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Drug Treatment of Diabetes Mellitus

By

Erika F. Brutsaert

, MD, New York Medical College

Last full review/revision Sep 2020| Content last modified Sep 2020
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General treatment of diabetes for all patients involves lifestyle changes, including diet and exercise. Regular monitoring of blood glucose levels is essential to prevent complications of diabetes. (See also Diabetes Mellitus.)

Patients with type 1 diabetes mellitus are treated with insulin as well as diet and exercise.

Patients with type 2 diabetes mellitus are often initially treated with diet and exercise. If those measures are not sufficient for glycemic control, patients may be prescribed oral antihyperglycemic drugs, injectable glucagon-like peptide-1 (GLP-1) receptor agonists, insulin, or a combination of these drugs.

For some patients with diabetes, drugs often are given to prevent diabetes complications. Agents include renin-angiotensin-aldosterone system blockers (angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs]), statins, and aspirin.

Insulin

Insulin is required for all patients with type 1 diabetes mellitus because they become ketoacidotic without it; it is also helpful for management of many patients with type 2 diabetes.

Insulin replacement in type 1 diabetes should ideally mimic beta-cell function using 2 insulin types to provide basal and prandial requirements (physiologic replacement or basal-bolus dosing); this approach requires close attention to diet and exercise as well as to insulin timing and dose.

When insulin is needed for patients with type 2 diabetes, glycemic control can often be achieved with basal insulin combined with non- insulin antihyperglycemic drugs, although prandial insulin may be needed in some patients.

Except for use of regular insulin, which is given IV in hospitalized patients, insulin is almost always administered subcutaneously. An inhaled insulin preparation is also available.

Insulin preparations

Most insulin preparations are now recombinant human, practically eliminating the once-common allergic reactions to the drug when it was extracted from animal sources. A number of analogs are available. These analogs were created by modifying the human insulin molecule that alters absorption rates and duration and time to action.

Insulin types are commonly categorized by their time to onset and duration of action (see table Onset, Peak, and Duration of Action of Human Insulin Preparations). However, these parameters vary within and among patients, depending on many factors (eg, site and technique of injection, amount of subcutaneous fat, blood flow at the injection site).

Table
icon

Onset, Peak, and Duration of Action of Human Insulin Preparations*

Insulin Preparation

Onset of Action

Peak Action

Duration of Action

Rapid-acting

Lispro, aspart, glulisine†

5–15 minutes

45–75 minutes

3–5 hours

Inhaled regular

< 15 minutes

50 minutes

2–3 hours

Short-acting

Regular†

30–60 minutes

2–4 hours

6–8 hours

Intermediate-acting

NPH‡

About 2 hours

4–12 hours

18–26 hours

U-500 regular

30 minutes

4–8 hours

13–24 hours

Long-acting

Glargine

3–4 hours

No peak

24 hours

U-300 insulin glargine

6 hours

No peak

24 hours

Detemir

1–2 hours

No peak

14–24 hours

Degludec

1–2 hours

No peak

> 40 hours

Premixed

70% NPH/30% regular

30–60 minutes

Dual (NPH & R)

10–16 hours

50% NPL/50% lispro

30–60 minutes

Dual (NPL & lispro)

10–16 hours

75% NPL/25% lispro

5–15 minutes

Dual (NPL & lispro)

10–16 hours

70% NPA/30% aspart

5–15 minutes

Dual (NPA & aspart)

10–16 hours

70% Degludec/30% aspart

15 minutes

Dual (degludec & aspart)

> 40 hours

* Times are approximate, assume subcutaneous administration, and may vary with injection technique and factors influencing absorption.

† Lispro and aspart are also available in premixed forms with intermediate-acting insulins.

‡ NPH also exists in premixed form (NPH/regular).

NPA = neutral protamine aspart; NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro.

Rapid-acting insulins, including lispro and aspart, are rapidly absorbed because reversal of an amino acid pair prevents the insulin molecule from associating into dimers and polymers. They begin to reduce plasma glucose often within 15 minutes but have short duration of action (< 4 hours). These insulins are best used at mealtime to control postprandial spikes in plasma glucose. Inhaled regular insulin is a newer rapid acting insulin that is taken with meals.

