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Published: February 2013

Medical Treatment of Diabetes Mellitus

Mario Skugor

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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 1 or more diabetes-related complication, and 14.3% have 3 or more.1 Strict glycemic control reduces 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

The primary techniques available to assess the quality of a patient's glycemic control are self-monitoring of blood glucose (SMBG) and interval measurement of hemoglobin A1c (HbA1c).

Self-Monitoring of Blood Glucose

SMBG is an effective way to evaluate short-term glycemic control. It helps patients and physicians assess the effect 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 blood glucose at least 3 times per day. Patients who use basal-bolus regimens should self-monitor before each meal and at bedtime (4 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 blood glucose at least 3 times daily. Patients should be educated on how to use real-time blood glucose values to adjust food intake and medical therapy.

It is commonly recommended that T2DM patients who use insulin self-monitor 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 HbA1c, 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 no 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 mg/dL to 130 mg/dL and <180 mg/dL for peak postprandial levels.10,12 The ADA's goals for gestational diabetes is preprandial blood glucose ≤95 mg/dL and either 1 hour postprandial glucose ≤140 mg/dL or 2 hours postprandial ≤120 mg/dL. For pregnant women with preexisting T1DM or T2DM, goals are preprandial, bedtime, and overnight glucose levels of 60 mg/dL to 99 mg/dL and peak postprandial levels between 100 mg/dL and 129 mg/dL.12 The American Association of Clinical Endocrinologists (AACE) recommends in nonpregnant adults a fasting blood glucose level <110 mg/dL and a 2-hour postprandial level <140 mg/dL.11

Hemoglobin A1c

HbA1c 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

HbA1c testing does have some limitations. HbA1c levels are influenced by the speed of 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 HbA1c and SMBG values. Episodes of hypoglycemia and hyperglycemia cannot be determined with HbA1c values. Table 1, adapted from the ADA's 2009 Executive Summary on diabetes management, demonstrates that correlation between HbA1c and average blood glucose values.

Table 1. Correlation between HbA1c and average blood glucose values.12
HbA1c (%) Mean Plasma Glucose (mg/dL)
6 126
7 154
8 183
9 212
10 240
11 269
12 298

HbA1c, glycated hemoglobin.

Traditionally, it has been recommended that therapy be adjusted to maintain HbA1c values at ≤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 <6.0%.12 The AACE recommended an HbA1c of <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 include insulin, insulin sensitizers, secretagogues, alpha glucosidase inhibitors, incretins, pramlintide, and bromocriptine. Table 2 summarizes the various noninsulin therapies available.

Table 2. Noninsulin therapies
Subgroup Generic Name (brand) Class Route Comments
Biguanides Metformin (Glucophage) Sensitizer Oral Weight loss
No hypoglycemia
GI upset
Thiazolidinediones Rosiglitazone (Avandia)
Pioglitazone (Actos)
Sensitizer Oral Weight gain
Peripheral edema
Alpha glucosidase inhibitors Acarbose (Precose)
Miglitol (Glyset)
Oral GI upset
No hypoglycemia
Sulfonylureas Chlorpropamide (Diabinese)
Glibenclamide (Glyburide)
Glimepiride (Amaryl)
Glipizide (Glucotrol)
Tolazamide (Tolinase)
Tolbutamide (Orinase)
Secretagogue Oral Hypoglycemia
Weight gain
Glinides Nateglinide (Starlix)
Repaglinide (Prandin)
Secretagogue Oral Weight gain
Exenatide Byetta GLP-1 analog Subcutaneous Weight loss
GI upset
Liraglutide Victoza GLP-1 analog Subcutaneous Weight loss
Nausea
Extended release exenatide Bydureon GLP-1 analog Subcutaneous Weight loss
Nausea
Pramlintide Symlin Incretin Subcutaneous Weight loss
GI upset
Adjunctive therapy with insulin
Dipeptidyl peptidase-4 inhibitors (DPP-4s) Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Trajenta)
DPP-4 inhibitors Oral No hypoglycemia
Nasopharyngitis
Weight neutral
Rapid release bromocriptine Cycloset Other Oral Taken within 2 hours of awakening

GI, gastrointestinal.

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, are also seen.

