Diabetes Mellitus Treatment

In patients diagnosed with diabetes mellitus (DM), the therapeutic focus is on preventing complications caused by hyperglycemia. In the United States, 57.9% of patients with diabetes have 1 or more diabetes-related complications and 14.3% have 3 or more.¹ Strict control of glycemia within the established recommended values is the primary method for reducing the development and progression of many complications associated with microvascular effects of diabetes (eg, retinopathy, nephropathy, and neuropathy). Aggressive treatment of dyslipidemia and hypertension focuses on decreasing the cardiovascular complications associated with macrovascular effects. The positive outcomes from adequate glycemic control on microvascular and macrovascular complications have been established in large well-controlled trials.^2-5 See the chapter on diabetes: Macro- and microvascular effects.

Glycemic Control

Two primary techniques are used to assess a patient’s glycemic control: Self-monitoring of blood glucose (SMBG) and serum measurement of hemoglobin A_1c (HbA_1c).

Self-Monitoring of Blood Glucose

Use of SMBG is an effective method to evaluate short-term glycemic control by providing real-time measure of blood glucose. It helps patients and physicians assess the effects of food, medications, stress, and activity on blood glucose levels and make appropriate adjustments.

For patients with type 1 DM or insulin-dependent type 2 DM, clinical trials have shown that SMBG plays a role in effective glycemic control because it helps patients refine and adjust insulin doses by monitoring for asymptomatic hypoglycemia as well as preprandial and postprandial hyperglycemia.^5-7

The frequency of SMBG depends on the type of medical therapy, risk for hypoglycemia, and need for short-term adjustment of therapy. The current American Diabetes Association (ADA) guidelines recommend that patients with diabetes self-monitor their glucose at least three times per day.⁸ Those 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 their blood glucose 3 or more times daily.

Recently, several companies have developed continuous glucose monitors that measure interstitial glucose levels, which have been shown to improve glycemic control without substantially increasing the risk of hypoglycemia.^9-10 Patients still need to check their blood glucose levels 2 times a day to calibrate the device.

It is commonly recommended that patients with type 2 DM self-monitor their blood glucose levels, but the evidence to support the effectiveness of this practice is inconclusive. Initial studies showed that SMBG in type 2 DM patients reduced HbA1c, but 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.^{2, 11} Follow-up studies that corrected for this did not find a significant improvement in glycemic control after 12 months.^12-13

It is important to individualize goals for patients regarding target blood glucose values. Table 1 lists recommendations from the ADA⁸ and the American Association of Clinical Endocrinologists (AACE).¹⁴

Hemoglobin A1c

HbA_1c measures nonreversible glycosylation of the hemoglobin molecule (expressed as a percentage of total hemoglobin), which is directly related to blood glucose concentrations. It reflects mean blood glucose values during a 2- to 3-month period and can be used as a predictor of a patient’s risk of microvascular complications.

Periodic testing is recommended in all patients with diabetes. The frequency 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.⁸ Quarterly testing is suggested for patients who have had a recent change in therapy or who are not meeting their glycemic goals.

Testing of HbA_1c does have limitations. HbA_1c levels are influenced by rapid red blood cell turnover and blood loss; therefore, patients with anemia or a hemoglobinopathy can have inaccurate values. Practitioners should check for these conditions if there is a substantial discrepancy between the estimated average glucose levels based on HbA_1c values (Table 2) and the patient’s SMBG readings. Also, episodes of hypoglycemia and hyperglycemia cannot be determined using HbA_1c values alone.