Regular insulin is slightly slower in onset (30 to 60 minutes) than lispro and aspart but lasts longer (6 to 8 hours). It is the only insulin form for IV use.

Neutral protamine Hagedorn (NPH, or insulin isophane) is intermediate-acting; onset of action is about 2 hours after injection, peak effect is 4 to 12 hours after injection, and duration of action is 18 to 26 hours. Concentrated regular insulin U-500 has a similar peak and duration of action (peak 4 to 8 hours; duration 13 to 24 hours) and can be dosed 2 to 3 times per day.

Long-acting insulins, insulin glargine, insulin detemir, and U-300 insulin glargine, unlike NPH, have no discernible peak of action and provide a steady basal effect over 24 hours. Insulin degludec (another long-acting insulin) has an even longer duration of action of over 40 hours. It is dosed daily, and although it requires 3 days to achieve steady state, the timing of dosing is less rigid.

Combinations of NPH and regular insulin and of insulin lispro and NPL (neutral protamine lispro or a form of lispro modified to act like NPH) are commercially available in premixed preparations (see table Onset, Peak, and Duration of Action of Human Insulin Preparations). Other premixed formulations include NPA (neutral protamine aspart or a form of aspart modified to act like NPH) with insulin aspart and a formulation of premixed degludec and aspart.

Different insulin types can be drawn into the same syringe for injection but should not be premixed in bottles except by a manufacturer. On occasion, mixing insulins may affect rates of insulin absorption, producing variability of effect and making glycemic control less predictable, especially if mixed > 1 hour before use. Insulin glargine should never be mixed with any other insulin.

Many prefilled insulin pen devices are available as an alternative to the conventional vial and syringe method. Insulin pens may be more convenient for use away from home and may be preferable for patients with limited vision or manual dexterity. Spring-loaded self-injection devices (for use with a syringe) may be useful for the occasional patient who is fearful of injection, and syringe magnifiers are available for patients with low vision. Recently developed "smart" insulin pens communicate with a smart phone application to track administered insulin and make dosing recommendations.

Insulin pumps

Lispro, aspart, or regular insulin can also be given continuously using an insulin pump (1). Continuous subcutaneous insulin infusion pumps can eliminate the need for multiple daily injections, provide maximal flexibility in the timing of meals, and substantially reduce variability in glucose levels. Disadvantages include cost, mechanical failures leading to interruptions in insulin supply, and the inconvenience of wearing an external device. Frequent and meticulous self-monitoring and close attention to pump function are necessary for safe and effective use of the insulin pump.

Sensor-augmented pumps communicate with a continuous glucose monitor and can suspend insulin delivery when the glucose level drops. In addition, 2 hybrid closed-loop insulin delivery systems are available, and there are other systems in development. A closed-loop system or "artificial pancreas" is one in which the device autonomously calculates and delivers insulin doses through an insulin pump based on input from a continuous glucose monitor and an internal algorithm. The available systems still require user input for bolus doses.

Insulin pumps reference

  • 1. Peters AL, Ahmann AJ, Battelino T, et al: Diabetes technology—Continuous subcutaneous insulin infusion therapy and continuous glucose monitoring in adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab  101(11):3922-3937, 2016.

Complications of insulin treatment

The most common complication is

Uncommon complications include

  • Local allergic reactions

  • Generalized allergic reaction

  • Local fat atrophy or hypertrophy

  • Circulating anti- insulin antibodies

Hypoglycemia is the most common complication of insulin treatment, occurring more often as patients try to achieve strict glucose control and approach near-normoglycemia. Symptoms of mild or moderate hypoglycemia include headache, diaphoresis, palpitations, light-headedness, blurred vision, agitation, and confusion. Symptoms of more severe hypoglycemia include seizures and loss of consciousness. In older patients, hypoglycemia may cause strokelike symptoms of aphasia or hemiparesis and is more likely to precipitate stroke, myocardial infarction, and sudden death. Patients with type 1 diabetes mellitus of long duration may be unaware of hypoglycemic episodes because they no longer experience autonomic symptoms (hypoglycemia unawareness).