Metformin is well tolerated. The most common side effects are gastrointestinal complaints, such as diarrhea, nausea, abdominal discomfort, and a metallic taste. All of these improve over time or with dose reduction. Metformin causes a small increase in basal and postprandial lactate concentrations in the blood, which enables it to cause a 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 male patients or ≥1.4 mg/dL 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 (3% to 5% of body weight), and it has been shown to decrease plasma triglycerides concentration by 10% to 20%.

Dosing is typically twice daily; however, it can be dosed 3 times daily or once daily when an extended-release formulation is used. The typical starting dose is 500 mg per day. The maximum dose is 2550 mg per day but most practitioners use 2000 mg per day as a maximum. Typically, the metformin dosage is gradually increased, starting with a dose of 500 mg with breakfast and increasing by 500 mg in weekly intervals until a dose of 1000 mg with breakfast and dinner is reached. This approach can help to prevent GI side effects.12,14-18

Thiazolidinediones

Thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptor gamma (PPARγ) and they 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. Due to controversy about a potential association of rosiglitazone with an increased risk of untoward cardiovascular events, the only TZD medication FDA approved for use in the U.S. is pioglitazone.

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 most commonly observed in patients who are taking 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. In June 2011 the FDA added a warning to the pioglitazone label about a potentially increased risk of bladder cancer when pioglitazone is used for longer than 1. The TZDs do not cause hypoglycemia when used as monotherapy. Pioglitazone lowers triglycerides levels, increases high-density lipoprotein cholesterol (HDL) levels, and increases the low-density lipoprotein cholesterol (LDL) particle size.

Dosing is once daily. It takes 2 to 12 weeks for TZDs to become fully effective. For rosiglitazone, the starting dose is 4 mg/day and the 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 reduce fasting and postprandial glucose levels. The 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 United Kingdom Prospective Diabetes (UKPDS) trial. Dosing is typically once or twice daily. Caution should be used in patients with liver or kidney dysfunction or those who often skip meals. Newer, second-generation, sulfonylureas (glipizide and glimepiride) may carry less risk of hypoglycemia than older ones (glibenclamide) due to a somewhat glucose-dependent mechanism of action.12,17-18,20,23

Glinides

Glinides work in a manner similar to that of the sulfonylureas; however, they have a more-rapid onset of action and a shorter duration of action, so they are a good option for patients who have erratic timing of meals. Glinides are associated with a lower risk of hypoglycemia than are sulfonylureas. Glinides are also linked to a similar risk of weight gain with initiation of therapy. Caution must be used in patients with liver dysfunction. Doses are taken immediately 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. Doses are to be taken before carbohydrate-containing meals.12,17-18,20,22

Incretin based therapies

Exenatide

Exenatide is a synthetic form of exendin-4, a hormone found in the saliva of the Gila monster. Exenatide mimics glucagon-like peptide type-1 (GLP-1). GLP-1 is produced in the small intestine. It 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 effects are 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. As with all incretin-based therapy there is a slightly increased risk of acute pancreatitis in patients taking exenatide. The medication should be stopped if the patient develops abdominal pain.

Dosing is twice daily by subcutaneous injection─with meals. The starting dose is 5 mcg. If this dose is tolerated, it can be increased to 10 mcg after 1 month.12,14,20

The new, extended action, preparation of exenatide was released in the spring of 2012. This formulation is administered as a weekly subcutaneous injection. Side effects and indications are same as for short acting exenatide.

Liraglutide

Liraglutide is another GLP-1 analog that is derived from the native human GLP-1 and maintains 97% homology with it. In a head-to-head study with exenatide liraglutide showed slightly better glycemic control with the same rate of hypoglycemia and slightly more weight loss. Liraglutide is taken once a day, at any time of the day; there is no need to take it with meals. Side effects include nausea, vomiting, and diarrhea but only a small percentage of patients stopped therapy due to side effects. The initial dose is 0.6 mg/day which is increased to 1.2 mg/day after 1 week. This dose is considered therapeutic but can be increased to 1.8 mg/day after another week if glycemic goals are not achieved.25

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 required in patients with renal impairment. In those with a creatinine clearance 30 mL/min to 50 mL/min, dosing is 50 mg once daily. In those patients with a creatinine clearance <30 mL/minute, dosing is 25 mg once daily.12,14

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 to 1.5 kg over 6 months and up to 4.5 kg with prolonged therapy.

