Next Article in Journal
Addisonian Crisis after Missed Diagnosis of Posttraumatic Hypopituitarism
Next Article in Special Issue
Renal Biopsy in Type 2 Diabetic Patients
Previous Article in Journal
Hyponatremia Associated with Heart Failure: Pathological Role of Vasopressin-Dependent Impaired Water Excretion
Previous Article in Special Issue
Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 4
Issue 5
10.3390/jcm4050948
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Hypoglycemia in Patients with Diabetes and Renal Disease

by
Mazen Alsahli
1 and
John E. Gerich
2,*
1
Department of Medicine, Southlake Health Center and University of Toronto Faculty of Medicine, 531 Davis Dr, Newmarket, Ontario L3Y 6P5, Canada
2
Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2015, 4(5), 948-964; https://doi.org/10.3390/jcm4050948
Submission received: 9 March 2015 / Revised: 19 April 2015 / Accepted: 28 April 2015 / Published: 13 May 2015
(This article belongs to the Special Issue Diabetic Nephropathy)
Browse Figure
Versions Notes

Abstract

:
This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.

1. Introduction

Hypoglycemia is a common occurrence in people with diabetes and most frequently it is the result of pharmacologic intervention. Avoidance of and fear of hypoglycemia are often the major impediment for achieving optimal glycemic control [1]. Moreover, hypoglycemia is associated with significant morbidity and mortality [2,3,4,5,6].
Chronic kidney disease (CKD) is an independent risk factor for hypoglycemia, and augments the risk already present in people with diabetes [7,8,9]. In addition, CKD imposes restrictions on antidiabetic therapeutic options and increases the risk of cardiovascular disease and death [7,10,11,12,13]. This review represents an update and expansion of a recent publication of ours on this subject with more detailed discussion on therapeutic options limitations facing care providers in this common clinical situation [14]. PubMed and MEDLINE were searched for literature published in English from January 1989 to January 2015 for diabetes mellitus, hypoglycemia, chronic kidney disease, diabetic nephropathy, diabetic kidney disease, and chronic renal insufficiency.

2. Definition and Classification of Hypoglycemia in Diabetes

The American Diabetes Association and Endocrine Society workgroup on hypoglycemia defined iatrogenic hypoglycemia in patients with diabetes as all episodes of an abnormally low plasma glucose concentration that expose the patient to potential harm [15]. No single threshold value was assigned to define hypoglycemia since this value may differ among patients. An alert value of <70 mg/dL (<3.8 mmol/L), however, was chosen to draw the attention of patients and caregivers and also for use as a cut-off value in the classification of hypoglycemia in diabetes as outlined in Table 1 [15].
Table
Table 1. Hypoglycemia categories as defined by the American Diabetes Association and the Endocrine Society [15].
Table 1. Hypoglycemia categories as defined by the American Diabetes Association and the Endocrine Society [15].
CategoryDefinition
Documented symptomaticAn event during which typical symptoms of hypoglycemia are associated by a measured plasma glucose concentration ≤70 mg/dL a
SevereAn event requiring assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions b
AsymptomaticAn event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration ≤70 mg/dL a
Probable symptomaticAn event during which symptoms of hypoglycemia are not accompanied by a plasma glucose measurement but that was presumably caused by a plasma glucose concentration ≤70 mg/dL a
Pseudo-hypoglycemiaAn event during which the person with diabetes reports any of the typical symptoms of hypoglycemia with a measured plasma glucose concentration >70 mg/dL a but approaching that level
a 70 mg/dL equals 3.8 mmol/L; b If plasma glucose measurements are not available during such an event; the neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by hypoglycemia.