Patients should be taught to recognize symptoms of hypoglycemia, which usually respond rapidly to the ingestion of sugar, including candy, juice, and glucose tablets. Typically, 15 g of glucose or sucrose should be ingested. Patients should check their glucose levels 15 minutes after glucose or sucrose ingestion and ingest an additional 15 g if their glucose level is not > 80 mg/dL (> 4.4 mmol/L). For patients who are unconscious or unable to swallow, hypoglycemia can be treated immediately with glucagon 1 mg given subcutaneously or intramuscularly, or with dry glucagon 3 mg intranasally, or a 50% dextrose solution 50 mL IV (25 g) followed, if necessary, by IV infusion of a 5% or 10% dextrose solution to maintain adequate plasma glucose levels.

Hyperglycemia may follow hypoglycemia either because too much sugar was ingested or because hypoglycemia caused a surge in counter-regulatory hormones ( glucagon, epinephrine, cortisol, growth hormone). Too high a bedtime insulin dose can drive glucose down and stimulate a counter-regulatory response, leading to morning hyperglycemia (Somogyi phenomenon). A more common cause of unexplained morning hyperglycemia, however, is a rise in early morning growth hormone (dawn phenomenon). In this case, the evening insulin dose should be increased, changed to a longer-acting preparation, or injected later.

Hypokalemia may be caused by intracellular shifts of potassium due to insulin-induced stimulation of the sodium-potassium pump, but it is uncommon. Hypokalemia more commonly occurs in acute care settings when body stores may be depleted and IV insulin is used.

Local allergic reactions at the site of insulin injections are rare, especially with the use of human insulins, but they may still occur in patients with latex allergy because of the natural rubber latex contained in vial stoppers. They can cause immediate pain or burning followed by erythema, pruritus, and induration—the latter sometimes persisting for days. Most reactions spontaneously disappear after weeks of continued injection and require no specific treatment, although antihistamines may provide symptomatic relief.

Generalized allergic reaction is extremely rare with human insulins but can occur when insulin is restarted after a lapse in treatment. Symptoms develop 30 minutes to 2 hours after injection and include urticaria, angioedema, pruritus, bronchospasm, and anaphylaxis. Treatment with antihistamines often suffices, but epinephrine and IV glucocorticoids may be needed. If insulin treatment is needed after a generalized allergic reaction, skin testing with a panel of purified insulin preparations and desensitization should be done.

Local fat atrophy or hypertrophy at injection sites is relatively rare and is thought to result from an immune reaction to a component of the insulin preparation. Either may resolve by rotation of injection sites.

Circulating anti-insulin antibodies are a very rare cause of insulin resistance. This type of insulin resistance can sometimes be treated by changing insulin preparations (eg, from animal to human insulin) and by administering corticosteroids if necessary.

Insulin regimens for type 1 diabetes

Regimens range from twice a day split-mixed (eg, split doses of rapid- and intermediate-acting insulins) to more physiologic basal-bolus regimens using multiple daily injections (eg, single fixed [basal] dose of long-acting and variable prandial [bolus] doses of rapid-acting insulin) or an insulin pump. Intensive treatment, defined as glucose monitoring 4 times a day and 3 injections a day or continuous insulin infusion, is more effective than conventional treatment (1 to 2 insulin injections a day with or without monitoring) for preventing diabetic retinopathy, nephropathy, and neuropathy. However, intensive therapy may result in more frequent episodes of hypoglycemia and weight gain and is more effective in patients who are able and willing to take an active role in their self-care.

In general, most patients with type 1 diabetes mellitus can start with a total dose of 0.2 to 0.8 units of insulin/kg/day. Obese patients may require higher doses. Physiologic replacement involves giving 40 to 60% of the daily insulin dose as an intermediate- or long-acting preparation to cover basal needs, with the remainder given as a rapid- or short-acting preparation to cover postprandial increases. This approach is most effective when the dose of rapid- or short-acting insulin is adjusted for preprandial blood glucose level and anticipated meal content. A correction factor, also known as the insulin sensitivity factor, is the amount that 1 unit of insulin will lower a patient's blood glucose level over 2 to 4 hours; this factor is often calculated using the "1800 rule" when rapid-acting insulin is used for correction (1800/total daily dose of insulin). For regular insulin, a "1500 rule" can be used. A correction dose (current glucose level - target glucose level/ correction factor) is the dose of insulin that will lower the blood glucose level into the target range. This correction dose can be added to the prandial insulin dose that is calculated for the number of carbohydrates in a meal, using the carbohydrate-to- insulin ratio (CIR). The CIR is often calculated using the "500 rule" (500/total daily dose).

