1 levels)
Sulfonylureas
No effect
No effect
Increase, with small increase in central adiposity
No change
No change
Meglitinides
No effect
No effect
Increase, with possible small increase in central adiposity
No change
No change
Biguanide (Metformin)
Decreased
Small changes;
TG
LDL
HDL
Decrease
Moderate decrease
Moderate decrease
Thiazolidinediones
Pioglitazone
Rosiglitazone
Decreased
Moderate to marked changes;
TG and FFA
HDL
LDL, but mainly in large less atherogenic buoyant particles
Increase, but visceral adiposity decreased
Moderate decrease
Moderate decrease
Alpha-Glucosidase inhibitors
No effect
No effect
No effect
No change
No change


INSULIN THERAPY

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:

Type of Insulin
Human
Analogues
Long acting
   
Detemir, Glargine
Intermediate acting
NPH
   
Short acting
Regular Human Insulin
Insulin Aspart, Lispro, Glulisine
Premixed
Biphasic Human Insulin (30/70,50/50)
Biphasic Insulin Aspart (30/70), Biphasic Insulin Lispro (25/75 and 50/50)

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.

PATIENTS WHO SHOULD USE ANALOG INSULINS

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.

TIME-ACTIVITY CHARACTERISTICS

   
Begins Working
Peaks At
Ends Working
Lows Occur At
Insulin-Lyspro
15-20 minutes
30-90 min
3-4 hours
2 to 4 hr
Insulin- aspart
15-20 minutes
40-50 min
3-4 hours
2 to 4 hr
Regular
30-60 minutes
80-120 min
4-6 hours
3 to 7 hr
NPH
2-4 hours
6-10 hours
14-16 hours
6 to 12 hr
Lente
3-4 hours
6-12 hours
16-18 hours
7 to 14 hr
Ultralente
4-6 hours
10-16 hours
18-20 hours
12 to 24 hr
Insulin Glargine/Levemir
2-3 hours
almost no peak
18-26 hours
4 to 24 hr

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.

INSULIN TREATMENT SCHEME



* 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.


Other Regimens


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.

INJECTION SITES


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.

COMMONLY SEEN SIDE EFFECTS

Hypoglycemia

Edema

Allergy

Lipodystrophy and scar formation



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