3. Definition and Classification of CKD

The Kidney Disease Improving Global Outcomes (KDIGO) has defined CKD as abnormalities of kidney structure or function, present for >3 months, with implications for health [16]. The group classified CKD based on cause, estimated glomerular filtration rate (eGFR), and albuminuria. Diabetic kidney disease (DKD) refers to CKD caused by diabetes. DKD is usually a presumptive diagnosis detected clinically by screening for increased albuminuria and decreased eGFR. Since there may be other causes of CKD in patients with diabetes (e.g., hypertension, pyelonephritis), kidney biopsies may sometimes be needed to establish a definitive diagnosis [16].
Increased albuminuria is usually detected through abnormal reagent strip test for total protein or a random urine albumin/creatinine ratio (ACR) assessment. Although the appearance of increased albuminuria is usually the earliest finding of DKD, the severity of albuminuria does not necessarily predict DKD progression in patients with either type 1 or type 2 diabetes [17,18,19]. The normal ACR in young adults is <10 mg/g (<1 mg/mmol) [16]. Abnormal results should be confirmed by repeat testing at least twice over a 6 month period because of frequent false positives [20]. An elevated random ACR can be confirmed by urine albumin excretion rate in a timed urine collection, as necessary. Albuminuria categories in CKD according to KDIGO are summarized in Table 2.
Table
Table 2. Albuminuria categories in chronic kidney disease (CKD) based on KDIGO a classification [16]. Adapted by permission from Macmillan Publishers Ltd.: Kidney International. KDIGO.
Table 2. Albuminuria categories in chronic kidney disease (CKD) based on KDIGO a classification [16]. Adapted by permission from Macmillan Publishers Ltd.: Kidney International. KDIGO.
Albumin Excretion Rate (mg/24 h)Albumin Creatinine Ratio (mg/mmol or mg/g)Category (Description)
<30<3 mg/mmol (<30 mg/g)A1 (Normal to mildly increased)
30–3003–30 mg/mmol (30–300 mg/g)A2 (Moderately increased)
>300>30 mg/mmol (>300 mg/g)A3 (Severely increased)
a KDIGO = Kidney Disease Improving Global Outcomes.
Estimating GFR from serum creatinine is appropriate for staging and tracking the progression of CKD in most clinical situations including in patients with DKD. The 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and its modifications, which have been adopted by many clinical laboratories, were found more accurate than the Modification of Diet in Renal Disease (MDRD) Study equation and its modifications [16,21,22]. Using 2009 CKD-EPI equation is thus recommended by the KDIGO over the MDRD study equation for estimating GFR [16]. GFR categories according to KDIGO are outlined in Table 3.
Table
Table 3. GFR categories in CKD based on KDIGO a classification [16]. Adapted by permission from Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int. 2013; 3(1):1–150, © 2013.
Table 3. GFR categories in CKD based on KDIGO a classification [16]. Adapted by permission from Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int. 2013; 3(1):1–150, © 2013.
GFR (mL/min/1.73 m2)Category (Description)
≥90G1 * (Normal or high)
60–89G2 * (Mildly decreased)
45–59G3a (Mildly to moderately decreased)
30–44G3b (Moderately to severely decreased)
15–29G4 (Severely decreased)
<15G5 (Kidney failure)
a KDIGO = Kidney Disease Improving Global Outcomes; * Glomerular filtration rate (GFR) categories G1 and G2 do not constitute CKD in the absence of evidence of kidney damage.

4. Epidemiology

The U.S. National Health and Nutrition Examination Survey (NHANES) of 2011–2012 found that about 19% of participants with diabetes (type 1 or 2) had an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 [23]. The prevalence of kidney disease, characterized by either reduced kidney function (eGFR of <60 mL/min/1.73 m2) or albuminuria (ACR ≥3 mg/mmol (≥30 mg/g)), was nearly 50% among patients with diabetes [23]. The prevalence appears to be similar in several other countries. In the United Kingdom, one study showed that patients with diabetes (type 1 or 2) were four times more likely to have clinically significant CKD (defined as an eGFR <60 mL/min/1.73 m2) than those without diabetes. Nearly one-third of people with diabetes (31%) had eGFR <60 mL/min/1.73 m2 compared with only 6.9% of the general population [24]. In 2011, diabetes was the primary cause of new cases of end stage renal disease (ESRD) in approximately 60% of patients in Malaysia, Mexico, and Singapore; and in more than 40% of patients in the Republic of Korea, Hong Kong, the Philippines, Japan, the United States, and New Zealand [25].
The exact incidence and prevalence of hypoglycemia in patients with diabetes and/or renal disease are difficult to define because mild to moderate hypoglycemia may go unnoticed or unreported. Overall, hypoglycemia unawareness can be found in 25% of patients with diabetes [26]. The complete detection of chemical hypoglycemia would require continuous blood glucose measurements over prolonged periods. Studies using this approach have generally found that the frequency and duration of hypoglycemia, especially nocturnal hypoglycemia, are greater than what was previously thought [27,28]. More reliable data are available from studies reporting severe hypoglycemia that is associated with loss of consciousness or requiring external assistance [15]. In general, the frequency of hypoglycemia is lower in people with T2DM than in those with type 1 diabetes [29,30,31,32,33,34]. For example, the UK Hypoglycemia Study Group reported severe hypoglycemia rates in patients with type 2 diabetes on insulin >2 years (10 episodes per 100 patient-year) to be far less than in patients with type 1 diabetes (<5 years disease duration, 110 episodes per 100 patient-year; >15 years disease duration, 320 episodes per 100 patient-year) [33].
Renal hypoglycemia (hypoglycemia associated with CKD without any other obvious cause) is known to occur spontaneously in non-diabetic individuals with an incidence of 1%–3% [35,36]. The presence of diabetes adds another layer of complexity. For example, Moen et al. found that the incidence of hypoglycemia is increased in the presence of either diabetes (type 1 or 2) or CKD, with the risk most pronounced in the presence of both conditions (Figure 1). Among patients with diabetes, the rate was 10.7 versus 5.3 per 100 patient-months and among patients without diabetes was 3.46 versus 2.23 per 100 patient-months, for CKD versus no CKD, respectively [7]. In a study by Muhlhauser et al., type 1 diabetes patients with impaired kidney function had a fivefold higher incidence of severe hypoglycemia than type 1 diabetes patients with normal serum creatinine [37].
Among people with T2DM the frequency of hypoglycemia will vary by treatment modality. In general the frequency of hypoglycemia is greatest with insulin and insulin secretagogues that are excreted primarily by the kidney and/or have active metabolites that may accumulate in patients with impaired renal function such as glibenclamide (glyburide) [2,34,38]. Prandial insulin (short-acting insulin administered before meals to limit postprandial hyperglycemia) is associated with a greater frequency of hypoglycemia than long-acting basal insulin [39]. Metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 (GLP-1) mimetics and sodium glucose cotransporter-2 (SGLT2) inhibitors do not increase the risk of hypoglycemia when used without sulfonylureas or insulin [30,34,40].
Jcm 04 00948 g001 1024
Figure 1. Risk for hypoglycemia of varying severity and expressed as an adjusted incidence rate ratio in patients classified by presence or absence of CKD and diabetes. Reference group are patients without CKD or diabetes. Rates adjusted for race, gender, age, Charlson comorbidity index, cancer, diabetes, and cardiovascular disease (all rate ratios p < 0.0001) [7].
Figure 1. Risk for hypoglycemia of varying severity and expressed as an adjusted incidence rate ratio in patients classified by presence or absence of CKD and diabetes. Reference group are patients without CKD or diabetes. Rates adjusted for race, gender, age, Charlson comorbidity index, cancer, diabetes, and cardiovascular disease (all rate ratios p < 0.0001) [7].
Jcm 04 00948 g001