To illustrate calculation of a lunchtime dose, assume the following:

  • Preprandial fingerstick glucose: 240 mg/dL (13.3 mmol/L)

  • Total daily dose of insulin: 30 units basal insulin + 10 units bolus insulin per meal = 60 units total, daily

  • Correction factor ( insulin sensitivity factor): 1800/60 = 30 mg/dL/unit (1.7 mEq/L/unit, or 1.7 mmol/L)

  • Estimated carbohydrate content of upcoming meal: 50 g

  • Carbohydrate: insulin ratio (CIR): 500/60 = 8:1

  • Target glucose: 120 mg/dL (6.7 mmol/L)

Prandial insulin dose = 50 g carbohydrate divided by 8 g/unit insulin = 6 units

Correction dose = (240 mg/dL - 120 mg/dL)/30 correction factor = 4 units ([13.3 mmol/L - 6.7 mmol/L]/1.7 = 4)

Total dose prior to this meal = prandial dose + correction dose = 6 + 4 = 10 units rapid-acting insulin

Such physiologic regimens allow greater freedom of lifestyle because patients can skip or time-shift meals and maintain normoglycemia. These recommendations are for initiation of therapy; thereafter, choice of regimens generally rests on physiologic response and patient and physician preferences. The carbohydrate-to- insulin ratio (CIR) and sensitivity factors need to be fine-tuned and changed according to how the patient responds to insulin doses. This adjustment requires working closely with a diabetes specialist.

Insulin regimens for type 2 diabetes

Regimens for type 2 diabetes mellitus also vary. In many patients, glucose levels are adequately controlled with lifestyle changes and non- insulin antihyperglycemic drugs, but insulin should be added when glucose remains inadequately controlled by 3 drugs. Although uncommon, adult-onset type 1 diabetes may be the cause. In most cases, in women who become pregnant, insulin should replace non- insulin antihyperglycemic drugs.

The rationale for combination therapy is strongest for use of insulin with oral biguanides and insulin sensitizers. Regimens vary from a single daily injection of long- or intermediate-acting insulin (usually at bedtime) to the multiple-injection regimen used by patients with type 1 diabetes. In general, the simplest effective regimen is preferred. Because of insulin resistance, some patients with type 2 diabetes require very large doses (> 2 units/kg/day). A common complication is weight gain, which is mostly attributable to reduction in loss of glucose in urine and improved metabolic efficiency.

Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs (see tables Characteristics of Oral Antihyperglycemics are a mainstay of treatment for type 2 diabetes mellitus, along with injectable glucagon-like peptide-1 (GLP-1) receptor agonists. Insulin is added when 3 drugs fail to provide adequate glycemic control. Oral antihyperglycemic drugs may

  • Enhance pancreatic insulin secretion (secretagogues)

  • Sensitize peripheral tissues to insulin (sensitizers)

  • Impair gastrointestinal absorption of glucose

  • Increase glycosuria

Drugs with different mechanisms of action may be synergistic.

Table
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Characteristics of Oral Antihyperglycemics

Generic Name

Daily Dosage

Duration of Action

Comments

Insulin secretagogues: Long-acting (sulfonylureas)

Augment pancreatic beta-cell insulin secretion

Can be used alone or in combination with insulin and other drugs

Their long duration of action may lead to serious hypoglycemia, especially in older patients

Efficacy may wane after 5 years of use

Acetohexamide*

250 mg once a day–750 mg twice a day

12–24 hours

No longer available in US

Chlorpropamide*

100 mg once a day–750 mg once a day

24–36 hours

Chlorpropamide: May cause hyponatremia and flushing after alcohol ingestion

Tolazamide*

100 mg once a day–500 mg twice a day

14–16 hours

No longer available in US

Tolbutamide*

250 mg once a day–1500 mg twice a day

12 hours

Glyburide, regular-release†

1.25 mg once a day–10 mg twice a day

12–24 hours

Glipizide and glyburide: No evidence of increased effectiveness of doses > 10 mg/day

