After diagnosis of diabetes, the importance of protecting the body from damage caused by hyperglycemia cannot be overstated. In the United States, 57.9% of diabetic patients have one or more diabetes complications, and 14.3% have three or more. ¹ Strict glycemic control is the primary method of reducing the development and progression of microvascular complications, such as retinopathy, nephropathy, and neuropathy. Aggressive treatment of dyslipidemia and hypertension decreases macrovascular complications. ^2-3,6

Glycemic control

There are two primary techniques available for physicians to assess the quality of a patient's glycemic control: self-monitoring of blood glucose (SMBG) and interval measurement of hemoglobin A_1c (HbA_1c).

Self-Monitoring of Blood Glucose

SMBG is an effective way to evaluate short-term glycemic control. It helps patients and physicians assess the affect of food, medications, stress, and activity on blood glucose levels. The frequency of checking depends on the type of medical therapy, risk for hypoglycemia, and need for short-term adjustment of therapy.

For patients with type 1 diabetes mellitus (T1DM) and insulin-dependent type 2 diabetes (T2DM) patients, clinical trials have demonstrated that SMBG plays a role in effective glycemic control because it helps to refine and adjust insulin doses by monitoring for and preventing asymptomatic hypoglycemia and preprandial and postprandial hyperglycemia. ^2,4-5,7 The current American Diabetes Association (ADA) guidelines recommend that T1DM patients self-monitor their glucose at least three times per day. Those who use basal–bolus regimens should self-monitor before each meal and at bedtime (four times daily). Initially some patients require more frequent monitoring, including both preprandial and postprandial readings. Patients with gestational diabetes who are taking insulin should monitor their blood glucose three or more times daily. Patients should be educated on how to use real-time blood glucose values to adjust their food intake and medical therapy.

It is commonly recommended that T2DM patients who use insulin self-monitor their blood glucose levels, but the evidence to support the effectiveness of this practice is inconclusive. Initial studies showed that SMBG in T2DM patients results in reduction in HbA_1c, but the inclusion of health-improving behavior such as diet and exercise in many of the analyses made it difficult to assess the degree of contribution of SMBG alone. ^{2 , 9} Follow-up studies that attempted to correct for this found there was not a significant improvement in glycemic control after 12 months. ⁸

It is important to establish individual goals with patients regarding target blood glucose measurements. The ADA recommends preprandial blood glucose levels in nonpregnant adults to be 70 to 130 mg/dL and less than 180 mg/dL for peak postprandial levels. ^{10 , 12} The ADA's goals for gestational diabetes is preprandial blood glucose 95 mg/dL or less and either 1 hour postprandial glucose no more than 140 mg/dL or 2 hours postprandial no more than120 mg/dL. For pregnant women with preexisting T1DM or T2DM, goals are preprandial, bedtime, and overnight glucose levels of 60 to 99 mg/dL and peak postprandial levels between 100 and 129 mg/dL. ¹² The American Association of Clinical Endocrinologists (AACE) recommends in nonpregnant adults a fasting blood glucose level lower than 110 mg/dL and a 2-hour postprandial level lower than 140 mg/dL. ¹¹

Hemoglobin A_1c

HbA_1c measures nonreversible glycosylation of the hemoglobin molecule, which is directly related to blood glucose concentrations. It reflects a mean of the patient's blood glucose values over a 2- to 3-month period and can be used as a predictor of a patient's risk of microvascular complications. ¹³ Periodic testing is recommended in all patients with diabetes. The frequency of testing depends on the clinical situation and the patient's treatment regimen. The ADA recommends that patients with stable glycemic control be tested at least twice a year. Quarterly testing is suggested for those with a recent change in therapy or not meeting glycemic goals. ¹²

HbA_1c testing does have some limitations. HbA_1c is influenced by rapid red blood cell turnover and blood loss; therefore, anemia and hemoglobinopathies can result in inaccurate values. Physicians should consider these conditions when there is a discrepancy between HbA_1c and SMBG values. Episodes of hypoglycemia and hyperglycemia cannot be determined with HbA_1c values alone. Table 1, adapted from the ADA's 2009 Executive Summary on diabetes management, demonstrates that correlation between HbA_1c and average blood glucose values.

