- Oral Antihyperglycemic Drugs
- Injectable Antihyperglycemic Drugs
- Adjunctive Drug Therapy for Diabetes
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Drug Treatment of Diabetes Mellitus
(See also Diabetes Mellitus.)
General treatment for all patients with diabetes mellitus (DM) involves lifestyle changes, including diet and exercise. Regular monitoring of blood glucose levels is essential to prevent complications of diabetes.
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, renin-angiotensin-aldosterone system (RAAS) blockers (ACE inhibitors or angiotensin II receptor blockers), statins, and aspirin often are given to prevent complications.
Insulin is required for all patients with type 1 DM if they become ketoacidotic without it; it is also helpful for management of many patients with type 2 DM.
Insulin replacement in type 1 DM should ideally mimic beta-cell function using 2 insulin types to provide basal and prandial requirements (physiologic replacement); 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 DM, glycemic control can often be achieved with basal insulin combined with non-insulin anti-hyperglycemic 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. Recently, an inhaled insulin preparation has also become available.
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).
Onset, Peak, and Duration of Action of Human Insulin Preparations*
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 min but have short duration of action (< 4 h). 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 min) than lispro and aspart but lasts longer (6 to 8 h). 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 h after injection, peak effect is 4 to 12 h after injection, and duration of action is 18 to 26 h. Concentrated regular insulin U-500 has a similar peak and duration of action (peak 4 to 8 h; duration 13 to 24 h) 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 h. Insulin degludec (another long-acting insulin) has an even longer duration of action of over 40 h. 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 h 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.
Lispro, aspart, or regular insulin can also be given continuously using an insulin pump. 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. The first hybrid, closed-loop insulin delivery system is now available. A closed loop system or "artificial pancreas" is one in which an algorithm is used to calculate and automatically deliver insulin doses through an insulin pump, based on input from a continuous glucose monitor. The approved system still requires input from the user for bolus doses.
The most common complication is
Uncommon complications include
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 min 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 sc or IM 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 min to 2 h 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.
Regimens range from twice/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/day and ≥ 3 injections/day or continuous insulin infusion, is more effective than conventional treatment (1 to 2 insulin injections daily 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 ration (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
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
Estimated carbohydrate content of upcoming meal: 50 g
Carbohydrate:insulin ratio (CIR): 500/60 = 8:1
Target glucose: 120 mg/dL
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
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 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.
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 DM may be the cause. Insulin should replace non-insulin antihyperglycemic drugs in women who become pregnant. 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 DM. In general, the simplest effective regimen is preferred. Because of insulin resistance, some patients with type 2 DM 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 (see Table: Characteristics of Oral Antihyperglycemics and see Table: Combination Oral Antihyperglycemics by Class) are a mainstay of treatment for type 2 diabetes mellitus, along with glucagon-like peptide-1 (GLP-1) receptor agonists. Insulin is often added when ≥ 3 drugs fail to provide adequate glycemic control. Oral antihyperglycemic drugs may
Drugs with different mechanisms of action may be synergistic.
Characteristics of Oral Antihyperglycemics
Combination Oral Antihyperglycemics by Class
Sulfonylureas (SUs) 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 drugs (see Table: Combination Oral Antihyperglycemics by Class) are more likely to cause adverse effects and are used infrequently. All SUs 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 SUs alone eventually require additional drugs to achieve normoglycemia, suggesting that SUs 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 (repaglinide, nateglinide) stimulate insulin secretion in a manner similar to SUs. 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 SUs. Patients who have not responded to other oral drug classes (eg, SUs, metformin) are not likely to respond to these drugs.
Biguanides 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 GI 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 SUs 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 GI 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, alcoholism, 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 (TZDs) 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 HDL levels, lower triglycerides, and may have anti-inflammatory and anti-atherosclerotic effects. TZDs are as effective as SUs and metformin in reducing HbA1c. TZDs may be beneficial in treatment of non-alcoholic 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 (AGIs) competitively inhibit intestinal enzymes that hydrolyze dietary carbohydrates; carbohydrates are digested and absorbed more slowly, thereby lowering postprandial plasma glucose. AGIs 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 (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. There is a slight increase in risk for pancreatitis with DPP-4 inhibitors, but they are otherwise considered safe and well-tolerated. The HbA1c decrease is modest with DPP-4 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. Empagliflozin was shown to decrease cardiovascular events in diabetic patients at high risk for cardiovascular disease.
The most common side effects are genitourinary infections, especially mycotic infections. Orthostatic symptoms can also occur. There have been reports of diabetic ketoacidosis in patients with both type 1 DM and type 2 DM.
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.
GLP-1 agonists (exenatide [an incretin hormone], liraglutide, dulaglutide, albiglutide) enhance glucose-dependent insulin secretion and slow gastric emptying. GLP-1 agonists may also reduce appetite and promote weight loss and stimulate beta-cell proliferation. Formulations are available for dosing twice/day, once/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.
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 sc before meals, and those with type 2 diabetes are given 120 mcg.
Characteristics of Injectable Non-Insulin Antihyperglycemic Drugs
ACE inhibitors or angiotensin II receptor blockers 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/day provides cardiovascular protection and should be used by most adults with DM in the absence of a specific contraindication.
Statins are currently recommended by the American Heart Association/American College of Cardiology guidelines for all diabetic patients 40 to 75 yr of age. Moderate to high intensity treatment is used, and there are no target lipid levels. 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 with the same treatment goals as those of patients with known coronary artery disease (LDL < 100 mg/dL [< 2.6 mmol/L], HDL > 40 mg/dL [> 1.1 mmol/L], and triglycerides < 150 mg/dL [< 1.7 mmol/L]).
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. Circulation132: 691–718, 2015.