The ADA recommends that therapy be adjusted to maintain HbA_1c values near or below 7% in nonpregnant adults.⁸ For patients with type 1 DM or type 2 DM who become pregnant, the goal is 6% to 6.5%; <6% if it can be achieved without causing significant hypoglycemia. The target HbA1c can be adjusted to <7% to prevent hypoglycemia. The AACE recommends an HbA1c of less than 6.5% in nonpregnant adults.¹⁴ The ADA recommends that select patients, especially those with long life expectancy and few comorbidities, adopt glycemic targets close to normal, providing the target can be achieved without causing significant hypoglycemia.⁸

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Pharmacologic Treatment: Noninsulin Therapies

When considering appropriate pharmacologic therapy, it is important to determine whether the patient is insulin-deficient, insulin-resistant, or both. Treatment options are divided into noninsulin therapies—insulin sensitizers, secretagogues, alpha-glucosidase inhibitors, incretins, pramlintide, bromocriptine, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors—and insulin therapies (insulin and insulin analogues).

Insulin Sensitizers

Insulin sensitizers reduce glycemic load primarily by improving insulin actions in peripheral tissues. Two classes of these oral hypoglycemic drugs are available: biguanides and thiazolidinediones. They have been shown in clinical use to have positive, durable effects in the treatment of diabetes. These drug classes can be used as monotherapy or in combination with a sulfonylurea, insulin, or with each other.

Biguanides (Metformin)

Metformin is the only biguanide drug, and it was first marketed in the 1950s. Since then, many metformin products have been approved by the FDA, both generic and proprietary. Its primary mechanism of action is suppression of hepatic glucose output, but it also enhances insulin sensitivity of muscle and fat. Metformin primarily lowers fasting glycemia; however, some decreases in postprandial glucose concentrations, especially after the midday meal, are seen.

Metformin is well tolerated, with the most common side effect being gastrointestinal (GI) complaints, such as diarrhea, nausea, and abdominal discomfort, and a metallic taste. All of these symptoms improve with time and dose reduction. Metformin causes a small increase in basal and postprandial lactate concentrations in the blood, which can produce rare but life-threatening lactic acidosis (<1 in 100,000).^15-16 It is best to avoid metformin use in patients with hepatic impairment. Metformin is contraindicated in males with a serum creatinine level of 1.5 mg/dL or higher and in females with a level of 1.4 mg/dL or higher.¹⁶

A major benefit of metformin is that it usually does not cause hypoglycemia when used as monotherapy. It can lead to weight loss, and it has been shown to decrease plasma triglycerides concentration by 10% to 20%.¹⁶

Metformin is usually dosed twice daily, but it can be dosed 3 times daily; the extended-release formulation is dosed once daily. The typical starting dose is 500 mg/day with a maximum dose of 2,550 mg/day. Gradually titrating metformin, starting at 500 mg with breakfast and increasing by 500 mg in weekly intervals until reaching a maximum dose of 1,000 mg with breakfast and dinner, helps prevent GI side effects.^16-17

Thiazolidinediones

There are 2 thiazolidinediones marketed: rosiglitazone and pioglitazone. Generic products are available for both drugs. Thiazolidinediones are agonists of peroxisome proliferator-activated receptor gamma. They primarily enhance sensitivity of muscle and fat, and, mildly, the liver, to exogenous and endogenous insulin. These effects 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 although heart failure has occurred on occasion. These effects mostly occur at higher doses. As a result, these agents should be avoided in patients with functional class III or IV heart failure.

The Prospective Pioglitazone Clinical Trial in Macrovascular Events showed that compared with placebo, pioglitazone does not increase cardiovascular risks.¹⁸ The thiazolidinediones have been associated with an increased risk of bone fractures, particularly in women. They do not cause hypoglycemia when used as monotherapy. Pioglitazone use can lower triglycerides, increase high-density lipoprotein (HDL), and increase the low-density lipoprotein particle size.

Dosing is once daily. It takes 2 to 12 weeks for thiazolidinediones to become fully effective. For rosiglitazone, the starting dose is 4 mg/day and maximum dose is 8 mg/day. For pioglitazone, the starting dose is 15 mg/day and the maximum dose is 45 mg/day.

Insulin Secretagogues

Insulin secretagogues stimulate secretion of insulin from the pancreas, thereby enhancing glucose uptake by muscles and fat and decreasing hepatic glucose production. Two types of secretagogues are marketed: sulfonylureas and glinides.

