After diagnosis of diabetes, the importance of protecting the body from damage caused by hyperglycemia cannot be overstated. In the US, 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 A1C.

SMBG

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 and insulin-dependant type 2 diabetics, 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 pre/post-prandial hyperglycemia.^2,4-5,7 The current American Diabetes Association (ADA) guidelines recommend that type 1 diabetics 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 may require more frequent monitoring, including both pre- and post-prandial readings. Patients with gestational diabetes (GDM) on 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.

While it is commonly recommended that non-insulin dependent type 2 diabetics (NIDDM) self monitor their blood glucose levels, the evidence to support the effectiveness of this practice is inconclusive. Initial studies showed that SMBG in NIDDM patients results in reduction in Hgb A1C, however the inclusion of health improving behaviors 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 attempted to correct for this found that 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 pre-prandial blood glucose levels in non-pregnant adults to be 70 to 130 mg/DL and less than 180 for peak post-prandial levels.^10,12 The ADA’s goals for GDM is pre-prandial ≤95 mg/dl and either 1 hour post-meal ≤140 mg/dl or 2 hours post-meal ≤120 mg/dl. For pregnant women with pre-existing type 1 or type 2 DM goals are pre-meal, bedtime, and overnight glucose levels of 60-99 mg/dl and peak postprandial levels between 100 and 129 mg/dl.¹² The American Association of Clinical Endocrinologists (AACE) recommends in non-pregnant adults a fasting blood glucose level <110 mg/dl and a 2-hour post-prandial level <140 mg/dl.¹¹

HgbA1C

Hgb A1C 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 two to three 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 which is dependent on the clinical situation and the patient’s treatment regimen. The ADA recommends that patients with stable glycemic control be tested at least two times a year. Quarterly testing is suggested for those with a recent change in therapy or not meeting glycemic goals.¹²

Hgb A1C testing does have some limitations. Hgb A1C 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 Hgb A1C and SMBG values. In addition, episodes of hypoglycemia and hyperglycemia cannot be determined with Hgb A1C values alone. The table below adapted from the ADA’s 2009 Executive Summary on diabetes management demonstrates that correlation between Hgb A1C and average blood glucose values.

Traditionally it has been recommended that therapy be adjusted to maintain Hgb A1C values near or less than 7% in non-pregnant adults. This target has been shown to reduce microvascular complications. For type 1 or type 2 diabetics who become pregnant, the goal is <6.0%.¹² The AACE recommended an Hgb A1C of <6.5% in non-pregnant adults.¹¹

The ADA recommends that selected individuals, especially those with a long life expectancy and little comorbidity may adopt glycemic targets as close to normal, providing it can be achieved without significant hypoglycemia.¹²

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Pharmacologic Treatment

When considering appropriate pharmacologic therapy for a patient a major factor to consider is whether the patient is insulin deficient or resistant or both.

Treatment options can be divided into insulin sensitizers, secretagogues, alpha glucosidase inhibitors, incretins, and insulin. Please refer to Table 2 for a summary of the different non-insulin 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 also enhances insulin sensitivity of muscle and fat. Its affects primarily fasting glycemia, however some decreases in post-prandial glucose concentrations, especially after the midday meal can also be seen. It 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 post-prandial 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 in males, or ≥1.4 mg/dL in females. The major benefits of metformin are that it usually does not lead to hypoglycemia when used as monotherapy, can lead to weight loss, and has been shown to decrease plasma triglycerides concentration (10 to 20%). Dosing is typically twice daily, however it can go up to three times daily or once daily (extended release). Typical starting dose is 500mg daily. The maximum dose is 2550mg per day. Gradual titration of metformin, starting at 500mg with breakfast and increasing by 500mg in weekly intervals until 1000mg with breakfast and dinner is reached help to prevent GI side effects.^12,14-18

Thiazolidinediones (TZDs)

TZDs are agonists of peroxisome proliferators-activated receptor gamma, and primarily enhance sensitivity of muscle and fat, and mildly of the liver to both exogenous and endogenous insulin. TZDs lower both fasting and post-prandial blood glucose levels. Major side effects include weight gain with an increase in subcutaneous adiposity and fluid retention which typically presents 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 4mg/day and maximum dose is 8mg/day. For pioglitazone, the starting dose is 7.5mg/day and that maximum dose is 45mg/day.^12,14,17-21