Glyburide, micronized†

0.75 mg once a day–6 mg twice a day

12–24 hours

Glipizide, regular-release†

2.5 mg once a day–20 mg twice a day

12–24 hours

Glipizide, extended-release†

2.5–20 mg once a day

24 hours

Glimepiride

1–8 mg once a day

24 hours

Insulin secretagogues: Short-acting (meglitinides)

Augment pancreatic beta-cell insulin secretion

Can be used alone or in combination with other oral drugs and insulin

Nateglinide

60–120 mg 3 times a day with meals

3–4 hours

Repaglinide

0.5–4 mg 3 times a day with meals

3–4 hours

Insulin sensitizers: Biguanides

Augment suppression of hepatic glucose production by insulin

Can be used alone or in combination with other oral drugs and insulin

Major adverse effects: Lactic acidosis (rare)

Contraindicated in at-risk patients, including those with renal insufficiency, metabolic acidosis, hypoxia, alcoholism, or dehydration

Does not cause hypoglycemia

Other adverse effects: Gastrointestinal distress (diarrhea, nausea, pain), vitamin B12 malabsorption

Potentiates weight loss

Should be stopped temporarily before radiologic procedures requiring use of contrast agents

Metformin, regular-release

500 mg once a day–1250 mg twice a day

6–10 hours

Metformin, extended-release

500 mg–2 g once a day

24 hours

Insulin sensitizers: Thiazolidinediones

Augment suppression of hepatic glucose production by insulin

Can be used alone or in combination with other oral drugs and insulin

Major adverse effects: Weight gain, fluid retention, anemia (mild)

Hepatotoxicity rare, but liver monitoring required

Pioglitazone

15–45 mg once a day

24 hours

Pioglitazone: May increase risk of bladder cancer, heart failure, and fractures

Rosiglitazone

2–8 mg once a day

24 hours

Rosiglitazone: May increase low-density lipoprotein cholesterol and may increase risk of heart failure, angina, myocardial infarction, stroke, and fractures

Alpha-glucosidase inhibitors

Intestinal enzyme inhibitors

Used as monotherapy or combination therapy with other oral drugs or insulin to decrease postprandial plasma glucose levels

Must be taken with the first bite of meal

Gastrointestinal adverse effects (flatulence, diarrhea, bloating) common but may decrease over time

Started with small dose (25 mg/day) and gradually titrated over several weeks

Acarbose

25–100 mg 3 times a day with meals

6–10 hours

Miglitol

25–100 mg 3 times a day with meals

6–10 hours

Dipeptidyl peptidase-4 (DPP4) inhibitors

Alogliptin

6.25–25 mg once a day

24 hours

Inhibit the enzyme DPP-4, which is involved in the breakdown of GLP-1, a peptide that stimulates insulin secretion and inhibits glucagon secretion

All DPP-4 inhibitors can be used in moderate to severe renal insufficiency. All, except linagliptin require dose adjustment for estimated glomerular filtration rate.

Well-tolerated but cause only modest improvements in hemoglobin A1C

A slight increase in risk of pancreatitis seen in several studies

Linagliptin

5 mg once a day

24 hours

Saxagliptin

2.5–5 mg once a day

24 hours

Sitagliptin

25–100 mg once a day

24 hours

Glucagon-like peptide-1 (GLP1) receptor agonists

Mimic the effects of GLP-1, a peptide made in the small intestine that enhances glucose-dependent insulin secretion

Semaglutide

3 mg once a day, increasing after 30 days to 7 mg once a day. If needed, after another 30 days increase to 14 mg once a day

24 hours

Low risk of hypoglycemia; may promote modest weight loss

Increased risk of pancreatitis

Thyroid C-cell tumors (medullary carcinoma) noted in rodents

Weekly preparations may cause fewer gastrointestinal adverse effects. When given once or twice a day, lowest starting dose may minimize nausea

Semaglutide is associated with increased progression of diabetic retinopathy.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Canagliflozin

100 or 300 mg once a day

24 hours

Inhibit SGLT2 in the proximal tubule of the kidney, which blocks glucose reabsorption, thus causing glycosuria

SGLT-2 inhibitors may cause Fournier gangrene, weight loss, orthostatic hypotension, yeast infections, and urinary tract infections

Use cautiously in older patients and in patients with renal impairment

Possible increase in risk of diabetic ketoacidosis

Canagliflozin is associated with a higher rate of limb amputations

Empagliflozin may have cardiovascular benefits

Dapagliflozin

5–10 mg once a day

24 hours

Empagliflozin

10–25 mg once a day

24 hours

Ertugliflozin

5–15 mg once a day

24 hours

* First-generation sulfonylureas.

