COMBINATION OF INSULIN AND ORAL HYPOGLYCEMIC AGENT IN TYPE II DIABETES – RATIONALE

COMBINATION OF INSULIN AND ORAL HYPOGLYCEMIC AGENT IN TYPE II DIABETES – RATIONALE

            Appropriate glycemic control (A_1C ≤ 7%) can reduce microvascular complications. Treating Type II diabetes patient with life style intervention and a single pharmacological agent is unlikely to achieve and sustain such glycemic control. The target of HbA_1c < 7% can be maintained to combine oral agents with different mechanism of action, to combine insulin with one or more oral agents, to use multiple injections of insulin without oral agents, or to use one of these approaches together with one of the new injectable therapies based on gastrointestinal peptide hormones.

Rationale for Combination Therapy

Factors influencing glucose metabolism

1. Glucose balance across the liver (production versus uptake)
2. Insulin and glucagon secretory rates.
3. Rate of gastrointestinal absorption of carbohydrates.
4. Rate of peripheral (muscle and adipose tissue).

Glucose uptake and utilization

            Judicious use of combinations of OHA and combination of insulin with OHA takes advantages of these different modes of action.

            Two main kinds of combinations

1. An agent that enhances the availability of insulin can be combined with one that improves effectiveness of insulin.
2. An agent that is most effective in controlling (fasting and preprandial) hyperglycemia can be combined with one that has its main effect on post prandial increase of glucose. Eg. The ability of metformin to prevent weight gain caused by insulin when the two are used together to improve glycemic control.

Combinations of Oral Antidiabetic Agents

The FDA approved combinations

1. Combinations of agents that increase insulin secretion eg. Sulfonylurea, repaglinide (or) neteglinide.
2. Combination of agents that decrease insulin requirements eg: Metformin a glucosidase inhibitors (acarbose and miglitol) and thiazolidinediones (pioglitazone and rosiglitazones). The combination of a glucosidase inhibitors such as acarbose with insulin secretagogues and insulin sensitizes are useful when additional effects in specifically lowering post prandial hyperglycemia are desired.

            The thiazolidinediones and metformin improve insulin sensititivity by different mechanisms and seen to preferentially affect different organs (metformin affects the liver and thiazolidinediones the skeletal muscle) combination therapy with these two classes of insulin sensitizers has added benefits in improving insulin sensitivity and achieving glycamic control. Sulfonylureas and nonsulfonyl urea secretogagues (repaglinide and nateglinide) have similar MOA and do not have additive effects.

            The combination of sitagliptin which potentates insulin secretion and also suppresses glucogon secretion, with metformin provides moderate additional reduction of glucose.  All of the combinations are effective only when endogenous insulin capacity is adequate to support their effect. As endogenosus  insulin secretion continuous to decrease with increasing duration of Type II DM,   combinations  of oral agents are progressively less effective. 

Widely used combination of OHA

1. Metformin added to sulfonylurea
2. Sulfonylurea added to metformin
3. Thiazolidinediones added to sulfonylurea
4. Thiazolidinediones added to metformin

