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Treatment Approach to Patients With Severe Resistance Timothy J. Church1 and Stuart T. Haines2 FEATURE ARTICLE ■ IN BRIEF Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause , which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin.

n increasing number of pa- require >1 unit/kg/day are considered tients have severe insulin resis- to have insulin resistance, and those Atance and require large doses requiring >2 units/kg/day have severe of insulin. Managing patients with resistance (3). Alternatively, a total severe insulin resistance is challenging daily insulin dose of >200 units is because it is difficult to achieve good commonly considered to be evidence glycemic control using conventional of severe insulin resistance. Large total treatment approaches (1). Moreover, daily dose requirements create practi- weight gain, , regimen cal problems with regard to insulin complexity, and cost are frequent con- delivery because 1) a large volume of cerns as insulin doses escalate. standard U-100 insulin can be pain- Insulin resistance is characterized ful to administer and 2) the onset and by an impaired response to either duration of insulin activity can be endogenous or exogenous insulin (2). altered with high-volume doses (4). Although insulin resistance is a com- Evaluating Patients mon feature of type 2 , cases There are several known causes of of severe insulin resistance remain severe insulin resistance, including relatively uncommon but are likely several rare disorders and genet- increasing as the prevalence of dia- ic conditions (Table 1) (3). Several betes and surges. The degree medications are known to contribute 1West Palm Beach Veteran’s Administration of insulin resistance can be measured Medical Center, West Palm Beach, FL to insulin resistance, including gluco- using the euglyemic insulin clamp corticoids, protease inhibitors, atyp- 2University of Maryland School of Pharmacy, Department of Pharmacy Practice and technique, but this is not a clinically ical antipsychotics, and calcineurin Science, Baltimore, MD useful method of determining whether inhibitors. In patients with severe Corresponding author: Stuart T. Haines, a patient has severe insulin resistance insulin resistance, an effort should be [email protected] in practice (3). The most widely made to discontinue such agents or DOI: 10.2337/diaclin.34.2.97 reported and clinically useful defini- switch to alternative medications if tions of severe insulin resistance are possible (5). ©2016 by the American Diabetes Association. Readers may use this article as long as the work based on exogenous insulin require- Poor medication-taking behaviors is properly cited, the use is educational and not ments using either the number of units or “pseudoresistance” should be ruled for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 per kilogram of body weight per day out before modifying or intensifying for details. or the total daily dose (1). Patients who therapy. Pseudoresistance may be the

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TABLE 1. Causes of Severe equal to what an average person with and clinical trials comparing these Insulin Resistance (3) diabetes might require (insulin dose products to U-500 insulin have not [units] = blood [mg/dL] – 100 been conducted. Although they are Syndromes of severe insulin × resistance / (1,500 / weight [kg] 1.0)] should two to three times more concentrated • Type A, due to defects in the be given. If there is not an appropri- than U-100 insulin, U-300 insulin gene ate drop in blood glucose within 4 glargine and U-200 insulin lispro can • Type B, due to insulin receptor hours, a second dose should be given. only deliver a maximum of 80 and antibodies If normoglycemia or hypoglycemia 60 units per injection, respectively. • Type C, cause unknown is not achieved after either dose, the They do offer the theoretical advan- (also known as HAIR-AN test confirms that a patient likely has tage of providing a dose of insulin in [Hyperandrogenism, Insulin severe insulin resistance. a smaller injection volume than would Resistance, and ] syndrome) Pharmacological Treatment be required with U-100 (8,9). Similar to U-100 regular insulin, Medications Options the onset of activity for U-500 regular • There are currently