Drug Treatment of Diabetes Mellitus

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 to alter 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 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).

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 rapid-acting insulin that is taken with meals. It has a slightly more rapid onset of action compared to subcutaneously injected rapid-acting insulin but dosing is less flexible and periodic pulmonary examinations are required.

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.

Intermediate-acting insulins include insulin isophane (Neutral protamine Hagedorn, or NPH) and U-500 regular. The onset of action for insulin isophane 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, such as 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 lispro protamine (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 Onset, Peak, and Duration of Action of Human Insulin Preparations* ). Other premixed formulations include aspart protamine (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. "Smart" insulin pens communicate with a smart phone application to track administered insulin and make dosing recommendations.

Lispro or aspart can also be given continuously using an insulin pump (1) Insulin pumps reference General treatment of diabetes mellitus for all patients involves lifestyle changes, including diet and exercise. Appropriate monitoring of blood glucose levels is essential to prevent complications... read more . In people with insulin resistance, higher concentration U500 is sometimes used. 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, hybrid closed-loop insulin delivery systems, also known as automated insulin delivery systems, are available. 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 Monitoring Diabetes Treatment Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more and an internal algorithm. The available systems still require user input for mealtime 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 or when blood glucose is not appropriately monitored. 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 stroke-like symptoms of aphasia or hemiparesis and is more likely to precipitate stroke, myocardial infarction, and sudden death.

Patients should be taught to recognize symptoms of hypoglycemia. Patients with type 1 diabetes mellitus of long duration may be unaware of hypoglycemic episodes because they no longer experience autonomic symptoms (hypoglycemia unawareness).

In patients treated with insulin or glucose-lowering drugs (eg, sulfonylureas), a blood glucose level < 70 mg/dL (< 3.9 mmol/L) is considered hypoglycemia and should be treated to avoid further decreases in glucose level and consequences of hypoglycemia. Symptoms of hypoglycemia usually respond rapidly to the ingestion of sugar.

Hypoglycemia is treated Treatment Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation, and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic... read more with the administration of a form of sugar (oral glucose or sucrose or IV dextrose) and/or glucagon or dasiglucagon. Patients at risk for hypoglycemia should have glucagon or dasiglucagon at home and elsewhere, and household members and trusted others should be instructed on management of hypoglycemic emergencies.

Hyperglycemia may result from too high a bedtime insulin dose, which 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 Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more 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 hypertrophy, or lipohypertrophy, is a common reaction caused by the lipogenic effect of insulin. Lipohypertrophy can lead to variability of insulin absorption and can be avoided by rotating injection sites. Lipoatrophy, a different entity, is thought to result from an immune reaction to a component of insulin preparation. It has become very rare with the use of human insulins but can be treated with steroids.

Circulating anti-insulin antibodies are a very rare cause of insulin resistance in patients still taking animal insulin and sometimes in those on human and analog insulins. Insulin resistance due to circulating anti-insulin antibodies can sometimes be treated by changing insulin preparations (eg, from animal to human insulin) and by administering corticosteroids or immunosuppressants and sometimes plasmapheresis if necessary.

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 Diabetic Retinopathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular)... read more , nephropathy Diabetic Nephropathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular)... read more , and neuropathy Diabetic Neuropathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular)... read more . 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:

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.

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, if the patient is suspected of having insulin deficiency, or the blood sugar level is very high. 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.

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 Hypoglycemia Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation, and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic... read more . 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 Syndrome of Inappropriate ADH Secretion (SIADH) The syndrome of inappropriate ADH (vasopressin) secretion is defined as less than maximally dilute urine in the presence of serum hypo-osmolality, in patients with normal adrenal, thyroid, renal... read more . 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 (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 (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 due to their hepatic effects. Biguanides also lower lipid levels and may also decrease gastrointestinal nutrient absorption and increase beta-cell sensitivity to circulating glucose. 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 Lactic Acidosis Lactic acidosis is a high anion gap metabolic acidosis due to elevated blood lactate. Lactic acidosis results from overproduction of lactate, decreased metabolism of lactate, or both. (See also... read more 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 (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 Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more (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 Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more 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 Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more , angina Angina Pectoris Angina pectoris is a clinical syndrome of precordial discomfort or pressure due to transient myocardial ischemia without infarction. It is typically precipitated by exertion or psychologic stress... read more , myocardial infarction Acute Myocardial Infarction (MI) Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and/or diaphoresis... read more , stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more , and fracture. Pioglitazone may increase the risk of bladder cancer Bladder Cancer Bladder cancer is usually transitional cell (urothelial) carcinoma. Patients usually present with hematuria (most commonly) or irritative voiding symptoms such as frequency and/or urgency; later... read more (although data are conflicting), heart failure, and fractures.

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 (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 Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more 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 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugiflozin) 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 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 adverse effects are genitourinary infections, especially mycotic infections. Orthostatic symptoms can also occur. SGLT-2 inhibitors can cause diabetic ketoacidosis Diabetic Ketoacidosis (DKA) Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. Hyperglycemia causes an osmotic diuresis with... read more (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. Diagnosis euglycemic DKA from SGLT-2 inhibitors is often delayed due to lower blood sugars. One large study showed an increase in lower limb amputation with canagliflozin.

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.

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. All GLP-1 agonists are given as subcutaneous injections, and semaglutide is also available in oral form. 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 Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more . They are contraindicated in patients with a personal or family history of medullary thyroid cancer Medullary Thyroid Carcinoma There are 4 general types of thyroid cancer. Most thyroid cancers manifest as asymptomatic nodules. Rarely, lymph node, lung, or bone metastases cause the presenting symptoms of small thyroid... read more because an increased risk of this cancer has occurred in tested rodents.

Tirzepatide is the first GIP/ GLP1 receptor agonist available for treatment of type 2 diabetes. It is a peptide that acts as a receptor agonist for the GIP and GLP1 receptors. GIP and GLP-1 are incretins that are produced in the small intestine. Tirzepatide increases glucose-dependent insulin secretion, decreases glucagon secretion, and slows gastric emptying. It also decreases appetite and induces weight loss.

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.