5. Pathogenesis

5.1. Hypoglycemia Counterregulation

Normally plasma glucose levels are maintained within a relatively narrow range (between 70 and 140 mg/dL (3.8 and 7.8 mmol/L)) despite considerable variations in frequency and magnitude of carbohydrate intake and in energy expenditure. The maintenance of the stability of plasma glucose is due to the glucose counterregulatory system. By the time plasma glucose levels reach 70 mg/dL (3.8 mmol/L), secretion of counterregulatory hormones is stimulated—the key ones being glucagon which increases hepatic glucose production and catecholamines which mainly increase renal glucose release but also reduce muscle glucose uptake [1].
Within a few years of diabetes onset, people with type 1 diabetes develop impaired counter-regulatory hormone responses, which are manifested first by decreased or absent glucagon responses to hypoglycemia [1]. This is followed by decreased catecholamine responses and later (and variably) by decreased growth hormone and cortisol responses. The mechanism of the loss of glucagon response is poorly understood but recent evidence suggests that it could be related to increased activity of ATP-regulated potassium channels in glucagon-producing alpha cells [41]. The pathogenesis for impaired catecholamines and other hormones responses is also not entirely clear but may be a result of recurrent hypoglycemia that: (a) impairs glucose sensing in the ventromedial hypothalamus (a brain region that plays a major role in controlling the counterregulatory responses to hypoglycemia); and (b) leads to cellular adaptation which results in hypoglycemia unawareness and reduced adrenomedullary response to subsequent hypoglycemia [42,43].
Defective glucose counterregulation plays a major role in the susceptibility to severe hypoglycemia in patients with T1DM. By contrast, people with T2DM experience more modest impairment in glucose counterregulation [44]. While the counterregulatory responses to hypoglycemia have not been evaluated in people with CKD, there are various factors that would predispose those individuals to impaired counterregulation; for example, impairment of glucose release into the circulation by both the liver and kidney [45].