Traditionally it has been recommended that therapy be adjusted to maintain HbA_1c values near or less than 7% in nonpregnant adults. This target has been shown to reduce microvascular complications. For patients with T1DM or T2DM who become pregnant, the goal is less than 6.0%. ¹² The AACE recommended an HbA_1c of less than 6.5% in nonpregnant adults. ¹¹ The ADA recommends that selected patients, especially those with a long life expectancy and little comorbidity, adopt glycemic targets close to normal, providing the target can be achieved without significant hypoglycemia. ¹²

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Pharmacologic treatment

When considering appropriate pharmacologic therapy, a major factor to consider is whether the patient is insulin deficient, insulin resistant, or both. Treatment options can be divided into insulin sensitizers, secretagogues, alpha glucosidase inhibitors, incretins, and insulin. Table 2 summarizes the different noninsulin therapies available.

Insulin Sensitizers

Biguanides (Metformin)

Available since the late 1950s, metformin can trace its roots back to medieval Europe, where biguanides in the form of French lilac were used in diabetes treatment. Its primary mechanism of action is suppression of hepatic glucose output, but it also enhances insulin sensitivity of muscle and fat. It affects primarily fasting glycemia; however, some decreases in postprandial glucose concentrations, especially after the midday meal, can also be seen.

Metformin is well tolerated, with the most common side effect being gastrointestinal complaints, such as diarrhea, nausea, abdominal discomfort, and a metallic taste. All of these improve with time and dose reduction. Metformin causes a small increase in basal and postprandial lactate concentrations in the blood, leading to potential to produce very rare but life-threatening lactic acidosis (<1 in 100,000). It is best to avoid use in patients with hepatic impairment. The use of metformin is contraindicated in patients with a serum creatinine 1.5 mg/dL or higher in male patients or 1.4 mg/dL or higher in female patients.

The major benefits of metformin are that it usually does not lead to hypoglycemia when used as monotherapy. It can lead to weight loss, and it has been shown to decrease plasma triglycerides concentration (10% to 20%).

Dosing is typically twice daily; however, it can be dosed three times daily or once daily (extended release). The typical starting dose is 500 mg daily. The maximum dose is 2550 mg per day. Gradual titration of metformin, starting at 500 mg with breakfast and increasing by 500 mg in weekly intervals until a dose of 1000 mg with breakfast and dinner is reached help to prevent GI side effects. ^12,14-18

Thiazolidinediones

Thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptor gamma (PPARγ) and primarily enhance sensitivity of muscle and fat, and mildly of the liver, to exogenous and endogenous insulin. TZDs lower fasting and postprandial blood glucose levels.

Major side effects include weight gain, with an increase in subcutaneous adiposity, and fluid retention which typically manifests as peripheral edema, but heart failure has been shown to occur on occasion. These agents should be avoided in patients with functional class III or IV heart failure. These effects are mostly seen at higher doses. The PROactive trial (PROspective pioglitAzone Clinical Trial In macroVascular Events) showed that compared with placebo, pioglitazone does not increase cardiovascular risks. TZDs have been shown to have an association with an increased risk of fractures, particularly in women. The TZDs do not cause hypoglycemia when used as monotherapy. Pioglitazone use leads to lowering triglycerides, increasing high-density lipoprotein cholesterol (HDL), and increasing the low-density lipoprotein cholesterol (LDL) particle size.

Dosing is once a day. It takes 2 to 12 weeks for TZDs to become fully effective. For rosiglitazone, starting dose is 4 mg/day and maximum dose is 8 mg/day. For pioglitazone, the starting dose is 7.5 mg/day and the maximum dose is 45 mg/day. ^12,14,17-21

Insulin Secretagogues

Insulin secretagogues stimulate secretion of insulin from the pancreas, thereby decreasing hepatic glucose production and enhancing glucose uptake by muscles and fat.

