Updates on the Administration of Diabetes in Dialysis Sufferers

Results from the Dialysis Outcomes and Practice Patterns Study
May 10, 2021 0 Comments

Oral Brokers

The armamentarium of therapeutic brokers used for the therapy of diabetes has expanded over the previous decade (). Nonetheless, the pharmaocokinetic properties of many of those medicine are altered in kidney dysfunction and should thus require dose adjustment or avoidance in dialysis sufferers.18,78

Desk 3

Treatment Class Mechanism of motion Treatment Utilization in dialysis sufferers Unwanted effects

Sulfonylureas 1st era:
Acetohexamide
Chlorpropamide
Tolazamide
Tolbutamide
Keep away from use of 1st era brokers in dialysis sufferers
2nd era:
Glipizide
Gliclazide
Glimepiride
Glyburide
Glipizide is the agent of selection

Meglitinides Repaglinide

Nateglinide

Dose reductions not specified, however no clear tips

Keep away from use in dialysis sufferers


Biguanides

  • Inhibits hepatic gluconeogenesis

  • Lower intestinal glucose absorption

  • Enhance peripheral insulin sensitivity

Metformin Keep away from use in dialysis sufferers

Thiazolidine-diones

  • Improves peripheral insulin sensitivity

  • Suppresses hepatic gluconeogenesis

  • Might enhance beta-cell operate

Rosiglitazone (soley PPAR-gamma agonist)

Pioglitazone (additionally has PPAR-alpha results)

Restricted use by producer

Dose adjustment not required

  • Hypoglycemia

  • Weight acquire

  • Fluid retention

  • Edema

  • Congestive coronary heart failure (contraindicated in sufferers with New York Coronary heart Affiliation Class III and IV Congestive Coronary heart Failure)

  • Irregular liver operate checks

  • Bone loss, decreased formation, elevated fracture threat


Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Sitagliptin

Saxagliptin

Linagliptin

Dose discount by 75%

Dose discount to 25 mg po qday, given after dialysis

Not effectively studied in dialysis sufferers


Glucagon-like Peptide 1 Analogues Exenatide

Liraglutide

Keep away from use in dialysis sufferers

Keep away from use in dialysis sufferers

  • Nausea

  • Pancreatitis

  • Diarrhea


Amylin Analogues Pramlintide Keep away from use in dialysis sufferers

Alpha-glucosidase inhibitors Acarbose

Miglitol

Keep away from use in dialysis sufferers attributable to restricted research

  • Stomach discomfort

  • Diarrhea

  • Flatulence


Sodium-glucose cotransporter 2 inhibitors Canagliflozin

Dapagliflozin

Keep away from use in dialysis sufferers

  • Vulvovaginal candidiasis

  • Genital tract infections

  • Urinary tract infections

Sulfonylureas (SUs) stimulate insulin secretion by binding to a receptor on the pancreatic beta cells that may be a part of the ATP-dependent potassium channel.18 The older first era SUs (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide) are hardly ever used and shouldn’t be utilized in dialysis sufferers, given their lengthy half-life and threat of hypoglycemia amongst this inhabitants. Among the many newer, second era SUs, short-acting glipizide is the popular agent in dialysis sufferers, as it’s largely metabolized by the liver, has inactive or weakly lively metabolites which can be excreted within the urine, and has a decrease threat of hypoglycemia in comparison with different SUs (e.g., glyburide, glimepiride).18,78 Most clinicians, nonetheless, keep away from the usage of SUs within the aged and in dialysis sufferers, because of the hypoglycemia threat.

Meglitinides embrace repaglinide and nateglinide, that are structurally totally different that SUs however equally stimulate insulin secretion by regulating ATP-dependent potassium channels on pancreatic beta cells.79 Repaglinide is the popular agent in dialysis sufferers, as it’s utterly metabolized by the liver, has inactive or weakly lively metabolites which can be excreted within the urine, and has decrease threat of hypoglycemia in contrast with different brokers.18,78 Nateglinide, whereas additionally hepatically metabolized, has renally-excreted lively metabolites that will lead to hypoglycemia in dialysis sufferers.

Biguanides encompass metformin, phenformin, and buformin which inhibit hepatic gluconeogenesis, lower intestinal glucose absorption, and enhance peripheral insulin sensitivity.80 Phenformin was faraway from the U.S. market attributable to its excessive frequency of extreme lactic acidosis, however it’s nonetheless obtainable in different international locations; buformin can be solely obtainable exterior of the U.S. Ninety-percent of metformin is renally excreted,81 and accumulation in kidney dysfunction causes sort B (nonhypoxic) lactic acidosis attributable to 1) enhanced conversion of glucose to lactate within the small gut, and a couple of) inhibition of hepatic gluconeogenesis by lactate, pyruvate, and alanine.82,83 The mortality fee of metformin-associated lactic acidosis is as excessive as 50%. Therefore, U.S. FDA tips advise towards metformin use when the creatinine in women and men is ≥1.5mg/dL and ≥1.4 mg/dL, respectively.18 Whereas some consultants have really useful metformin dose discount (i.e., 50% discount, or half of maximal dose) when the eGFR is 30–45ml/min/1.73m2,84 the latest KDIGO tips suggest that metformin use ought to be reevaluated at this vary of eGFR, and discontinued when eGFR is <30ml/min/1.73m2 and therefore shouldn’t be utilized in dialysis sufferers.69