Mechanism of Action

1. Decreases hepatic glucose production

Sulfonylurea                  à Glimipride, Glipizide, Glyburide

Biguanide                     à Metformin

Basal insulin                  à NPH, Glargine, Determir

Prandial Insulin             à Regular, Asparta, Glulisine, Lispro

2. Increase Insulin Secretion

Sulfonylurea                  à Glimipride, Glipizide, Glyburide

Non-sulfonylurea Secretagogues à Repaglinide Neteglinide

Basal insulin                  à NPH, Glargine, Determir

Prandial Insulin             à Regular, Asparta, Glulisine, Lispro

3. Delays carbohydrate absorption à a glucosidase inhibitor

                                                                  Acarbose, Miglitol

4. Increase peripheral glucose uptake

Non-sulfonylurea Secretagogues à Repaglinide Neteglinide

Thiazolidinedione à Pioglitazone, Rosiglitazone

Prandial Insulin             à Regular, Asparta, Glulisine, Lispro

5. Decrease fasting plasma glucose

Sulfonylurea                  à Glimipride, Glipizide, Glyburide

Biguanide                     à Metformin

Basal insulin                  à NPH, Glargine, Determir

6. Decrease post prandial insulin

      a glucosidase inhibitor à  Acarbose, Miglitol

Prandial Insulin àAsparta, Glulisine, Lispro

Combination of Oral Anti-diabetic Agents with Insulin

            In later stages of Type II diabetes, results of treatment can be improved by combining the oral agents with insulin.

1. Metformin and thiazolidinediones both increases tissue sensitivity to endogenous and injected insulin and thereby maximize the effectiveness of remaining endogenous insulin while permitting small dosages of injected insulin to be effective.
2. a glucosidase inhibitors delay the absorption of dietary carbohydrates, making the reduced and delayed secretion of endogenous insulin more effective and potentially extending the time when basal insulin without prandial injections can be successful.
3. Oral agents that potentiate the secretion of endogenous insulin can provide a more physiological insulin response when combined with exogenous insulin, improved glycemic control without increased risk of hypoglycemia.

Wide used combination

1. Basal insulin added to metformin (~2.5%)
2. Basal insulin added to sulfonylurea (~2.1%)
3. Basal insulin added to sulfonylurea and metformin (~-1.9%)

1. Combination insulin treatment with metformin. There is a main decrease in A_1c of 0.7-2.5% depending partly on whether insulin dosage was simultaneously adjusted. There is reduced risk of insulin induced hypoglycemic with this combination. Metformin largely prevents the weight gain frequently seen during insulin use.
2. The combination of sulfonylurea with insulin reduce A_1c by 0.3-2.3% depending on whether insulin dosage is adjusted i.e. use of glyburide, an agent more likely to cause hypoglycemia than other sulfonylurea. The glycemic benefits of later generation sulfonylurea combined with insulin often become apparent when the sulfonylurea is discontinued and A_1c increases.
3. Addition of pioglitazone to insulin therapy can improve glycemic control in insulin resistant Type II diabetes patients who are inadequately controlled specially those taking substantial doses (eg. ³ 70 u/day) of insulin. The improvement of glycemic control is accompanied by variable (15-50%) decreases of mean insulin requirement.

            Monitor this combination because

1. Added effect of a thiazolidinedione may develop over ³ 3 months and lead to anticipated hypoglycemia.
2. Combination causes significant fluid retention.
3. Mild to moderate edema is quite common and congestive cardiac failure can occur, even in patients without recognized heart disease.

            Patients at risk for heart failure should not use either thiazolidinedione, and patients adding  pioglitazone to insulin should begin with a lower dosage, increase dosage slowly and be carefully observed. Adding acarbose to insulin can limit post prandial glycemia increases, moderately improve A_1c (~0.5%) and perhaps reduce episodes of hypoglycemia.

            Adding a basal insulin dose at night to oral medications during the day is a single approach that improves glycemic control by reducing overnight hepatic glucose production. The goal is to give enough basal insulin to achieve a fasting plasma glucose (FPG) level between 100-130mg/dl.

Scheme for adding basal (glargine) or intermediate acting insulin (NPH) to oral agents. Start with 10 units of basal or intermediate insulin at bed time (~10pm) adjust the dose weekly accordingly.

Self Monitoring, Fasting Plasma Glucose	Increase in insulin dose (u/day)
³ 180 mg/dl	8 units/day
³ 140 mg/dl but < 180 mg/dl	6 units/day
³ 120 mg/dl but < 140 mg/dl	4 units/day
³ 100 mg/dl but < 120 mg/dl	2 units/day
Treat to target FPG ≤ 100mg/dl

            Do not increase insulin dose if FPG is <72mg/dl on 2 days. Decrease insulin dose 2-4 units/day if FPG is <56mg/dl or clinically significant hypoglycemia occurs.