no guidelines or insulin is ~30–45 minutes. However, • Atypical antipsychotics consensus statements describing how the time to peak activity (4–6 hours) • Calcineurin inhibitors best to treat patients with severe in- and duration of action (12–14 hours) • Protease inhibitors sulin resistance. Until recently, insu- for U-500 is most similar to NPH • Oral contraceptives lin was the only therapy available to insulin (6). treat those with severe insulin resis- Endocrine disorders In several crossover studies in tance. Despite the use of high doses • Acromegaly which patients with severe insulin of insulin, however, many patients • Glucagonoma resistance were switched from U-100 do not reach their glycemic targets • Thyrotoxicosis insulin products to U-500 regular • Cushing’s syndrome and are hampered by undesirable insulin, significant improvements in • Pheochromocytoma adverse effects such as hypoglycemia glycemic control have been observed and weight gain. To mitigate some of Anti-insulin antibodies (10–18). An analysis of nine studies these challenges, several new thera- HIV-associated (n = 310 patients) found that U-500 pies have emerged and can be used in reduced mean A1C by 1.59% (95% CI Physiological causes combination with insulin. • Severe stress 1.26–1.92) in patients who previously ❍❍ Trauma Concentrated Insulin Products used a multiple daily injection (MDI) ❍❍ Sepsis Concentrated insulin products can regimen with various U-100 insulin ❍❍ Surgery help improve the delivery of insulin products. At baseline, these patients ❍❍ when very large doses are needed. had an A1C between 9.1 and 11.3% • Pregnancy U-500 insulin is five times more con- and a total daily insulin requirement • Puberty centrated than standard U-100 insu- of 219–391 units. They were followed Pseudoresistance lin and is considered the cornerstone for 6–36 months. Weight gain was • Poor administration technique of therapy for most patients with se- a substantial problem, with a mean • Incorrect storage of insulin vere insulin resistance (6). When dai- increase of 4.4 kg (95% CI 2.4–6.4) • Malingering for secondary gain ly insulin doses exceed 200 units/day, in body weight. The mean total daily the volume of U-100 insulin needed insulin dose increased by 52 units makes insulin delivery challenging. (95% CI 20–84) (19). U-500 insulin result of nonadherence, poor injec- Available insulin syringes can deliver delivered by continuous subcutaneous tion technique, improper insulin a maximum of 100 units, and insulin insulin infusion (CSII) is a potential storage, or malingering for secondary pen devices can deliver only 60–80 option. In one study, U-500 delivered gain. Pseudoresistance can be ruled units per injection. In addition, the via CSII reduced mean A1C by 1.1% out by conducting a modified insu- administration of doses >1 mL in (P = 0.026) in a cohort of patients lin tolerance test (3). During such a volume can be painful and may alter with severe insulin resistance who test, patients are administered a wit- insulin absorption (7). were switched from a variety of insu- nessed dose of short-acting insulin Two new concentrated insulin lin regimens, including U-500 insulin in the clinic, and their blood glucose pen products are now available in the via MDI (20). is monitored every 30 minutes for a United States—U-200 insulin lispro The risk of severe hypoglycemia period of 4–8 hours. Patients should and U-300 insulin glargine. There is does not appear to increase when be for the test and should have no reported experience using these patients are switched from U-100 to a blood glucose level >150 mg/dL. A new concentrated insulin products in U-500 insulin (6,19). However, some witnessed insulin dose approximately patients with severe insulin resistance, studies have reported an increase in

