endocrine and metabolic disorders
Medications for Diabetes Mellitus Treatment
Insulin
 (due to destruction of the pancreatic beta-cells) and will develop Diabetic Ketoacidosis (DKA) without it. Insulinreplacement in type 1 diabetes should ideally mimic beta-cell function to provide basal and prandial requirements (physiologic replacement or basal-bolus dosing). To achieve this, different preparations ofinsulinand methods of administration can be used. , which is given IV in Hospitalization , Insulinis typically administered as either: Multiple daily subcutaneous injections administered by the patient, with 2 preparations ofinsulinused depending on the anticipated glycemic control needs Aninsulinpump that delivers a rapid- or short-actinginsulinand administers a basal rate ofinsulinand additional boluses with meals or for correcting a high blood glucose level Both strategies require close attention to diet and exercise as well as toinsulintiming and dose. Wheninsulinis needed for patients with type 2 diabetes, glycemic control can often be achieved with basalinsulincombined with non-insulinantihyperglycemic medications, although some patients may require prandialinsulin. Mostinsulinpreparations 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 humaninsulinmolecule to alter absorption rates and duration and time to action. Insulintypes 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 theinsulinmolecule from associating into dimers and polymers. They begin to reduce plasma glucose often within 15 minutes but have short duration of action (<4 hours). Theseinsulinsare best used at mealtime to control postprandial spikes in plasma glucose. Inhaledregular insulinis a rapid-actinginsulinthat is taken with meals. It has a slightly more rapid onset of action compared to subcutaneously injected rapid-actinginsulinbut dosing is less flexible, and periodic pulmonary examinations are required. Regular insulinis slightly slower in onset (30 to 60 minutes) than lispro and aspart but lasts longer (6 to 8 hours). It is the onlyinsulinform for IV use. Intermediate-acting insulinsincludeinsulinisophane (NeutralprotamineHagedorn, or NPH) and U-500 regular. The onset of action forinsulinisophane 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 regularinsulinU-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 asinsulinglargine,insulindetemir, and U-300insulinglargine, unlikeinsulinisophane, have no discernible peak of action and provide a steady basal effect over 24 hours.Insulindegludec (another long-actinginsulin) 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. Combinationsofinsulinisophane and regularinsulinand ofinsulinlispro and lisproprotamine(a form of lispro modified to act likeinsulinisophane) are commercially available in premixed preparations (see table). Other premixed formulations include aspartprotamine(a form of aspart modified to act likeinsulinisophane) withinsulinaspart and a formulation of premixed degludec and aspart. Differentinsulintypes can be drawn into the same syringe for injection but should not be premixed in bottles except by a manufacturer. On occasion, mixinginsulinsmay affect rates ofinsulinabsorption, producing variability of effect and making glycemic control less predictable, especially if mixed>1 hour before use.Insulinglargine should never be mixed with any otherinsulin. Many prefilledinsulinpen devices are available as an alternative to the conventional vial and syringe method.Insulinpens 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"insulinpens and pen caps communicate with a smart phone application to track administeredinsulinand make dosing recommendations. pump ( Insulin references ). In people with Sensor-augmented pump therapy is the use of Continuous glucose monitoring (CGM) in conjunction with an pump ( Insulin references ). 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 bolusinsulindoses 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. Themost common complicationis Hypoglycemia None Uncommon complicationsinclude Hypokalemia None Local allergic reactions Generalized allergic reaction Local fat atrophy or hypertrophy Circulating anti-insulinantibodies Hypoglycemiais the most common complication ofinsulintreatment, 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 withinsulinor 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. Treatment with the administration of a form of sugar (oral glucose or sucrose or IV Hyperglycemiamay result from too high a bedtimeinsulindose, 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 eveninginsulindose should be increased, changed to a longer-acting preparation, or injected later. -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 Local allergic reactionsat the site ofinsulininjections are rare, especially with the use of humaninsulins, 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 reactionis extremely rare with humaninsulinsbut can occur wheninsulinis 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, butepinephrineand IV glucocorticoids may be needed. Ifinsulintreatment is needed after a generalized allergic reaction, skin testing with a panel of purifiedinsulinpreparations and desensitization should be done. Local fat hypertrophy,or lipohypertrophy, is a common reaction caused by the lipogenic effect ofinsulin. Lipohypertrophy can lead to variability ofinsulinabsorption 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 ofinsulinpreparation. It has become very rare with the use of humaninsulinsand can be treated with corticosteroids. Circulating anti-insulinantibodiesare a very rare cause ofinsulinresistance in patients taking animalinsulinand sometimes in those taking human and analoginsulins.Insulinresistance due to circulating anti-insulinantibodies can sometimes be treated by changinginsulinpreparations (eg, from animal to humaninsulin) 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-actinginsulins) 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-actinginsulin) or aninsulinpump. injections a day with or without monitoring) for preventing Diabetic Retinopathy , In general, most patients with type 1 diabetes mellitus can start with a total dose of 0.2 to 0.8 units ofinsulin/kg/day. Patients with obesity may require higher doses. Physiologic replacement involves giving 40 to 60% of the dailyinsulindose 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-actinginsulinis adjusted for preprandial blood glucose level and anticipated meal content. A correction factor, also known as theinsulinsensitivity factor, is the amount that 1 unit ofinsulinwill lower a patient's blood glucose level over 2 to 4 hours; this factor is often calculated using the "1800 rule" when rapid-actinginsulinis used for correction (1800/total daily dose ofinsulin). For regularinsulin, a "1500 rule" can be used. A correction dose (current glucose level - target glucose level/ correction factor) is the dose ofinsulinthat will lower the blood glucose level into the target range. This correction dose can be added to the prandialinsulindose that is calculated for the number of carbohydrates in a meal, using the carbohydrate-to-insulinratio (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 ofinsulin: 30 units basalinsulin+10 units bolusinsulinper meal=60 units total, daily Correction factor (insulinsensitivity 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:insulinratio (CIR): 500/60=8:1 Target glucose: 120 mg/dL (6.7 mmol/L) Prandialinsulindose=50 g carbohydrate divided by 8 g/unitinsulin=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-actinginsulin 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-insulinratio (CIR) and sensitivity factors need to be fine-tuned and changed according to how the patient responds toinsulindoses. 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-insulinantihyperglycemic medications, butinsulinshould be added when glucose remains inadequately controlled by≥3 medications, if the patient is suspected of havinginsulindeficiency, 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,insulinshould replace non-insulinantihyperglycemic medications. The rationale for combination therapy is strongest for use ofinsulinwith oral biguanides andinsulinsensitizers. Regimens vary from a single daily injection of long- or intermediate-actinginsulin(usually at bedtime) to the multiple-injection regimen used by patients with type 1 diabetes. In general, the simplest effective regimen is preferred. Because ofinsulinresistance, 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.Kravarusic J, Aleppo G: Diabetes Technology Use in Adults with Type 1 and Type 2 Diabetes.Endocrinol Metab Clin North Am49(1):37–55, 2020. doi: 10.1016/j.ecl.2019.10.006 2.Renard E. Automatedinsulindelivery systems: from early research to routine care of type 1 diabetes.Acta Diabetol2023;60(2):151-161. doi:10.1007/s00592-022-01929-5 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 Pract2021;27(6):505-537. doi:10.1016/j.eprac.2021.04.008 