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

Bromocriptine

The exact mechanism of action by which bromocriptine improves glycemic control is not known. Bromocriptine is a central dopamine agonist and when given in rapid-release form in the morning within 2 hours of awakening it improves glycemic control for patients with DMT2. Studies have demonstrated the cardiovascular safety of bromocriptine. Observed side effects include hypotension, somnolence, and nausea. Individuals with psychiatric disorders may experience exacerbation while taking bromocriptine. The initial dose is 0.8 mg. This is increased in weekly increments by 0.8 mg until the therapeutic dose of 1.6 to 4.8 mg is achieved. Bromocriptine is taken with food in order to diminish nausea.26

Insulin

Insulin is the oldest medical therapy available for diabetes. It was discovered in 1921 and clinical testing in humans began in 1922. Today it remains the most direct method of reducing hyperglycemia. There is no upper limit in dosing for therapeutic effect, so it can be used to bring any HbA1c down to near normal levels. Other benefits of insulin include its effects on reducing triglycerides levels and increasing HDL. Hypoglycemia is a concern, but the actual risk of severe episodes is relatively small. Studies have shown that episodes where the patient required assistance due to hypoglycemia occurred in 1 to 3 patients per 100,000 patient-years. Weight gain can occur after initiation and is typically about 2 kg to 4 kg. Most brands of insulin are available in both vial and pen form for delivery. Table 3 summarizes the variety of available insulin formulations.4,11-12,14,17-18,24

Table 3. Currently available insulin formulations.27
Insulin (Brand) Onset Peak Effective Duration
Rapid-Acting
Aspart (NovoLog) 5-15 min 30-90 min <5 h
Lispro (Humalog) 5-15 min 30-90 min <5 h
Glulisine (Apidra) 5-15 min 30-90 min <5 h
Short-Acting
Regular 30-60 min 2-3 h 5-8 h
Intermediate, Basal
Neutral protamine Hagedorn (NPH) 2-4 h 4-10 h 10-16 h
Long-Acting, Basal
Insulin glargine (Lantus) 2-4 h No peak 20-24 h
Insulin detemir (Levemir) 3-8 h No peak 17-24 h
Premixed
75% Insulin lispro protamine/25% insulin lispro (Humalog mix 75/25) 5-15 min Dual 10-16 h
50% Insulin lispro protamine/50% insulin lispro (Humalog mix 50/50) 5-15 min Dual 10-16 h
70% Insulin lispro protamine/30% insulin aspart (NovoLog mix 70/30) 5-15 min Dual 10-16 h
70% NPH/30% regular 30-60 min Dual 10-16 h

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Initiation and Titration Of Therapy

There are several regimens for insulin therapy. These are summarized in Table 4. All patients with T1DM require therapies with insulin products. There are 2 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.

Table 4. Regimens for insulin therapy
Insulin Regimen HbA1c (%) Medication Pattern Diet History Lifestyle Monitoring
Basal-only >7.5-10 Oral medications adequately control postprandial glucose excursions High fasting glucose with minimal glucose rise during the day Small, regular meals; large meals will result in postprandial hyperglycemia Reluctance to do MDI; requires oral agents Fasting
Basal–bolus (MDI) >7.5 Regimen can be matched to any pattern to achieve glycemic control Regimen can be matched to any diet to achieve glycemic control Erratic schedule, motivated to achieve tight glycemic control Frequent blood glucose monitoring (minimum before meals and bedtime)
Once- or Twice-Daily Premixed
Rapid-acting analogue and intermediate acting >7.5 Oral agent failure (maximum tolerated dosages, contraindications, cost issues) Any fasting glucose; glucose rises during the day Large suppers, small lunches Consistent daily routine, reluctance to do MDI Fasting and pre-supper (if insulin is administered twice daily)
Regular and NPH >7.5 Oral agent failure (maximum tolerated dosages, contraindications, cost issues) Any fasting glucose; glucose rises during the day Isocaloric meals or larger lunches Consistent daily routine, reluctance to do MDI Fasting and pre-supper (if insulin is administered twice daily)

HbA1c, glycated hemoglobin; MDI, multiple daily injections.

Type I Diabetes

Basal–Bolus

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. Patient are, also, provided with sliding scale (supplemental insulin) to use as a third component of therapy at the time when blood glucose is higher than desired.