98 CLINICAL.DIABETESJOURNALS.ORG c h u r c h a n d h a i n e s mild hypoglycemic events, defined meal. One of the biggest drawbacks tial pharmacological option for most as symptomatic episodes that did not to using U-500 insulin is the poten- people with . It has a require assistance (13,15). One retro- tial for dosing errors that can lead to strong record of safety and efficacy, spective study reported an increase severe hypoglycemia, coma, or death. as well as a favorable effect on weight in the frequency of mild hypoglyce- Clear communications between the (22). Although it is common practice mic episodes only during the first 3 prescriber, pharmacist, and patient to combine with insulin, months after transitioning to U-500 are crucial. When prescribing and metformin use has not been specifi- insulin (13). dispensing U-500 regular insulin, cally evaluated in the setting of severe When transitioning a patient the dose should be expressed in both insulin resistance. from U-100 to U-500 insulin, the units and volume (mL) to be adminis- In most studies of U-500 regular insulin, patients have been permitted dose and dosing frequency should tered. To minimize the risk of errors, to continue metformin use (6,23,24). be determined based on the patient’s a 0.5–1 mL tuberculin syringe with a In patients who do not have severe current A1C and total daily insulin 29-gauge or higher needle should be

insulin resistance, metformin use FEATURE ARTICLE dose. Dosing algorithms have not yet used to administer each dose—not a U-100 insulin syringe (6,21). reduces insulin requirements and has been prospectively evaluated (Figure a positive impact on glycemic control 1); nonetheless, they have been widely Metformin and weight. A meta-analysis of 26 ran- used. In general, U-500 should be The American Diabetes Association domized, controlled trials assessed the given at least 30 minutes before a recommends metformin as the ini- effects of metformin plus insulin versus insulin alone. Metformin combined with insulin resulted in a significant reduction in A1C (mean difference –0.60%, P <0.001) and lower insulin requirements (mean difference –18.9 units/day, P <0.001) when compared to insulin therapy alone. Moreover, weight gain was mitigated with combi- nation therapy (mean difference –1.68 kg, P <0.001). The largest study con- ducted to date combining metformin with insulin therapy is the HOME (: the Outcome of its Metabolic Effects) study (25). The HOME study randomized 390 patients with type 2 diabetes currently using basal-bolus insulin regimens to either metformin titrated to 850 mg three times daily or placebo. At base- line, patients’ mean total daily insulin dose was ~70 units, mean A1C was 7.8%, and mean body weight was 86 kg. At the end of the 16-week treat- ment period, those in the metformin group had a significant reduction in A1C of 0.9% compared to 0.3% in the placebo group (P <0.0001). Total mean daily insulin requirements were reduced by ~10% (7.2 units) from baseline in the metformin group (P <0.0001), along with a small but statistically significant reduction in weight of 0.4 kg (P <0.0001). Metformin is known to cause gas- n FIGURE 1. U-500 regular insulin initial dosing recommendations (6,55). trointestinal (GI) side effects, which can lead to discontinuation of ther-

VOLUME 34, NUMBER 2, SPRING 2016 99 FEATURE ARTICLE apy (26). This typically manifests as have sparked interest in using GLP- requiring assistance in any subjects diarrhea and less commonly as nausea 1 receptor agonists in patients with during the study. or abdominal cramping (22,26). One severe insulin resistance (23,24). In another small, open-label, pro- option to mitigate these effects is to In one recent, prospective, spective study, 30 obese patients with use the extended-release formulation open-label study, 37 obese patients type 2 diabetes treated with U-100 of metformin, which has been shown using basal-bolus insulin with total insulin and requiring >200 units/ to reduce the frequency of any GI daily insulin requirements >100 day of insulin were randomized to side effects, including diarrhea (27). units/day and a baseline A1C >6.5% U-500 insulin or U-500 plus exen- atide titrated to 10 μg twice daily (34). Use of metformin in the setting were randomized to receive either All patients in both treatment groups of mild to moderate renal impair- liraglutide titrated to 1.8 mg/day or ment is controversial. The potential also received metformin in doses of continued uptitration of their insu- risk of lactic acidosis appears to be 1,700–2,550 mg/day. Baseline A1C lin doses (24). Seventeen patients negligible in the absence of other risk (9.2 vs. 8.7%), weight (118 vs. 119 kg), factors. Current U.S. Food and Drug were using U-500 insulin at baseline. and total daily insulin dose (237 vs. Administration (FDA)-approved Mean baseline