Thiazolidinediones (TZDs) bind to the peroxisome proliferator-activated receptor-gamma (PPAR-γ) receptor and improves peripheral insulin sensitivity and suppresses hepatic gluconeogenesis.18 TZDs are wholly metabolized within the liver, and neither the mother or father drug nor its main metabolites are renally excreted. TZDs could promote edema and congestive coronary heart failure by way of PPAR-γ-mediated stimulation of distal tubular sodium channels and sodium reabsorption, however this threat could also be irrelevant in oliguric and anuric dialysis sufferers.85–87 TZDs can also lower bone formation and enhance bone loss and fracture threat, which can bear consequence in sufferers with underlying CKD-mineral bone illness.88 Nonetheless, TZDs can also favorably impression well being by enhancing lipid (e.g., triglyceride, HDL) and adiponectin ranges; decreasing visceral adiposity; lowering irritation; and decreasing muscle catabolism and protein-energy losing.89–91

Within the normal inhabitants, observational information and meta-analyses counsel that TZD security and effectiveness could also be depending on the particular agent used. Whereas research of rosiglitazone have proven an elevated threat of cardiovascular occasions,92 research of pioglitazone have demonstrated a diminished threat of cardiovascular morbidity and mortality.93

To this point, two rigorous research inspecting TZDs and mortality within the dialysis inhabitants have proven blended findings. In a research of 5290 incident dialysis sufferers with diabetes from the ArMORR cohort, Brunelli et al. confirmed that TZD use was related to decrease all-cause mortality amongst insulin-free sufferers, however not in those that have been insulin-requiring.89 This was no matter the kind of TZD agent used, and findings have been sturdy in various sensitivity analyses that accounted for confounding by indication, severity of illness, reverse causation, and time-varying publicity standing. On the idea of those information, it was posited that the advantages of TZDs on peripheral insulin sensitivity could also be annulled amongst these uncovered to exogenous insulin. In distinction, Ramirez et al. confirmed that rosiglitazone use was related to elevated all-cause and cardiovascular mortality amongst 2393 diabetic hemodialysis sufferers from the U.S. DOPPS cohort, no matter insulin use.87 Nonetheless, related associations weren’t noticed amongst those that acquired pioglitazone, and rising information counsel that pioglitazone is related to improved survival in dialysis sufferers.94

Dipeptidyl Peptidase-4 Inhibitors (DPP-4 inhibitors) are incretin system compounds and embrace linagliptin, sitagliptin, and saxagliptin;18,78 a number of extra brokers on this class have been permitted lately or are in improvement. DPP-4 is an enzyme expressed on the floor of varied varieties of cells and deactivates glucagon-like peptide-1 (GLP-1), an incretin hormone which stimulates glucose-dependent insulin secretion. By growing GLP-1 availability, DPP-4 inhibitors promote insulin launch and cut back postprandial glucose ranges. Linagliptin is minimally excreted within the urine, nevertheless it has not been effectively studied within the dialysis inhabitants. Sitagliptin is essentially excreted within the urine, and the really useful dose in dialysis sufferers is 25 mg orally per day. Saxagliptin and its main lively metabolite are cleared by hemodialysis and thus ought to be administered utilizing a diminished dose (2.5 mg orally as soon as a day) after dialysis.

Exenatide and liraglutide are GLP-1 analogues that not solely facilitate insulin secretion, but additionally lower glucagon secretion, delay gastric empying, and promote early satiety and weight reduction.18 Exenatide is an injectable, renally-excreted drug and never really useful in sufferers with an eGFR<30/ml/min/1.73m2. Though liraglutide isn’t metabolized or eradicated by the kidney, there are few information of its use in dialysis sufferers, and producers warning towards administration in gentle to extreme kidney dysfunction.69

Pramlintide is an analogue of amylin, a pancreatic beta cell hormone that delays gastric emptying, will increase satiety, and suppresses postprandial rises in glucagon ranges.78 It’s co-secreted with insulin, primarily renally metabolized and excreted, and has not been studied in dialysis sufferers.

Alpha-glucosidase inhibitors operate by delaying gastrointestinal glucose absorption and decreasing postprandial blood glucose peaks.18,69,78 Gastrointestinal negative effects (e.g., belly ache, diarrhea, flatulence) has rendered its use rare within the normal diabetic inhabitants. Whereas <2% of acarbose and its lively metabolites are renally excreted, its use in dialysis sufferers isn't really useful given insufficient research on this inhabitants. Miglitol is renally excreted, and administration can be not suggested in sufferers with kidney dysfunction.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors embrace canagliflozin and dapagliflozin and are a brand new line of diabetic drugs that modestly decrease elevated blood glucose and HbA1c ranges by inhibiting reabsorption of the filtered glucose load and therefore promote the renal excretion of glucose.95 In animal research, SGL2 inhibitors have additionally been proven to cut back albuminuria.96 At the moment, there’s a lack of long-term security and effectiveness information supporting their use within the normal sort 2 diabetic inhabitants, and their use is contraindicated in dialysis sufferers.

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