Insulin Secretagogues

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

Sulfonylureas

Sulfonylureas lower both fasting and post-prandial 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 frequently 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 hepatic or renal dysfunction or those that frequently 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. Cautioned use in patients with hepatic 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 post-prandial 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

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, inhibits glucagons secretion and hepatic glucose production in a glucose dependent manner. It also delays gastric emptying and suppresses appetite through central pathways. It primarily decreases post-prandial 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 used as monotherapy or with metformin, but is seen when combined with sulfonylurea. Benefits include weight loss up to 2-3 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 mcg, if tolerated, titrate after 1 month to 10 mcg.^12,14,20

Pramlintide

Pramlintide is a synthetic form of amylin, a hormone secreted by beta-cells which acts to suppress glucagons secretion, slow gastric emptying and suppress appetite through central pathways. It acts primarily on post-prandial 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 U.S. it is approved only as an adjunctive therapy with insulin, however it can be used both type 1 and type 2 diabetes. Patients can see up to a 50% reduction in their insulin requirements with the addition of pramlintide. Starting doses for type 2 diabetes is generally 60 mcg subcutaneously prior to meals and for type 1 DM is 15 mcg prior to each meal. It can be used in patients on insulin, metformin, and/or sulfonyureas.^12,14,20

Dipeptidyl Peptidase IV (DPP IV) Inhibitors

DPP IV is a cell membrane protein that rapidly degrades GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Suppression of DPP IV leads to higher levels of insulin secretion and suppression of glucagon secretion in a glucose dependent manner. Acts primarily on post-prandial blood glucose levels, but reductions in fasting glycemia are also seen. It is generally well tolerated with the most common side effect being headaches. 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. Dosing reduction in needed in renal impairment. Patients with a creatinine clearance ≥30 to <50 mL/minute dosing is 50 mg once daily. Those patients with a creatinine clearance <30 mL/minute dosing is 25 mg once daily.^12,14

Insulin

Insulin is the oldest therapy available for diabetes. It was first discovered in 1921 with clinical testing in humans starting in 1922. To this date it remains the most effective method to reducing glycemia. There is no upper limit in dosing for therapeutic effect, so it can be used to bring any Hgb A1C down to near normal levels. Other benefits to 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. Recent studies have shown that episodes where the patient required assistance from another due to the hypoglycemia occurred between 1-3 in 100,000 patient-years. Weight gain can occur after initiation and is typically about 2-4 kg. Most brands are available in both vial and pen form for delivery. Please refer to Table 3 for a summary of 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 Figure 1. All patients with type I diabetes require therapies with insulin products. There are two available regimens: basal-bolus and insulin pump therapy. Patients with type 2 diabetes frequently require insulin, which can be combined with oral anti-diabetic agents. Regimens include: basal insulin only, twice daily premixed insulin, basal-bolus and insulin pump therapy.

Figure 1: Click to Enlarge

Type I DM

Basal-Bolus

This regimen involves combining a long-acting agent which 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 is given as basal 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 diabetic educator is needed for this to be achieved.

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

Insulin Pump Therapy

Insulin pump allows for use of different basal insulin rates in different periods of day and administration of the meal bolus as single discrete bolus or as extended bolus (square bolus) over the certain amount of time which allows 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 patients who meet the following criteria:

1. unable to achieve target goals with basal-bolus regimens
2. frequent hypoglycemia, dawn phenomenon, or brittle diabetes
3. pregnant patients
4. insulin sensitivity or requiring more intense monitoring due to complications
5. able to monitor blood glucose several times daily and make insulin dosage adjustments

Type 2 DM

The AACE and the ADA 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 into Figure 2 and 3. The writers of this chapter support the AACE’s algorithm (Figure 2), as the ADA’s algorithm is significantly influenced by cost of therapy.¹² Please refer to Figure 4 for a summary on titration of insulin therapy. Starting daily insulin dose is typically 0.5 units/kg total (divided between long- and rapid-acting) daily. Therapy can be combined with oral insulin sensitizers but not secretagogues.

Figure 2: Click to Enlarge Figure 3: Click to Enlarge Figure 4: Click to Enlarge

Gestational Diabetes

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

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