The 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 the use of varying basal insulin rates in different periods of the day. It also allows the administration of the meal bolus as a single discrete bolus or as an extended bolus (square bolus) over a set period of time. This which allows a better match between insulin delivery and glucose absorption from the meal in patients with abnormalities of gastric emptying. The 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 those requiring more intense monitoring due to complications
  • Patients who are able to monitor blood glucose several times daily and make insulin dosage adjustments

Recently, continuous glucose monitors have been developed that measure interstitial glucose levels every 20 minutes and are used in conjunction with insulin pumps. Their use improves the management of HbA1c levels and decreases the number of hypoglycemic episodes in patients with brittle DMT1.

Type 2 Diabetes

Figure 1 includes examples of pharmacologic regimens for treating T2DM. The ADA and the AACE have different algorithms for initiation and maintenance of therapy. No studies have been conducted to either evaluate the efficacy of the methods or to compare the efficacy. The algorithms are summarized in Figures 2 and 3. We support the AACE's algorithm (Figure 3), because the ADA's algorithm is significantly influenced by the cost of therapy.12  Figure 4 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 and some incretin based therapies.

Figure 1. Examples of Pharmacologic Regimens for Treating Type 2 Diabetes Mellitus*
Patients Naive to Pharmacologic Therapy
Monotherapy

Initiate monotherapy when HbA1c levels are 6% to 7%
Options include:

  • Metformin
  • Thiazolidinediones
  • Secretagogues
  • Dipeptidyl-peptidase 4 inhibitors
  • Alpha-glucosidase inhibitors

Monitor and titrate medication for 2 to 3 months

Consider combination therapy if glycemic goals are not met at the end of 2 to 3 months

Combination Therapy

Initiate combination therapy when levels are 7% to 8%
Options include:

  • Secretagogue + metformin
  • Secretagogue + thiazolidinedione
  • Secretagogue + alpha-glucosidase inhibitor
  • Thiazolidinedione + metformin
  • Dipeptidyl-peptidase 4 inhibitor + metformin
  • Dipeptidyl-peptidase 4 inhibitor + thiazolidinedione
  • Secretagogue + metformin + thiazolidinedione
  • Fixed-dose (single pill) therapy
    • Thiazolidinedione (pioglitazone) + metformin
    • Thiazolidinedione (rosiglitazone) + metformin
    • Thiazolidinedione (rosiglitazone) + secretagogue (glimepiride)
    • Thiazolidinedione (pioglitazone) + secretagogue (glimepiride)
    • Secretagogue (glyburide) + metformin

Rapid-acting insulin analogues or premixed insulin analogues may be used in special situations

Inhaled insulin may be used as monotherapy or in combination with oral agents and long-acting insulin analogues

All oral medications may be used in combination with insulin; therapy combinations should be selected based on the patient's profiles of self-monitoring of blood glucose

Initiating or Intensifying Therapy

Initiate or intensify combination therapy using options listed above when HbA1c levels are 8% to 10% to address fasting and postprandial levels

Initiate or intensify insulin therapy when HbA1c levels are >10%

Rapid-acting insulin analogue or inhaled insulin with long-acting insulin analogue or NPH

Premixed insulin analogues

Patients Currently Treated Pharmacologically

The therapeutic options for combination therapy listed for patients naive to therapy are appropriate for patients being treated pharmacologically

Exenatide may be combined with oral therapy in patients who have not achieved glycemic goals

Approved exenatide + oral combinations:

  • Exenatide + secretagogue (sulfonylurea)
  • Exenatide + metformin
  • Exenatide + secretagogue (sulfonylurea) + metformin
  • Exenatide + thiazolidinedione

Pramlintide may be used in combination with prandial insulin

Add insulin therapy in patients on maximum combination therapy (oral-oral, oral-exenatide) whose HbA1c levels are 6.5% to 8.5%

Consider initiating basal–bolus insulin therapy for patients with HbA1c levels >8.5%

HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn.

Adapted from reference 27.

*The options listed are in no order of preference.