Sulfonylureas

Sulfonylureas lower fasting and postprandial glucose levels. Many products are available, both first generation and second generation. The main adverse effects are weight gain (about 2 kg a few months after initiation) and hypoglycemia. Some hypoglycemia episodes can be significant, leading to a need for medical care, coma, or seizure, and occur more often in the elderly. Benefits include a 25% reduction in microvascular complications with or without insulin, as noted in the United Kingdom Prospective Diabetes Study (UKPDS).³ Dosing is typically once or twice daily. Caution should be used in patients with liver or kidney dysfunction or in those who often skip meals.

Glinides

Two drugs are available in this class: Nateglinide and repaglinide; both are available in generics. The glinides have a similar mode of action as sulfonylureas; however, glinides have a more rapid onset of action and shorter duration, so they are a good option for patients with erratic timing of meals. Also, the hypoglycemia risk is lower than with sulfonylureas; however, glinides have a similar-to-lower risk of weight gain after initiating therapy. Caution must be used in patients with liver dysfunction. Dosing is before meals.

Alpha-Glucosidase Inhibitors

This drug class competitively blocks 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 but do it without causing hypoglycemia. GI 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 occur before carbohydrate-containing meals. Two drug products are marketed, and both are available in generics.

Incretins

Incretin-based therapies are available as injections (glucagon-like peptide-1 [GLP-1] receptor agonists) or oral formulations (dipeptidyl peptidase-4 [DPP-4] inhibitors). These therapies differ slightly in their mechanisms of actions, as described in the following sections. All incretin-based medications carry an increased risk of acute pancreatitis. Patients must be warned about this risk and be advised to stop taking these medications and to seek medical evaluation if acute abdominal pain develops.

These medications should not be given to individuals who have a history of medullary thyroid carcinomas or have multiple endocrine neoplasia type 2. This restriction is based on increased incidences of thyroid C-cell tumors observed with these medications in murine models. So far, no increased risk in humans has been observed. Nevertheless, these patients should not use incretin therapies.

GLP-1 Receptor Agonists

The GLP-1 agonists are administered by injection and stimulate insulin secretion and suppress glucagon secretion after meals in a glucose-dependent manner.

Short-Acting (4-6 hrs)

Exenatide is a synthetic form of exendin 4, a hormone found in the saliva of the Gila monster, which mimics 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 also occurs.

Due to its delaying effects on gastric emptying, the major side effects are GI complaints of 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.⁸ There are no clinical trial data on the diabetes or cardiovascular impact of exenatide.

Dosing is twice daily by subcutaneous (SC) injection at least 60 minutes before the 2 main meals. The initial starting dose is 5 mcg. If this dose is tolerated, titrate after 1 month to 10 mcg.

Intermediate-Acting

Liraglutide is a GLP-1 analog derived from human GLP-1. It is administered once a day as a subcutaneous injection from its pen device. Timing is independent of meals. Half-life is about 13 hours. Its beneficial effects and side effects are similar to those of exenatide, but it may be slightly more powerful in its actions.

The initial dose is 0.6 mg/day for a week. If there are no side effects, the dose is increased to 1.2 mg/day (the dose at which most clinical benefits are seen). For most patients, the dose will be increased to 1.8 mg/day after another week, if there are no side effects. Liraglutide has shown cardiovascular protection in a clinical study.¹⁹

Long-Acting

Exenatide also is available as a once per week SC injection (extended-release exenatide). If a dose is missed, it should be administered as soon as possible, provided that the next dose is scheduled 3 or more days later. Albiglutide is a newer GLP-1 analog that has a half-life of 4 to 7 days. Dosing is 30 or 50 mg/wk subcutaneously. Dulaglutide is another long-acting GLP-1 analog. Dosing is 0.75 or 1.5 mg/wk subcutaneously.