A1C (7.8%) was sim- 253 units) were reasonably similar labeling for metformin still recom- ilar in the two groups, but the mean in the two groups. After 6 months mends against using metformin in total daily insulin dose was greater of treatment, there were significant men with a serum creatinine ≥1.5 mg/ in the liraglutide group (199 vs. 171 improvements in glycemic control in dL and in women with a serum cre- units/day) and baseline weight was both groups compared to baseline, atinine ≥1.4 mg/dL (28). However, greater in the insulin treatment group but there was no difference in the a Cochrane review including 347 (112 vs. 131 kg). At 6 months, both between-group comparison (P = 0.80). studies concluded that the incidence groups had statistically significant There was a slight but nonsignificant of lactic acidosis was 4.3 cases per improvements in A1C compared to mean in the exenatide 100,000 patient-years in those treated baseline. However, the A1C reduc- group (–0.4 kg) and a slight but non- with metformin compared to 5.4 cases tion was significantly greater in the significant mean weight gain (3.6 kg) per 100,000 patients for those not liraglutide treatment group than in in the U-500 insulin-only group compared to baseline, with a between- treated with metformin (29). Several the insulin treatment group (mean group difference (4.0 kg) that was organizations, including the American A1C at 6 months 7.14 vs. 7.40%, not statistically different at 6 months Geriatric Society, and the KDIGO P = 0.047). Moreover, time spent in (Kidney Disease: Improving Global (P = 0.07). Similarly, total daily insu- the euglycemic range (blood glucose lin doses were slightly lower in the Outcomes) guidelines now advocate 70–180 mg/dL) based on continuous for continued metformin use as long U-500 insulin (–7 units/day) and glucose monitoring increased from as a patient’s estimated glomerular fil- exenatide (–27 units) treatment groups 57% of the time at baseline to 75% tration rate is >30 mL/min (30,31). at 6 months compared to baseline, but of the time at 6 months in the lira- the within- and between-group differ- Glucagon-Like Peptide 1 glutide group. The liraglutide group ences were not statistically significant. Receptor Agonists experienced significant weight loss None of the patients experienced Glucagon-like peptide 1 (GLP-1) re- (–5.3 kg, P <0.001) compared to a severe hypoglycemia requiring assis- ceptor agonists stimulate the GLP-1 nonsignificant weight gain in the tance, and mild symptomatic episodes receptors in the and thereby insulin-only treatment group (0.4 were more frequent in the exenatide increase insulin release and inhibit kg, P = 0.595). The mean total daily treatment group (50 vs. 11 episodes, glucagon secretion, but only in the insulin dose in the liraglutide group P <0.001) over the 6-month treatment presence of elevated blood glucose dropped by 34% from 199 to 132 period. (32). A recent meta-analysis of 15 units (P <0.0001), whereas insulin A small, retrospective, observa- studies showed that a GLP-1 receptor tional study analyzed the effects of requirements in the insulin titration agonist combined with basal insulin adding liraglutide to U-500 insu- group remained relatively unchanged, was superior to basal-bolus insulin lin in 15 obese patients with severe combinations in patients with type with a nonsignificant 4% increase insulin resistance (23). The cohort’s 2 diabetes (33). The GLP-1 receptor from 171 to 178 units (P = 0.453). mean baseline A1C was 8.5%, total agonist–basal insulin combination Hypoglycemia (blood glucose <70 daily insulin dose was 192 units, and led to significantly improved glyce- mg/dL) based on continuous glu- weight was 137 kg. After 12 weeks mic control and reduced body weight cose monitoring was similar in both of liraglutide treatment at a dose of without increasing the risk of hypo- groups (<5% of the time) at baseline 1.2 or 1.8 mg/day, there was a signif- glycemia when compared to basal- and 6-month follow-up. There were icant mean reduction in A1C (1.4%, bolus insulin alone. These features no episodes of severe hypoglycemia P = 0.0001), total daily insulin dose