Figure 4. Summary of insulin therapy titration.*
Type 1 Diabetes Mellitus
Initial basal dose (detemir or glargine) 10 units or 0.15 units/kg (whichever is greater) Adjustments (desired range 90-140 mg/dL): Increase/decrease by 3 units every 3 days if out of range
Initial basal coverage (NPH insulin): 10 units or 0.15 units/kg divided into 2 doses; 1 at breakfast and 1 at dinner Adjustments (desired range 90-140 mg/dL): Increase/decrease by 10% every 3 days, if out of range
Meal coverage (regular insulin, glulisine, aspart, lispro) 4 units per or 0.15 units/kg divided among 3 meals Adjustments (postprandial <180 mg/dL): Increase/decrease by 1 unit or 10% (whichever is greater)
Carbohydrate counting (1 units per 15 g of carbohydrate) Increase to 1 unit per 10 g of carbohydrate or decrease to 1 unit per 20 g of carbohydrate
Type 2 Diabetes Mellitus
Initial basal dose (detemir or glargine) 15 units or 0.25 units/kg (whichever is greater) Adjustments (desired range 90-140 mg/dL): Increase/decrease by 3 units or 10% (whichever is greater) every 3 days, if out of range
Initial basal coverage (NPH insulin) 15 units or 0.25 units/kg divided into 2 doses; 1 given at breakfast and 1 at dinner Adjustments (desired range 90-140 mg/dL): Increase/decrease by 10% every 3 days, if out of range
Meal coverage (regular insulin, glulisine, aspart, lispro) 6 units per meal or 0.25 units/kg divided between 3 meals Adjustments (postprandial <180 mg/dL): Increase/decrease by 2 units or 10% (whichever is greater)
Carbohydrate counting (1 unit per 10 g of carbohydrate) Increase to 1 unit per 5 g of carbohydrate or decrease to 1 unit per 15g of carbohydrate

NPH, neutral protamine Hagedorn

*This is only one of the titration protocols, others are available in literature.

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 A1c. 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.

References

  1. Mitka M: Report quantifies diabetes complications. JAMA 2007;297(21): 2337-2338.
  2. Welschen LM, Bloemendal E, Nijpels G, et al: Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: A systematic review. Diabetes Care 2005;28(6):1510-1517.
  3. 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.
  4. 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. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
  5. Evans JM, Newton RW, Ruta DA, et al: Frequency of blood glucose monitoring in relation to glycaemic control: observational study with diabetes database. BMJ 1999;319(7202):83-86.
  6. 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.
  7. Bergenstal, RM, James GR: The role of self-monitoring of blood glucose in the care of people with diabetes: Report of a global consensus conference. Am J Med 2005;118(9A):1S-6S.
  8. Farmer A, Wade A, Goyder E, Yudkin P, et al: Impact of self monitoring of blood glucose in the management of patients with non–insulin treated diabetes: Open parallel group randomized trial. BMJ 2007;335(7611): 132.
  9. Meal-related structured self-monitoring of blood glucose: Effect on diabetes control in non–insulin-treated type 2 diabetic patients. Diabetes Care 2002;25(11):1928-1932.
  10. Saudek CD, Derr RL, Kalyani RR: Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A1c. JAMA 2006;295(14): 1688-1697.
  11. 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.
  12. Executive summary: Standards of medical care in diabetes—2009. Diabetes Care 2009;32 Suppl 1:S6-S12.
  13. Delamater A: Clinical use of HbAlc to improve diabetes management. Clinical Diabetes 2006;24(1):6-8.
  14. ACP Diabetes Care Guide: A team-based practice manual and self-assessment program. 2007.
  15. Bailey CJ, Turner RC: Metformin. N Engl J Med 1998;339(25):1860-1861.
  16. Bailey CJ: Biguanides and NIDDM. Diabetes Care 1992;15(6):755-772.
  17. 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. Diabetes Care 2006; 29(8):1963-1972.
  18. Nathan, DM: Clinical practice. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347(17):1342-1349.
  19. Dormandy JA, Charbonnel C, Eckland DJ, et al: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005; 8:1279-1289.
  20. Fonseca V, Kulkarni K: Management of type 2 diabetes: Oral agents, insulin, and injectables. J Am Dietetic Assoc 2008;108(4):S29-S33.
  21. 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.
  22. Chiasson JL, Josse RG, Gomis R, et al: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM Trial. JAMA 2003;290:486-494.
  23. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood- glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):837-853.
  24. Hirsch IB, Bergenstal RM, Parkin CG, et al: A real-world approach to insulin therapy in primary care practice. Clinical Diabetes 2005; 23:78-86.
  25. Victoza (liraglutide): www.accessdata.fda.gov/drugsatfda_docs/label/2011/022341s004lbl.pdf. (Accessed December 31, 2012.).
  26. Cycloset (bromocriptine mesylate): www.accessdata.fda.gov/drugsatfda_docs/label/2009/020866lbl.pdf. (Accessed December 31, 2012.).
  27. 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.

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