Medications for Diabetes Mellitus Treatment

Most insulin preparations are recombinant human, mostly eliminating the once-common allergic reactions to the medication when it was extracted from animal sources. A number of analogs are also 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 ). 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 insulinsinsulin 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.

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 insulin isophane, 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 insulin isophane and regular insulin and of insulin lispro and lispro protamine (a form of lispro modified to act like insulin isophane) are commercially available in premixed preparations (see table ). Other premixed formulations include aspart protamine (a form of aspart modified to act like insulin isophane) 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" or "connected" insulin pens and pen caps 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). 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 pump therapy is the use of continuous glucose monitoring (CGM) in conjunction with an insulin pump. Several systems are available, in which glucose sensor data is communicated to an insulin pump and an algorithm adjusts insulin delivery through the pump. Systems with "low-glucose suspend" algorithms can stop insulin delivery when the sensor detects that glucose is low or is predicted to go low.

Hybrid closed-loop insulin delivery systems, or automated insulin delivery (AID) systems, are more sophisticated systems in which an algorithm calculates and adjusts the basal insulin dose based on CGM sensor input, which is then delivered by the connected insulin pump (2).

The available systems still require user input for mealtime bolus doses. There are several "fully closed-loop" systems being investigated, in which the pump automatically calculates both basal and bolus insulin doses with little to no input from the user. A new closed-loop system that uses meal announcements, rather than carbohydrate counting has been developed recently.

The most common complication is

• Hypoglycemia

Uncommon complications include

• Hypokalemia

• 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 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 medications (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 treatedglucagon 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 more commonly occurs in acute care settings when body potassium 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 insulininsulin 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 loss of subcutaneous adipose tissue, 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 and can be treated with corticosteroids.

Circulating anti-insulin antibodies are a very rare cause of insulin resistance in patients taking animal insulin and sometimes in those taking 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, 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. Patients with obesity 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 insulininsulin). 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.

Regimens for type 2 diabetes mellitus also vary. In many patients, glucose levels are adequately controlled with lifestyle changes and non-insulin antihyperglycemic medications, but insulin should be added when glucose remains inadequately controlled by ≥ 3 medications, 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 medications.

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.

1. 1. Kravarusic J, Aleppo G: Diabetes Technology Use in Adults with Type 1 and Type 2 Diabetes. Endocrinol Metab Clin North Am 49(1):37–55, 2020. doi: 10.1016/j.ecl.2019.10.006

2. 2. Renard EActa Diabetol 2023;60(2):151-161. doi:10.1007/s00592-022-01929-5

3. 3. Grunberger G, Sherr J, Allende M, et al. American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus. Endocr Pract 2021;27(6):505-537. doi:10.1016/j.eprac.2021.04.008

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 >

Hypoglycemia caused by long-acting medications 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 medications 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 medications used to treat it.

Short-acting insulininsulin secretion in a manner similar to sulfonylureas. They are faster acting, however, and may stimulate insulin

Biguanides (metformin) lower plasma glucose by decreasing hepatic glucose production (gluconeogenesis and glycogenolysis). They are considered peripheral insulininsulin. In addition, metformin does not cause weight gain and may even promote weight loss by suppressing appetite. However, the medication 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.

lactic acidosis is very rare, but the medication 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 medication should be withheld during surgery, administration of IV contrast, and any serious illness. Many people receiving metformin monotherapy eventually require an additional medication.

insulin resistance (insulin sensitizers). The medications bind a nuclear receptor primarily present in fat cells (peroxisome-proliferator-activated receptor-gamma [PPAR-γmetabolic associated steatotic liver disease (MASLD; formerly nonalcoholic fatty liver disease [NAFLD]).

Though one TZD (troglitazone) caused acute liver failure, currently available medications 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 (>heart failure, angina, myocardial infarction, strokebladder cancer (although data are conflicting), heart failure, and fractures.

insulin.

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.

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 ketoacidosis1).

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.

1. 1. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377(7):644-657. doi:10.1056/NEJMoa1611925

GLP-1 receptor agonists mimic the effects of GLP-1, a peptide made in the small intestine that enhances glucose-dependent insulin

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.

insulin secretion, decreases glucagon secretion, and slows gastric emptying. It also decreases appetite and induces weight loss.

The amylinglucagon 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.

1. 1. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes [published correction appears in N Engl J Med 2020 Feb 6;382(6):586]. N Engl J Med 2019;381(7):603-613. doi:10.1056/NEJMoa1902226

2. 2. Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med 2021;13(583):eabc8980. doi:10.1126/scitranslmed.abc8980

1. 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. 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.

3. 3. Grundy SM, Stone NJ, Bailey AL, et al: 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 73(24):3168–3209, 2019. doi: 10.1016/j.jacc.2018.11.002

4. 4. American Diabetes Association: Standards of Medical Care in DiabetesDiabetes Care 46 (Supplement 1): 1-291, 2023.