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(44 units, P = 0.0001), and weight A1C of study subjects at baseline was insulin resistance, it is premature to (5.1 kg, P = 0.0001). Hypoglycemia, 8.3%, and patients had an average recommend their use. defined as blood glucose <70 mg/dL, daily insulin dose of 92 units. At 18 Dipeptidyl Peptidase-4 occurred in eight patients, but there weeks, A1C was reduced by 0.4% in Inhibitors were no severe episodes requiring the empagliflozin 10 mg group and Dipeptidyl peptidase-4 (DPP-4) assistance. by 0.5% in the 25 mg group com- inhibitors prolong the activity of Nausea and vomiting are the most pared to placebo (P <0.001), and these endogenous GLP-1 and glucose insu- common adverse effects associated improvements in glycemic control linotropic polypeptide by preventing with GLP-1 receptor agonist use, were largely sustained at 52 weeks in their breakdown and potentiating but they are often transient. It is a both treatment groups. When com- their actions. On the surface, DPP- dose-dependent phenomenon, and pared to insulin requirements in the 4 inhibitors, which are taken orally, the incidence varies among the FDA- placebo group, the mean total daily would appear to be an attractive al- approved products in this class (35). insulin dose in the empagliflozin 10 ternative to GLP-1 receptor agonists Although combination therapy mg group was 8.8 units lower (P = for the management of patients with FEATURE ARTICLE with GLP-1 receptor agonists and 0.004) and in the 25 mg group was severe insulin resistance. Indeed, all basal-bolus insulin is not approved by 11.2 units lower (P <0.001). Patients FDA-approved DPP-4 inhibitors the FDA, there are several potential who received empagliflozin lost ~2 have been studied in combination benefits when adding these agents to kg of weight compared to a 0.4-kg with insulin. However, none have U-100 insulin, including improve- weight gain in the placebo group been studied in patients with severe ment in glycemic control, weight loss, (P <0.001). Objectively confirmed insulin resistance (39). When com- and reduced insulin requirements hypoglycemia during the 52-week bined with insulin, DPP-4 inhibitors (24). Some patients may be able to study occurred in a similar percent- produce roughly similar reductions in discontinue prandial insulin use. age of patients in the empagliflozin mean A1C of 0.4–0.6% over a period However, it remains unclear whether 10 mg (51.1%), empagliflozin 25 mg of 24–52 weeks (40–43). However, combining U-500 insulin with a (57.7%), and placebo (58.0%) groups. unlike treatment with GLP-1 recep- GLP-1 receptor agonist is an effec- Three patients each in the placebo tor agonists, DPP-4 inhibitors, when tive or cost-effective strategy. More and empagliflozin 10 mg groups and combined with insulin, do not pro- studies are needed comparing GLP-1 1 patient in the empagliflozin 25 mote weight loss or reduce total daily receptor agonists to U-500 regular mg group had severe hypoglycemia insulin requirements. Although DPP- insulin to define which patients with requiring assistance. 4 inhibitors are well tolerated and severe insulin resistance would bene- SGLT2 inhibitors are known typically do not increase the risk of fit most from these therapies. to increase the risk of urinary tract hypoglycemia, their role in the man- Sodium-Glucose Cotransporter and genital mycotic infections, par- agement of patients with severe insu- 2 Inhibitors ticularly in women with a history of lin resistance is questionable (22,39). Sodium-glucose cotransporter 2 these infections (38). Some patients Pramlintide (SGLT2) inhibitors increase the ex- experience orthostatic hypotension Pramlintide is a synthetic analog of cretion of urinary glucose, thereby and changes in renal function sec- , a neuroendocrine hormone reducing plasma glucose concentra- ondary to the osmotic diuresis. Thus, that is cosecreted with insulin from tions independent of the presence of in patients with severe insulin resis- pancreatic β-cells. It is effective as insulin (36). These medications have tance who have very poor glycemic an adjunct to insulin therapy in pa- been shown to reduce body weight, control, SGLT2 inhibitors are not the tients with type 1 or type 2 diabetes and this is one of the features that has best choice because these patients are by reducing postprandial glucose prompted studies in obese patients already at higher risk for dehydration excursions (44). None of the studies treated with