Drug Treatment of Diabetes Mellitus

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:

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.

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がんま]) 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 HbA_1c. 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 Hb_A1c 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.

Bromocriptine is a dopamine agonist that lowers HbA_1c about 0.5% by an unknown mechanism. Although approved for type 2 diabetes, it is not commonly used because of potential adverse effects.

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.