DPP-4 Inhibitors

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

The DPP-4 inhibitors act primarily on postprandial blood glucose levels, but reductions in fasting glycemia are also seen. These agents are generally well tolerated, with the most common side effect being headache. An increase in nasopharyngitis also has been seen. Benefits include being weight-neutral and not causing hypoglycemia either as monotherapy or when combined with metformin or thiazolidinediones. When combined with sulfonylurea or insulin, however, DPP-4 inhibitors increase the risk of hypoglycemia.

Four DPP-4 inhibitors are FDA approved for use in patients with type 2 DM: sitagliptin, saxagliptin, linagliptin, and alogliptin. These agents are indicated for use as monotherapy or in combination with other agents such as metformin, sulfonylureas, thiazolidinediones, or insulin.

Sitagliptin dosing is 100 mg orally once daily with or without meals. Dose reduction is needed in patients with renal impairment. For patients with a creatinine clearance of 30 to 50 mL/min, dosing is 50 mg once daily. For patients with a creatinine clearance less than 30 mL/min, dosing is 25 mg once daily.

Saxagliptin dosing is 2.5 or 5 mg orally once daily with or without meals. The 2.5-mg daily dose is used in patients whose estimated glomerular filtration rate (eGFR) is <50 mg/mL and those using the strong inhibitors of P450 3A4/5 (eg, ketoconazole, ritonavir).

Linagliptin dosing is 5 mg orally once daily with or without meals. Dose reduction is not needed in patients with renal impairment.

Alogliptin dosing is 25 mg orally once daily with or without meals. Dose reduction is needed in patients with renal impairment. If the creatinine clearance is 30 to 60 mL/min, dosing is 12.5 mg once daily. If the creatinine clearance is below 30 mL/min, dosing is 6.25 mg once daily.

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. Efficacy data from well-conducted studies are lacking.

The major side effects are GI 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 after chronic therapy.

Pramlintide is approved by the US Food and Drug Administration (FDA) only as adjunctive therapy with insulin, but it is used off-label in patients with either type 1 DM or type 2 DM. Pramlintide can reduce insulin requirements by up to 50%. The starting dose for patients with type 2 DM is generally 60 μg subcutaneously before meals. In patients with type 1 DM, the starting dose is 15 μg before each meal. Pramlintide can be used by patients taking insulin, metformin, or sulfonylureas.

Bromocriptine

Fast-release bromocriptine improves glycemic control in patients with type 2 DM when taken within the 2 hours of waking up. Its mechanism of action is not known. Improvement in HbA_1c is 0.6% to 0.7%.²⁰ It is available as a 0.8 mg oral tablet, and therapeutic dosing varies from 1.6 to 4.8 mg. Generic products are marketed. Nausea is the main side effect.

SGLT-2 Inhibitors

The SGLT-2 inhibitors are the newest group of FDA-approved medications for type 2 DM. SGLT-2 is a protein acting as sodium-glucose cotransporter in the kidney’s proximal tubules whose main function is reabsorption of the filtered glucose from the urine back into the circulation. It is responsible for about 90% of total glucose reabsorption. Inhibition of this protein leads to the excretion of glucose in the urine at much lower blood glucose levels than normal (at approximately 120 mg/dL instead of 180 mg/dL). It is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 DM. Additional benefits are weight loss (two-thirds of weight loss is related to loss of fat tissue and one-third is related to loss of water) and lower blood pressure.

The most common side effects of SGLT-2 inhibitors are vaginal yeast infections and urinary tract infections. The greatest risk is seen in females and uncircumcised males. Polyuria also may occur.

These medications are not indicated in children, in patients with type 1 DM, or in patients with frequent ketones in their blood or urine or severe renal impairment. Patients should be advised to expect glucose to be in the urine and, thus, urine glucose strips will usually have a positive reading.

Three oral products are marketed: canagliflozin, dapagliflozin, and empagliflozin.

Canagliflozin is dosed at 100 mg/day before the first meal of the day and can be increased to 300 mg/day, if tolerated. Canagliflozin should not be used in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m² and should be limited to 100 mg in those with an eGFR 45 to 60 mL/min/1.73 m².

