Treatment of type 2 Diabetes
As noted in module 2, the foundation of successful management of diabetes to is ifestyle, diet and exercise.
If a patient is able to adhere to a exercise and diet regimen, they will usually show significant improvements in glycemic control within six weeks and may have blood glucose values near their target within three months.
However this approach ultimately will be effective and successful in only 10 percent of patients with type 2 diabetes. If your patient does not show significant progress over six to 12 weeks it is time to initiate pharmacotherapy.
The American Diabetes consensus statement recommends initial therapy for most patients with either a
Sulfonylurea (particularly for patients early on in their disease who are likely to have residual pancreatic function, who may have a pattern of high post prandial BS), or a
Biguanide such as metformin (particularly for obese patients with elevated fasting BS, likely to have significant insulin resistance), or an
Alpha-glucosidase inhibitor.
A number of factors can influence medication choice including
If the initial oral agent is inadequate, changing to another month of therapy or agent is not generally effective. In such patients, combination therapy should generally be the next step.
Next is specific information about each class of drug.
Stephanie, the following section should be organized like a question and answer sequence, with the answer to be revealed by the reader clicking a on a icon like Green? That you use....
Sulfonylureas ( example Glipidize, Glimepiride)
What is the mechanism of action of this class of drug?
Stimulation of pancreatic cells secrete insulin
How effective are these drugs?
Among patients who are not controlled by diet and exercise alone, these drugs initially will reduce serum glucose in about 50% of treated patients.
In whom are these drugs effective?
Only those patients who have adequate residual insulin secretory function will benefit from this class of medication, that is, patients who have not had diabetes for extended duration.
What is the natural history of patients on sulfonylureas?
Patients with type 2 diabetes will progressively lose insulin secretory function as the pancreas " burns out"; thus the effectiveness of sulfa drugs will decline as beta cell function declines. Overall 3 to 10% of patients will fail sulfonylureas each year.
What are the side effects of sulfa drugs?
Rarely, hypoglycemia. This is usually mild but more severe episodes can occur. Weight gain has also been observed. It is recommended to start therapy with the lowest recommended dose and gradually increase the dose over one week until the desired effect or maximum dose is reached.
The effects on lipid some are a lowering of triglycerides and minimal effect on cholesterol or HDL.
Biguanides (example: Metformin)
What is the mechanism of action of this class of drug?
This class of drugs was introduced in the 1950's. Perhaps the most commonly used agents is metformin (Glucomet, Glucophage). This works by decreasing hepatic gluconeogenesis, but it also improves insulin and sensitivity.
Metformin does not stimulate pancreatic insulin secretion.
How effective are these drugs?
Metformin will decrease the HbA1C by 1.5 to 2.0 percentage points, It is also effective in lowering LDL cholesterol and triglyceride levels.
Metformin will be effective in about 3/4 of patients who use it as monotherapy.
In whom are these drugs effective or appropriate?
Metformin as monotherapy is considered a first line drug and is especially appropriate for patients who are obese, with high fasting blood glucose levels and among those who have elevated lipids.
It can be combined with multiple other agents, including with insulin.
What are the side effects of this class of drugs?
Minor side effects, which can be reduced by taking the drug with food, include diarrhea, abdominal discomfort, and nausea. For this reason the drugs should be started at a low dose and increased slowly and until target blood sugar is achieved.
Lactic acidosis can occur in patients with renal disease (serum creatinine above 133 umol per L in men or 124 umol per L in women), and in patients with shock, acute myocardial infarction, septicemia, congestive heart failure, metabolic acidosis, respiratory insufficiency, significant liver dysfunction, or alcoholism. In such patients metformin should not be used.
It does not cause hypoglycemia.
What monitoring is necessary?
Creatinine baseline should be obtained on all patients.
What are some other unique characteristics of these drugs?
Initial dose is 500 mg daily taken with food. Monitoring of response will determine further dosage increases. Increase dose gradually every 1 to 2 weeks until target blood sugar control is reached or a total daily dose of 2 g is reached. Note there is now also an extended release formulation available of metformin.
Alpha glucosidase inhibitors (Acarbose)
What is the mechanism of action of this class of drug?
Partial inhibition of intestinal enzymes responsible for digesting carbohydrates. Effectively blunts postprandial blood glucose peak.
How effective are these drugs?