insulin. and developing genitourinary tract conducted to date have specifically A 52-week, double-blind, pla- infections. examined the benefits of pramlintide cebo-controlled trial of 563 obese Available data suggest that SGLT2 in patients with severe insulin resis- patients with uncontrolled type 2 inhibitors, when combined with tance, but two studies in patients with diabetes on a total daily insulin dose insulin therapy, may lead to modest poorly controlled type 2 diabetes pro- >60 units were randomized to receive improvements in glycemic control vide some insights. Patients in these once-daily empagliflozin 10 mg, and modest weight loss without placebo-controlled studies received empagliflozin 25 mg, or placebo (37). increasing the risk of hypoglyce- pramlintide in doses ranging from During weeks 19–40 of this study, mia. However, given the lack of data 90 to 300 µg/day (45,46). The mean insulin doses were titrated to achieve regarding the benefits of SGLT2 baseline A1C was ~9% in both stud- specified glucose targets. The mean inhibitors in patients with severe ies, and the total daily insulin dose was

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60–70 units. After 52 weeks, there was randomized to (titrated to ing effect is unknown (49). It has been a statistically significant reduction in 45 mg/day) or placebo after titrating shown to produce a modest reduction A1C of 0.6–0.7% and in weight of basal insulin doses to achieve a fasting in A1C of 0.5% in patients treated 1.4–1.5 kg. In one study, insulin to- blood glucose <140 mg/dL. After 20 with ~75 units of insulin/day in one tal daily dose requirements increased weeks, both groups experienced a re- 16-week study (50). Bromocriptine is in all treatment groups but to a lesser duction in A1C of 1.4–1.6%, but the a dopamine receptor agonist indicated degree in the pramlintide groups (46). difference between the groups was not as adjunct therapy for type 2 diabetes, Severe hypoglycemia requiring statistically significant. The mean daily but its efficacy has not been evaluated assistance may occur during the first 4 insulin dose was lower in the pioglita- in patients taking insulin (51). weeks of treatment with pramlintide, zone group (mean difference 12 units, but beyond the initial treatment P <0.001), but more patients in the pi- Conclusion period, the risk appears to be similar oglitazone group experienced hypogly- Several medications are available to to placebo (45). To mitigate the poten- cemia (46 vs. 31%, P <0.005). Weight treat patients with type 2 diabetes, tial risk of severe hypoglycemia, the gain was greater in the pioglitazone but few have been studied in the set- manufacturer recommends reducing group than the placebo group (4.4 ting of severe insulin resistance (Table prandial insulin doses when initiating vs. 2.2 kg, statistical comparison not 2). The majority of patients with pramlintide, and this practice also reported). The magnitude of weight severe insulin resistance will likely would be prudent in patients with gain appears to be comparable to have taken metformin. For patients severe insulin resistance (44). Nausea what patients might experience when who are currently taking metformin is a common adverse effect associated switching to U-500 insulin. However, with insulin therapy, the metformin with pramlintide use (45,46), but it the lack of improvement in glycemic should be continued based on its does not appear to be dose dependent control, coupled with potential serious track record of safety and efficacy, and is typically transient, subsiding adverse effects (e.g., heart failure and low cost, and potential to reduce the after 4–8 weeks of therapy. fractures), limit the usefulness of this long-term complications related to di- Pramlintide produces modest class of agents in patients with severe abetes (52). In the absence of a true improvements in glycemic control insulin resistance (6,22). contraindication, metformin should be added to high-dose U-100 insulin and weight without significantly Other Therapies increasing the risk of hypoglycemia. therapy if patients are able to toler- Several other oral antidiabetic thera- Its major drawback is frequent sub- ate it. However, switching patients pies are available, but there is a lack cutaneous administration; it must be to U-500 regular insulin