Dapagliflozin is dosed at 5 mg/day and can be increased to 10 mg/day, if tolerated. It should not be used if the eGFR is less than 60 mL/min/1.73m².

Empagliflozin is dosed at 10 or 25 mg once a day. It should not be started if the eGFR is less than 60 mL/min/1.73m². If the patient’s eGFR decreases to below 60 mL/min/1.73 m² while taking this medication, dosing should be reduced to 10 mg/day. It should be stopped if the eGFR decreases below 45 mL/min/1.73 m². Empagliflozin is the only antidiabetic medication shown to decrease cardiovascular risk in patients with type 2 DM.

Pharmacologic Treatment: Insulin Therapies

Insulin was the first treatment for diabetes. It was discovered in 1921, and clinical testing in humans started in 1922. Insulin therapy helps regulate glucose metabolism and is the most effective method of reducing hyperglycemia. There is no upper limit in dosing for therapeutic effect, so it can be used to reduce any elevated HbA_1c level. It also reduces triglycerides and increases HDL.^{8, 14}

Hypoglycemia is a concern, although the actual risk of severe episodes is small. Studies have shown that insulin-induced hypoglycemic episodes requiring therapy occur in 1 to 3 patients per 100,000 patient-years. Weight gain can occur after therapy initiation and is typically about 2 to 4 kg.^{8, 14}

Most brands of insulin are available in both vial and pen form for delivery. Table 4 lists the insulin formulations.

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Initiation, Titration of Insulin

Type 1 DM

All patients with type 1 DM require insulin therapy. Some patients with type 2 DM require insulin, which can be combined with oral hypoglycemic agents. Regimens used are basal insulin only, basal-bolus, once or twice daily premixed insulin, and insulin pump (Table 5).

Basal–Bolus

The basal-bolus regimen combines a long-acting agent (administered once or twice daily) that provides basal insulin needs and a rapid-acting agent for prandial coverage. Traditionally, when initiating therapy with glargine or detemir as the basal insulin, 50% of the total daily dose is given as basal insulin and the rest as prandial insulin divided equally before meals. The prandial insulin dose can be fixed, but it is better to determine the dose based on the carbohydrate content of the meal. This requires knowing the carbohydrate content of foods and knowing the insulin dose required to cover the carbohydrates. A diabetic educator can help patients adjust their insulin dose based on carbohydrate consumption.

The starting daily insulin dose is typically 0.3 U/kg total daily (divided between long-acting and rapid-acting) (Table 6). A key to achieving glycemic control is appropriate SMBG by the patient and frequent adjustment of the regimen.

Insulin Pump Therapy

The insulin pump allows administration of different basal insulin rates during different periods of the day. It also allows administration of the meal bolus as a single discrete bolus or as an extended bolus (square bolus) over a specific time, which provides a better match between insulin delivery and glucose absorption from the meal in patients with gastric emptying abnormalities. Use of insulin pump therapy is increasing in all diabetic populations. It should be considered in these populations:

• Patients 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 during the day and to make insulin dose adjustments.

Type 2 DM

The ADA and the AACE have published different algorithms for initiation and maintenance of therapy in patients with type 2 DM.^{8, 23} No studies have compared the efficacy of these algorithms.

Table 7 lists the initial dose and titration of insulin therapy for type 2 DM. The starting daily insulin dose is typically 0.5 U/kg total, divided between long-acting and rapid-acting. 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 basal-bolus regimens are often required.

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Summary Points

• Glycemic control is crucial for preventing microvascular and macrovascular complications of diabetes.
• Type 2 DM is a progressive disease and requires therapy intensification with time.
• Insulin sensitizers and incretin-based therapy should be used early in the course of type 2 DM.
• Patients with type 1 DM require insulin therapy; some patients with advanced type 2 DM also require insulin.
• Multiple daily doses of insulin providing basal, prandial, and supplemental insulin are the mainstay of insulin therapy.

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