Indications of combination therapy:

1. Individual with little elevation of FPG (<130mg/dl) often show improved A_1c with diet and increased physical activity. Some require the addition of monotherapy with metformin, a thia zolidinedione or a a glucosidase inhibitor; agents have little risk of causing hypoglycemia, to achieve A_1c between 6-7%.
2. Patient with severe and symptomatic hyperglycemia (FPG>270mg/dl and A1c >10%) are best treated initially with insulin.
3. Most II DM patients fall between these extremes (FPG 130-270mg/dl) and A_1c (10% should be started on life style intervention accompanied by monotherapy with an oral antihyperglycemic agent.
4. Those who are predominantly insulin resistant (with centre and / or generalized obesity) might be best treated with an agent that decreases insulin resistance (usually metformin).
5. Those who are more insulin deficient and have relatively high glucose levels (less obese individual with FPG>180mg/dl) treated with an agent that increases insulin secretion (usually a sulfonylurea).
6. Most patients will not achieve their target glycemic control on monotherapy either initially or after several years of treatment. These individuals require combination therapy. Because of long experience, low cost, and convincing evidence for medical benefits, the combinations of metformin and a sulfonylurea is most widely used.

            Combination oral agent therapy will lose its effectiveness when insulin secretion becomes markedly deficient. At that stage, endogenous insulin capacity is so depleted that overnight hepatic glucose production is unrestrained and marked fasting hyperglycemia ensues.  This can be ameliorated by administering NPH or basal insulin at bed time (~10.00pm) and continuing oral agents during the day. If endogenous secretory capacity declines even further and little or no insulin secretion occurs with meals, than OHA becomes ineffective and a multiple insulin injection regime becomes necessary.

1. A regime  combining intermediate acting and short acting insulin before breakfast, short acting insulin before the evening meal, and intermediate acting insulin at bed time.
2. A basal insulin (such as glargine) once daily or NPH or determir twice daily and to precede each meal with a rapid acting insulin analog (lispro, asparta or glulisine).
3. Twice daily premixed insulin (70/30 or 75/25).
4. The Type II DM patient are severely insulin resistance, it may be necessary to treat them with very large doses of insulin (>100 u/day) and in this situation better glycemic control at lower doses of insulin may be achieved by continuing or adding pioglitazone  or metformin to the insulin regime.

Note:

Useful guidelines for combination therapy in II DM patients

1. About 5-10% of patients who develop diabetes in adults, have II DM, actually have slowly evolving Type I diabetes (LADA). These individual younger and leaner than II DM typical patient and lack of family history of diabetes. They usually require insulin therapy within the first 6 years of diagnosis. Measurement of GAD anti-bodies can confirm this diagnosis.
2. Lab confirmation of insulin resistance at diagnosis of diabetes is necessary because clinical features are usually sufficient.
1. Central obesity
2. Acanthosis nigrican
3. Hypertension
4. Hypertriglyceridemia
5.  Decreased plasma HDL cholesterol

            In selected cases demonstration of elevated plasma C peptide, fasting or after a meal challenge can verify the presence of severe insulin resistance.

3. Maximal dosage of a single agent before adding a second agent is usually not effective and can increase side effects.
4. If one OHA doesnot lower glycemia to the target range, changing to a different oral agent rarely achieve better glycemic control. However combining two oral agents with different modes of action will result in improved glycemic control.
5. Adding the third oral agent rarely lowers the A_1c, to <7% of the A_1c before adding the third agent is much higher than 8%.
6. Bed time insulin and oral agents taken during the day one frequently as effective in achieving glycemic control as multiple injections of insulin in patients with earlier Type II diabetes or in those for whom oral agents have initially failed.

REFERENCE:

Therapy for Diabetes Mellitus and Related Disorders ADA