Sulfonylureas

Sulfonylureas lower fasting and postprandial glucose levels. Main adverse effects include weight gain (about 2 kg upon initiation) and hypoglycemia. The hypoglycemia episodes can be significant (leading to need for assistance, coma, or seizure) and are seen more often in the elderly. The benefits include a 25% reduction in microvascular complications with or without insulin found by a UKPDS trial. Dosing is typically once or twice daily. Caution should be used in patients with liver or kidney dysfunction or patients who often skip meals. ^{12,17-18,20,23}

Glinides

Glinides work in a manner similar to sulfonylureas; however, they have a more-rapid onset of action and a short duration of action, so they are a good option for patients with erratic timing of meals. They have a lower risk of hypoglycemia than sulfonylureas; they have a similar to lower risk of weight gain with initiation of therapy. Caution must be used in patients with liver dysfunction. Dosing is before meals. ^12,14,20

Alpha Glucosidase Inhibitors

Alpha glucosidase inhibitors competitively block the enzyme alpha glucosidase in the brush borders of the small intestine, which delays absorption of carbohydrates (absorbed in the mid and distal portions of the small intestine instead). They primarily target postprandial hyperglycemia without causing hypoglycemia. Gastrointestinal complaints, such as bloating, abdominal cramps, flatulence, and diarrhea are the main side effects. Use should be avoided in patients with severe hepatic or renal impairment. Dosing must be prior to carbohydrate-containing meals. ^{12,17-18,20,22}

Incretins

Exenatide

Exenatide is a synthetic form of exendin 4, hormone found in the saliva of the Gila monster, that mimics glucagon-like peptide type 1 (GLP-1). GLP-1 is produced in the small intestine and stimulates insulin secretion and inhibits glucagon secretion and hepatic glucose production in a glucose-dependent manner. It also delays gastric emptying and suppresses appetite through central pathways. It primarily decreases postprandial blood glucose levels; however, a moderate reduction in fasting blood glucose levels can also be seen.

Due to its delaying effects on gastric emptying, the major side effect is gastrointestinal complaints such as nausea, vomiting, and diarrhea. Hypoglycemia does not occur when exenatide is used as monotherapy or with metformin, but it does occur when exenatide is combined with a sulfonylurea. Benefits include weight loss up to 2 to 3 kg in the first 6 months and up to 5.5 kg in the first 2 years.

Dosing is twice daily by subcutaneous injection. Start with a dose of 5 µg. If this dose is tolerated, titrate after 1 month to 10 µg. ^12,14,20

Pramlintide

Pramlintide is a synthetic form of amylin, a hormone secreted by beta-cells that acts to suppress glucagon secretion, slow gastric emptying, and suppress appetite through central pathways. It acts primarily on postprandial blood glucose levels.

As with exenatide, the major side effects are gastrointestinal complaints, especially nausea, and hypoglycemia. Benefits of therapy include weight loss of 1-1.5 kg over 6 months and up to 4.5 kg after chronic therapy.

Currently in the United States it is approved only as an adjunctive therapy with insulin, but it can be used both T1DM and T2DM. Patients can see up to a 50% reduction in their insulin requirements with the addition of pramlintide. Starting dose for T2DM is generally 60 µg subcutaneously before meals and for T1DM is 15 µg before each meal. It can be used in patients taking insulin, metformin, or sulfonyureas. ^12,14,20

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP 4) is a cell membrane protein that rapidly degrades GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Suppression of DPP 4 leads to higher levels of insulin secretion and suppression of glucagon secretion in a glucose-dependent manner.

DPP 4 inhibitors act primarily on postprandial blood glucose levels, but reductions in fasting glycemia are also seen. It is generally well tolerated, and the most common side effect is headache. An increase in nasopharyngitis has also been seen. Benefits include that it is weight neutral and does not cause hypoglycemia when used as monotherapy or in combination with metformin or TZDs.

Dosing is 100 mg orally once daily with or without meals. Dose reduction in needed in renal impairment. In patients with a creatinine clearance 30 to 50 mL/min, dosing is 50 mg once daily. Those patients with a creatinine clearance less than 30 mL/minute, dosing is 25 mg once daily. ^{12 , 14}

Insulin

Insulin is the oldest therapy available for diabetes. It was discovered in 1921, and clinical testing in humans started in 1922.

To this date it remains the most effective method of reducing hyperglycemia. There is no upper limit in dosing for therapeutic effect, so it can be used to bring any HbA_1c down to near normal levels. Other benefits of insulin include its effects on reducing triglycerides levels and increasing HDL.

Hypoglycemia is a concern for many, but the actual risk of severe episodes is small. Studies have shown that episodes where the patient required assistance from another due to the hypoglycemia occurred between 1 and 3 per 100,000 patient-years. Weight gain can occur after initiation and is typically about 2 to 4 kg.