or adding a of evidence and experience using these taken two or three times daily before agents in patients with severe insulin GLP-1 receptor agonist will produce meals. In the setting of severe insu- resistance. Given the very high insu- greater reductions in blood glucose lin resistance, pramlintide use might lin requirements of patients with se- and be more likely to achieve glyce- result in reduced insulin requirements vere insulin resistance, sulfonylureas mic goals. U-500 regular insulin has and significantly greater weight loss, or meglitinides are not likely to have the most data and greatest clinical but data are lacking. GLP-1 receptor any clinical utility. α-Glucosidase experience to support its use in pa- agonists appear to be a better option inhibitors (AGIs) reduce prandial hy- tients with severe insulin resistance, to achieve these goals. perglycemia by retarding hydrolysis of but weight gain is a problem that can complex carbohydrates. The AGI acar- escalate insulin resistance and dose re- Thiazolidinediones (TZDs) improve bose was studied in patients with type quirements over time. GLP-1 recep- insulin sensitivity by increasing insu- 2 diabetes with a mean total daily dose tor agonists, although not as potent lin-dependent glucose disposal and of insulin of 62 units and baseline A1C as U-500 regular insulin in terms of decreasing hepatic glucose output. of 8.7%. After 26 weeks of therapy, A1C reduction, are an attractive alter- Given their mechanism of action, patients who received acarbose had a native for obese patients with severe TZDs commonly have been combined significant reduction in A1C of 0.7%. insulin resistance (53). SGLT2 inhib- with insulin in practice. TZDs have However, these findings have not been itors and pramlintide have a favorable not been evaluated specifically in the replicated in patients with severe in- impact on weight and can be consid- setting of severe insulin resistance, but sulin resistance, and dose-dependent ered. Other treatment options offer a few studies have examined their use GI effects (i.e., flatulence, diarrhea, limited benefits but may be useful in in combination with insulin (47). A and abdominal pain) often limit use specific patient circumstances. There double-blind trial of 222 patients with of these agents (48). Colesevelam is a is a paucity of evidence regarding the uncontrolled type 2 diabetes (mean bile acid sequesterant approved to treat optimal treatment of patients with A1C of 8.5%) requiring insulin (mean hyperlipidemia and type 2 diabetes. severe insulin resistance, and many total daily dose of 56 units/day) were The mechanism for its glucose-lower- questions remain unanswered.

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TABLE 2. Pharmacological Treatment Options in the Setting of Severe Insulin Resistance Medication A1C Hypo- Weight Ease of Use Tolerability Relative Class Lowering* glycemia Risk Effect Issues Cost† Treatment options that have been evaluated in patients with severe insulin resistance U-500 regular Subcutaneous; two ↓↓↓ ↑ ↑↑ $$$$ insulin to four times daily Subcutaneous; GLP-1 receptor ↓↓ ←→ ↓↓ once daily or once Nausea, vomiting $$$ agonists weekly One to four tablets Diarrhea, loose Metformin ↓ ←→ ←→,↓ $ once or twice daily stools Treatment options that have not been evaluated in patients with severe insulin resistance

SGLT-2 Urogenital FEATURE ARTICLE ↓ ←→ ↓ Oral; once daily $$$ inhibitors infections DPP-4 inhibitors ↓ ←→ ←→ Oral; once daily Well tolerated $$$ Lower extremity TZDs ↓ ←→ ↑↑ Oral; once daily edema, new-on- $$$ set heart failure Subcutaneous; two Pramlintide ↓ ↑, ←→ ↓ Nausea, vomiting $$$$ to three times daily Oral; once or twice Sulfonylureas ↓ ↑ ↑ $ daily Oral; two or three Meglitinides ↓ ↑ ↑, ←→ $$ times daily α-Glucosidase Oral; three times Flatulence, GI ↓ ←→ ←→ $ inhibitors daily distress Oral; one packet Colesevelam ↓ ←→ ←→ or six tablets once Constipation $$$ daily Nausea, vomit- Oral; four to six Bromocriptine ↓ ←→ ←→ ing, somnolence, $$$ tablets once daily rhinitis, dizziness *Additional A1C lowering in previously treated patients; ↓ = 0.5–1%, ↓↓ = 1–1.5%, ↓↓↓ =1.5 –2%. †Relative cost per 30-day supply; $ = <$100, $$ = $100–299, $$$ = $300–750, $$$$ = >$750 based on average wholesale price (54).

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