† 2nd-generation sulfonylureas.

(See below for information on Glucagon-like peptide-1 (GLP1) receptor agonists.)

Sulfonylureas

Sulfonylureas (eg, glyburide, glipizide, glimepride) are insulin secretagogues. They lower plasma glucose by stimulating pancreatic beta-cell insulin secretion and may secondarily improve peripheral and hepatic insulin sensitivity by reducing glucose toxicity. First-generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, tolbutamide) are more likely to cause adverse effects and are used infrequently. All sulfonylureas promote hyperinsulinemia and weight gain of 2 to 5 kg, which over time may potentiate insulin resistance and limit their usefulness. All also can cause hypoglycemia. Risk factors include age > 65, use of long-acting drugs (especially chlorpropamide, glyburide, or glipizide), erratic eating and exercise, and renal or hepatic insufficiency.

Hypoglycemia caused by long-acting drugs may last for days after treatment cessation, occasionally causes permanent neurologic disability, and can be fatal. For these reasons, some physicians hospitalize hypoglycemic patients, especially older ones. Chlorpropamide also causes the syndrome of inappropriate ADH secretion. Most patients taking sulfonylureas alone eventually require additional drugs to achieve normoglycemia, suggesting that sulfonylureas may exhaust beta-cell function. However, worsening of insulin secretion and insulin resistance is probably more a feature of diabetes mellitus itself than of drugs used to treat it.

Short-acting insulin secretagogues

Short-acting insulin secretagogues (repaglinide, nateglinide) stimulate insulin secretion in a manner similar to sulfonylureas. They are faster acting, however, and may stimulate insulin secretion more during meals than at other times. Thus, they may be especially effective for reducing postprandial hyperglycemia and appear to have lower risk of hypoglycemia. There may be some weight gain, although apparently less than with sulfonylureas. Patients who have not responded to other oral drugs (eg, sulfonylureas, metformin) are not likely to respond to these drugs.

Biguanides

Biguanides (metformin) lower plasma glucose by decreasing hepatic glucose production (gluconeogenesis and glycogenolysis). They are considered peripheral insulin sensitizers, but their stimulation of peripheral glucose uptake may simply be a result of reductions in glucose from their hepatic effects. Biguanides also lower lipid levels and may also decrease gastrointestinal nutrient absorption, increase beta-cell sensitivity to circulating glucose, and decrease levels of plasminogen activator inhibitor 1, thereby exerting an antithrombotic effect. Metformin is the only biguanide commercially available in the US. It is at least as effective as sulfonylureas in reducing plasma glucose, rarely causes hypoglycemia, and can be safely used with other drugs and insulin. In addition, metformin does not cause weight gain and may even promote weight loss by suppressing appetite. However, the drug commonly causes gastrointestinal adverse effects (eg, dyspepsia, diarrhea), which for most people recede with time. Less commonly, metformin causes vitamin B12 malabsorption, but clinically significant anemia is rare.

Contribution of metformin to life-threatening lactic acidosis is very rare, but the drug is contraindicated in patients at risk of acidemia (including those with significant renal insufficiency, hypoxia or severe respiratory disease, alcohol use disorder, other forms of metabolic acidosis, or dehydration). The drug should be withheld during surgery, administration of IV contrast, and any serious illness. Many people receiving metformin monotherapy eventually require an additional drug.

Thiazolidinediones

Thiazolidinediones (TZDs—pioglitazone, rosiglitazone) decrease peripheral insulin resistance ( insulin sensitizers), but their specific mechanisms of action are not well understood. The drugs bind a nuclear receptor primarily present in fat cells (peroxisome-proliferator-activated receptor-gamma [PPAR-γ]) that is involved in the transcription of genes that regulate glucose and lipid metabolism. TZDs also increase high-density lipoprotein (HDL) levels, lower triglycerides, and may have anti-inflammatory and anti-atherosclerotic effects. TZDs are as effective as sulfonylureas and metformin in reducing hemoglobin A1C. TZDs may be beneficial in treatment of nonalcoholic fatty liver disease (NAFLD).