Most brands are available in both vial and pen form for delivery. Table 3 summarizes the different formulations of insulin available. ^{4,11-12,14,17-18,24}

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Initiation and titration of therapy

There are several different regimens for insulin therapy. These are summarized in Table 4. All patients with T1DM require therapies with insulin products. There are two available regimens: basal–bolus and insulin pump therapy. Patients with T2DM often require insulin, which can be combined with oral hypoglycemic agents. Regimens include basal insulin only, twice-daily premixed insulin, basal–bolus, and insulin pump therapy.

Type I Diabetes

Basal–Bolus

Figure 1: Click to Enlarge

Figure 2: Click to Enlarge

The basal–bolus regimen involves combining a long-acting agent that is used once or twice daily and provides basal insulin needs and a rapid-acting agent for prandial coverage used with meals. When initiating therapy with glargine or detemir as the basal insulin, traditionally 50% of the total daily dose is given as basal insulin and the rest as prandial insulin divided equally before meals. Meal dose of insulin can be fixed, but it is better to determine the dose based on carbohydrate content of the meal. This requires learning carbohydrate counting and knowing the dose of insulin required to cover counted carbohydrates. Help of a diabetic educator is needed for this to be achieved.

Starting daily insulin dose is typically 0.3 U/kg total (divided between long acting and rapid acting) daily. Key to good control is blood glucose self-monitoring by the patient and frequent adjustment of the regimen until control is achieved. ^{11 , 14}

Insulin Pump Therapy

The insulin pump allows use of different basal insulin rates in different periods of day and administration of the meal bolus as a single discrete bolus or as an extended bolus (square bolus) over a certain amount of time, which allows a better match between insulin delivery and glucose absorption from the meal in patients with abnormalities of gastric emptying. This use of this therapy is spreading in all diabetic populations and particularly should be considered in the following patients:

• Those unable to achieve target goals with basal–bolus regimens
• Patients with frequent hypoglycemia, dawn phenomenon, or brittle diabetes
• Pregnant patients
• Patients with insulin sensitivity or requiring more intense monitoring due to complications
• Patients who are able to monitor blood glucose several times daily and make insulin dosage adjustments

Type 2 Diabetes

The ADA and the AACE have different algorithms for initiation and maintenance of therapy. No studies are available comparing the efficacy of either method or comparing the two. Each algorithm is summarized in Box 1 and Figure 1. We support the AACE's algorithm (see Box 2), because the ADA's algorithm is significantly influenced by cost of therapy. ¹² Figure 2 gives a summary of titration of insulin therapy. Starting daily insulin dose is typically 0.5 U/kg total (divided between long-acting and rapid-acting) daily. Therapy can be combined with oral insulin sensitizers but not secretagogues.

Gestational Diabetes

In patients with gestational diabetes, insulin therapy is indicated when exercise and nutritional therapy are ineffective in controlling prandial and fasting blood glucose levels. Basal therapy alone may be sufficient, but often basal–bolus regimens are required.

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Summary

• Glycemic control is critical for preventing microvascular complications.
• Type 2 diabetes is progressive disease and requires therapy intensification with time.
• Insulin sensitizers and incretin-based therapy should be used early in the course of the disease.
• Type 1 diabetes must be treated with insulin.
• Multiple daily doses of insulin providing basal, prandial, and supplemental insulin are a mainstay of insulin treatment.

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Suggested Readings

• Chase HP, Jackson WE, Hoops SL, et al: Glucose control and the renal and retinal complications of insulin-dependent diabetes. JAMA. 1989, 261: 1155-1160.
• Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993, 329: 977-986.
• Executive summary: standards of medical care in diabetes—2009. Diabetes Care.. 2009, 32: (Suppl 1): S6-S12.
• Fonseca V, Kulkarni K. Management of type 2 diabetes: oral agents, insulin, and injectables. J Am Dietetic Assoc. 2008, 108: (4): S29-S33.
• Nathan DM, Buse JB, Davidson MB, et al: Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: Update regarding thiazolidinediones. Diabetes Care. 2008, 31: (1): 173-175.
• Rodbard HW, Blonde L, Braithwaite SS, et al: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2008, 14: (6): 802-803.
• Saudek CD, Derr RL, Kalyani RR. Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A_1c. JAMA. 2006, 295: (14): 1688-1697.
• UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34): UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998, 352: 854-865.