Modestly effective in reducing hGA1C (0.6 to 1.0 percentage points).
In whom are these drugs effective or appropriate?
Appropriate as first line model therapy or second line and in combination with sulfonylureas.
May be a good choice in the older patient since there is no risk of hypoglycemia, and no GI absorption.
What are the side effects of this class of drugs?
The beneficial side effects: a modest decrease in triglyceride levels. Does not change LDL or HDL.
Other: diarrhea, flatulence, an abdominal bloating. Start with a low dose and titrate carefully. Does not cause hypoglycemia in mono -therapy.
What monitoring is necessary?
None
What are some other unique characteristics of these drugs?
May cause hypoglycemia if used with a sulfonylurea. If occurs, use oral glucose and not sucrose.
There are no NICE documents on this drug.
Thiazolidinediones
What is the mechanism of action of this class of drug?
Rosiglitazone (Avandia) and Pioglitazone (Actos) appear to increase muscle insulin sensitivity.
How effective are these drugs?
These agents are quite effective in lowering BS as monotherapy but are not so recommended in the UK. Pioglitazone, among previously untreated patients, showed good initial glycemic response in several trials.
In whom are these drugs effective or appropriate?
NICE recommends:
Pioglitazone is indicated only in oral combination treatment of type 2 diabetes mellitus in patients with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy with either metformin or a sulphonylurea:
Click here for more information from NICE (National Institute for Clinical Excellence) STEF- HOTLINK TO: http://www.nice.org.uk/
These agents reduce total and LDL levels and triglyceride levels.
What are the side effects of this class of drugs?
Liver dysfunction, is the most serious risk with these agents. See section on monitoring below. Otherwise few side effects. Mild to moderate edema has also been observed.
What monitoring is necessary?
Liver enzymes should be checked in all patients prior to initiation of therapy, every 2 months for the first year, and periodically thereafter. If ALT levels increase to >3 times the ULN, therapy should be discontinued.
Patients should also be monitored for signs and symptoms of heart failure, (particularly patients with reduced cardiac reserve) and weight gain.
What are some other unique characteristics of these drugs?
These agents may be taken without regard to meals.
Meglitinides
What is the mechanism of action of this class of drug?
Repaglinide (NovoNorm) and Nateglinide (Starlix) stimulate pancreatic insulin release. They decrease postprandial glucose spikes.
How effective are these drugs?
Repaglinide reduces HBA1C to a similar degree as sulfonylureas. Patients who have not previously used oral hypoglycemic agents seem to respond better.
In whom are these drugs effective or appropriate?
NovoNorm has a rapid onset and short duration of action, particularly useful for patients who each irregularly or skip meals.
Nateglinide is very short acting and is taken just a minute or so before meals. Because of its short duration of action it does not linger in the bloodstream where it might cause over secretion of insulin and hypoglycemia. Patients must be willing to take this medication three times a day.
The NICE guideline on Nateglinide will be issued Sept 2001- check the NICE website.
What are the side effects of this class of drugs?
Use with caution in patience with liver dysfunction. Can cause hypoglycemia. In the US, the FDA recommends against combining these agents with sulfonylureas, and to avoid concomitant use of NSAIDs. Causes minimal weight gain. No significant effect on lipids. No monitoring is recommended.
Insulin
What is the mechanism of action of this class of drug?
decreases hepatic glucose production, increases peripheral tissue glucose uptake.
Schiedam Haag's
May improve insulin resistance and may improve endogenous insulin secretion due to a correction of hyperglycemia (perspectives in diabetes management, volume one number to winter 2001 )
in the U.K. P D S, insulin was equivalent to oral agents in preventing diabetes related connotations. There was also a suggestion of reduction risk of myocardial infarction among patients on insulin. Most patience on insulin required multiple injections daily (baseline and mealtime injection).
How effective are these drugs?
in adequate doses can normalize hemoglobin a one C. Also triglycerides.
In whom are these drugs effective or appropriate?
as initial therapy in patients with severe hyperglycemia (>13.9 mmol per L) for initial rapid control while oral therapy is started.
Up to one half of type 2 diabetics will require insulin to control blood sugar eventuallly. insulin is a crucial component and management of type 2 diabetes.
What are the side effects of this class of drugs?
every-weight gain is about 5 to 10 kg.
What monitoring is necessary?