Though one TZD (troglitazone) caused acute liver failure, currently available drugs have not proven hepatotoxic. Nevertheless, periodic monitoring of liver function is recommended. TZDs may cause peripheral edema, especially in patients taking insulin, and may worsen heart failure in susceptible patients. Weight gain, due to fluid retention and increased adipose tissue mass, is common and may be substantial (> 10 kg) in some patients. Rosiglitazone may increase risk of heart failure, angina, myocardial infarction, stroke, and fracture. Pioglitazone may increase the risk of bladder cancer (although data are conflicting), heart failure, and fractures.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors (acarbose, miglitol) competitively inhibit intestinal enzymes that hydrolyze dietary carbohydrates; carbohydrates are digested and absorbed more slowly, thereby lowering postprandial plasma glucose. Alpha-glucosidase inhibitors are less effective than other oral drugs in reducing plasma glucose, and patients often stop the drugs because they may cause dyspepsia, flatulence, and diarrhea. But the drugs are otherwise safe and can be used in combination with all other oral drugs and with insulin.

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 inhibitors (eg, alogliptin, linagliptin, saxagliptin, sitagliptin) prolong the action of endogenous glucagon-like peptide-1 (GLP-1) by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is involved in the breakdown of GLP-1. GLP-1 is a peptide made in the small intestine that stimulates insulin secretion and inhibits glucagon secretion; prolonging its action thereby lowers plasma glucose. There is a slight increase in risk for pancreatitis with DPP-4 inhibitors, but they are otherwise considered safe and well-tolerated. The hemoglobin A1C decrease is modest with DPP-4 inhibitors.

Sodium-glucose co-transporter 2 inhibitors

Sodium-glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) inhibit SGLT2 in the proximal tubule of the kidney, which blocks glucose reabsorption, thus causing glycosuria and lowering plasma glucose. SGLT2 inhibitors may also cause modest weight loss and lowering of blood pressure. SGLT-2 inhibitors have recently been shown to decrease mortality, major adverse cardiovascular events and heart failure hospitalizations in patients with an increased risk for cardiovascular disease. In addition SGLT-2 inhibitors have been shown to prevent progression of chronic kidney disease in patients with diabetes and reduced glomerular filtration rate or albuminuria.

The most common side effects are genitourinary infections, especially mycotic infections. Orthostatic symptoms can also occur. SGLT-2 inhibitors have been implicated in causing diabetic ketoacidosis (DKA) in patients with both type 1 and type 2 diabetes and ketoacidosis may occur at lower blood glucose levels than in other causes of DKA. One large study showed an increase in lower limb amputation with canagliflozin.

Dopamine agonist

Bromocriptine is a dopamine agonist that lowers hemoglobin A1C about 0.5% by an unknown mechanism. Although approved for type 2 diabetes, it is not commonly used because of potential adverse effects.

Injectable Antihyperglycemic Drugs

Injectable antihyperglycemic drugs other than insulin are the glucagon-like peptide-1 (GLP-1) receptor agonists and the amylin analog, pramlintide (see table Characteristics of Injectable Non-Insulin Antihyperglycemic Drugs). These drugs are used in combination with other antihyperglycemics.

-like peptide-1 (GLP-1) receptor agonists

GLP-1 receptor agonists mimic the effects of GLP-1, a peptide made in the small intestine that enhances glucose-dependent insulin secretion and slows gastric emptying. GLP-1 agonists may also reduce appetite and promote weight loss and stimulate beta-cell proliferation. Examples include exenatide (an incretin hormone), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Formulations are available for dosing twice a day, once a day, and weekly. The most common adverse effects of GLP-1 agonists are gastrointestinal, especially nausea and vomiting. GLP-1 agonists also cause a slight increase in the risk of pancreatitis. They are contraindicated in patients with a personal or family history of medullary thyroid cancer because an increased risk of this cancer has occurred in tested rodents.

Amylin analog

The amylin analog pramlintide mimics amylin, a pancreatic beta-cell hormone that helps regulate postprandial glucose levels. Pramlintide suppresses postprandial glucagon secretion, slows gastric emptying, and promotes satiety. It is given by injection and is used in combination with mealtime insulin. Patients with type 1 diabetes are given 30 to 60 mcg subcutaneously before meals, and those with type 2 diabetes are given 120 mcg.