What are some other unique characteristics of these drugs?
a sulfonylurea may be combined with insulin give it bedtime to control fasting glucose. Many practitioners will start with tender 15 units of mph a bad time, an increase by three units every three nights until target level is attained. Dosage of both the sulfonylurea and insulin is subsequently adjusted. Similar effects may be obtained using metformin with insulin however this is not FDA-approved in the U.S. ( AFP monograph). be
note: For a list of oral agents used in the including brand names go to this web site:
http://www.diabetes.org.uk/manage/products/tablets.htm
Combination Therapy
he who combinations are used when model therapy fails to achieve target glucose levels. Combinations are either oral-oral or oral-insulin. Once combination therapy is inadequate, the next step is insulin therapy.
possible combinations include:
sulfonylurea and metformin. This is the most widely used and Bess studied combination. It may delay a need for insulin. in the U.K. P D S the sulfonylurea- metformin therapy proved more effective and class in the control compared with sulfonylurea treatment alone. a combination pill is available known as Glucovance.
Pioglitazone and sulfonylurea or insulin: This is approved in the U.S..
Metformin and Repaglinide: approved in the U.S.: appears to be synergistic combination.
insulin and sulfonylurea: See section of insulin.
Triple therapy: this has not been well studied. Ahead
Insulin
What is the mechanism of action of this class of drug?
Decreases hepatic glucose production, increases peripheral tissue glucose uptake.
May improve insulin resistance and may improve endogenous insulin secretion due to a correction of hyperglycemia.
In the UKPDS, insulin was equivalent to oral agents in preventing diabetes related complications. Myocardial Infarction risk among patients on insulin was also reduced. Most patients on insulin required multiple injections daily (baseline and mealtime injection).
Insulin may be either temporary or ongoing. Temporary insulin treatment is appropriate for:
How effective are these drugs?
In adequate doses can normalize HbA1C. Triglycerides benefit.
In whom are these drugs effective or appropriate?
As initial therapy in patients with severe hyperglycemia (>13.9 mmol per L) for initial rapid control while oral therapy is started.
Up to one half of type 2 diabetics will require insulin to control blood sugar eventuallly. Insulin is a crucial component and management of type 2 diabetes.
When oral drugs fail, insulin usually begins with a basal dose alone as pancreatic insulin will usually be sufficient to cover postprandial glucose spikes.
Generally, an evening dose of intermediate acting, long acting, or premixed insulin is given in doses from 0.2 to 0.6 units/kg per day.
Most commonly is used " BIDS ", ie, Bedtime Insulin and a Daytime Sulfonylurea. This combination may be appropriate in patients with elevated fasting plasma glucose (> 130 mg per deciliter) on maximum oral sulfonylurea.
Intensified insulin regimen with intermediate acting or short or rapid acting insulin is needed when single insulin injection combined with one of more oral agents is inadequate. It appears that multiple (three more) daily insulin injections is superior to once-daily injections in type 2 diabetics.
Over time, insulin can sometimes be tapered every two weeks as pathophysiologic defects improve. Other patients require increasingly complicated regimens. On the horizon are wider use of the insulin pump and inhalable insulin.
What are the side effects of this class of drugs?
Average weight gain is about 5 to 10 kg.
What monitoring is necessary?
None.
What are some other unique characteristics of these drugs?
A sulfonylurea may be combined with insulin given at bedtime to control fasting glucose. Many practitioners will start with 10- 15 units of NPH at bed time, and increase by three units every three nights until target level is attained. Dosage of both the sulfonylurea and insulin is subsequently adjusted. Similar effects may be obtained using metformin with insulin however this is not FDA-approved in the U.S.
d include here table one and the insulin table from UMass diabetes monograph.
d include here table one and the insulin table from UMass diabetes monograph.
Tailored therapy
There is increasing interest in individualizing treatment. Drug choices for type 2 diabetes can address each of the four major causes of hyperglycemia:
1. Decline in insulin secretion: sulfonylureas, Repaglinide, Nateglinide, and insulin
2. Excess glucose influx: alpha-glucosidase inhibitors
3. Excessive hepatic glucose output: metformin and insulin
4. Peripheral resistance to glucose uptake: Thiazolidinediones
Understanding how the match pharmacology to pathophysiologic mechanisms is also important for combination therapy. I