Table
icon

Characteristics of Injectable Non-Insulin Antihyperglycemic Drugs

Generic Name

Daily Dosage

Duration of Action

Comments

Glucagon-like peptide-1 (GLP-1) agonists

Albiglutide

30 mg or 50 mg subcutaneously once a week

7 days

Low risk of hypoglycemia; may promote modest weight loss

Increased risk of pancreatitis

Thyroid C-cell tumors (medullary carcinoma) noted in rodents

Weekly preparations may cause fewer GI adverse effects. When given once/day or bid, lowest starting dose may minimize nausea

Liraglutide also comes as a combination pen with insulin degludec.

Lixisenatide is also available in a combination pen with insulin glargine.

Semaglutide is associated with increased progression of diabetic retinopathy.

Dulaglutide

0.75 mg or 1.5 mg subcutaneously once a week

7 days

Exenatide

5 mcg or 10 mcg subcutaneously twice a day before meals

4–6 hours

Exenatide, once/wk

2 mg subcutaneously once a week

7 days

Liraglutide

1.2–1.8 mg subcutaneously once a day

24 hours

Lixisenatide

10 mcg or 20 mcg subcutaneously once a day

24 hours

Semaglutide

0.25 mg, 0.5 mg, or 1 mg subcutaneously once a week

7 days

Amylin analog

Pramlintide

For type 1 diabetes mellitus: 30–60 mcg subcutaneously before meals

For type 2 diabetes mellitus: 120 mcg subcutaneously before meals

2–4 hours

For use in combination with insulin, but injected using a separate syringe

May need to adjust insulin dose to avoid hypoglycemia

Nausea common but declining with time

May promote modest weight loss

Adjunctive Drug Therapy for Diabetes

Pharmacologic measures to prevent or treat complications of diabetes mellitus (1, 2) are critical, including

  • Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)

  • Aspirin

  • Statins

ACE inhibitors or ARBs are indicated for patients with evidence of early diabetic nephropathy (albuminuria), even in the absence of hypertension, and are a good choice for treating hypertension in patients who have diabetes mellitus and who have not yet shown renal impairment.

ACE inhibitors also help prevent cardiovascular events in patients with diabetes mellitus.

Aspirin 81 to 325 mg once a day provides cardiovascular protection. Aspirin is recommended for secondary prevention in patients with a history of atherosclerotic cardiovascular disease (ASCVD). The benefits of aspirin in patients without established cardiovascular disease (ie, for primary prevention) are less clear. Aspirin might be considered for primary prevention in patients ≥ 50 years of age, with at least one additional risk factor for ASCVD who are not at increased risk for bleeding. In patients >70 years, bleeding risk may outweigh benefits of primary prevention.

Statins are currently recommended by the American Heart Association/American College of Cardiology guidelines for all diabetic patients 40 to 75 years of age. Moderate- to high-intensity treatment is used, and there are no target lipid levels (see table Statins for ASCVD Prevention in Dyslipidemia). For patients < 40 or > 75, statins are given based upon individual assessment of the risk:benefit ratio and patient preference. Patients with type 2 diabetes mellitus tend to have high levels of triglycerides and small, dense low-density lipoproteins (LDL) and low levels of HDL; they should receive aggressive treatment.

Adjunctive drug therapy references

  • 1. Fox CS, Golden SH, Anderson C, et al: AHA/ ADA Scientific Statement: Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence. Circulation 132: 691–718, 2015.

  • 2. Garber AJ, Handelsman Y, Grunberger G, et al: Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm--2020 executive summary. Endocrine Practice 26:107–139, 2020.

More Information

Drugs Mentioned In This Article

Drug Name Select Trade
DIABINESE
FARXIGA
INVOKANA
Ertugliflozin
PARLODEL
JARDIANCE
AVANDIA
Lixisenatide
ACTOS
PRANDIN
VICTOZA
AMARYL
TRADJENTA
TANZEUM
No US brand name
SYMLIN
ADRENALIN
ONGLYZA
Semaglutide
JANUVIA
TRULICITY
STARLIX
NESINA
GLUCOPHAGE
GLUCOTROL
BYETTA
DIABETA, GLYNASE
PRECOSE
GLYSET
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