5.2. Renal Insufficiency as a Risk Factor for Hypoglycemia

Presence of CKD adds risk factors for hypoglycemia to these already existing in patients with diabetes. Some of the additional factors are altered drug metabolism, drug-drug interactions (e.g., angiotensin-converting enzyme inhibitors), albuminuria, autonomic neuropathy, anorexia, malnutrition, infections, problems linked to dialysis, associated cardiac and hepatic disease, and impaired renal glucose release [46,47].
In healthy people, both the liver (via glucagon) and kidney (via catecholamines) equally contribute to the increase in glucose release into the circulation during counterregulation of hypoglycemia; this is largely achieved by gluconeogenesis [1,45,48]. People with moderate to severe CKD have reduced renal mass, and therefore, a reduced capacity for renal glucose release. Moreover, these individuals could be malnourished and/or have muscle wasting, which decreases their hepatic glycogen stores and reduces the availability of gluconeogenic substrates [49]. Finally, acidosis would limit the ability of the liver to compensate via hepatorenal reciprocity (reciprocal changes in hepatic and renal glucose release to maintain normoglycemia) [45].
A decrease in renal clearance of insulin is evident when GFR falls below 15–20 mL/min/1.73 m2 [50]. At this point, a decline in hepatic insulin metabolism is also noted and is thought to be due to uremic toxins effects on the liver [50]. Management of CKD with dialysis reduces insulin resistance and increases insulin degradation and this includes an improvement in hepatic insulin metabolism [50,51]. Additionally, glucose is the most commonly used osmotic agent in peritoneal dialysis and glucose containing dialysis solutions can in many cause alternating hyperglycemia and hypoglycemia unless antidiabetes regimen and dialysis schedule is carefully managed [52].
Management of CKD consequences may also affect diabetes and alter insulin requirements. Examples of which include; increased insulin-induced glucose utilization following correction of anemia by erythropoietin [53,54], and improved insulin sensitivity following intravenous administration of calcitriol [55,56,57].
Over a 10-year follow-up period, Yun et al. demonstrated that the presence of baseline macroalbuminuria (defined as urinary albumin excretion ≥300 mg/day) was an independent risk factor for future development of severe hypoglycemia in T2DM patients with apparently normal or only minimally decreased renal function (e.g., GFR >60 mL/min/1.73 m2) irrespective of whether or not they were receiving insulin [9]. The exact underlying pathogenic mechanism for this is unclear.

6. Hypoglycemia Morbidity and Mortality

Both hypoglycemia and CKD are associated with increased morbidity and mortality, particularly from cardiovascular disease [3,4,12,58,59,60]. Renal disease is associated with classic major cardiovascular risk factors, including hypertension, hyperlipidemia, and diabetes. Whether hypoglycemia per se is an additional risk factor or only a marker of cardiovascular frailty is currently a matter of debate [61,62]. There are theoretical, experimental and clinical considerations that suggest a causal effect, such as effects of hypoglycemia on oxidative stress, endothelial dysfunction, ST-segment prolongation and precipitation of arrhythmias via activation of the sympathetic nervous system [59,63,64].

7. Therapeutic Considerations

Prescribing protocols change in patients with CKD mostly to account for predicted pharmacokinetic changes. Recognizing these changes and applying principles of good prescribing is needed to reduce risk of hypoglycemia in patients on insulin or insulin secretagogues. Guidelines for use of antidiabetic agents vary among medical communities [65,66,67,68,69,70]. Information about dosing adjustments in patients with CKD and diabetes is summarized in Table 4.
Table
Table 4. Recommended dosing adjustments of antidiabetic drugs in patients with diabetes and CKD.
Table 4. Recommended dosing adjustments of antidiabetic drugs in patients with diabetes and CKD.
Class and AgentsReferencesTherapeutic Considerations
Biguanides[65,66,67,68,69,71,72,73]
Metformin
  • Review use/reduce dose if eGFR < 45–60 mL/min/1.73 m2
  • Avoid if eGFR < 30 mL/min/1.73 m2
  • FDA is more restrictive indicating that metformin is contraindicated if serum creatinine ≥1.5 mg/dL (133 μmol/L) in males or ≥1.4 mg/dL (124 μmol/L) in females
Sulfonylureas[65,69,70,74]
Glyburide (glibenclamide)
  • Not recommended if eGFR <60 mL/min/1.73 m2
Gliclazide
  • Reduce dose if eGFR <30 mL/min/1.73 m2
  • Not recommended if eGFR <15 mL/min/1.73 m2
Glimepiride
  • Reduce dose if eGFR <30 mL/min/1.73 m2
  • Start at 1 mg daily or consider alternative agent if eGFR < 15 mL/min/1.73 m2
Glipizide
  • Can be used in all stages of CKD with caution. May need dose reduction
Meglitinides[65,70,75,76]
Repaglinide and Nateglinide
  • Can be used in all stages of CKD with caution. May need dose reduction if eGFR <30 mL/min/1.73 m2
DPP-4 inhibitors[65,69,70]
Sitagliptin
  • Reduce dose to 50 mg daily if eGFR 30–50 mL/min/1.73 m2 and to 25 mg daily if eGFR <30 mL/min/1.73 m2
Saxagliptin
  • Reduce dose to 2.5 mg daily if eGFR <50 mL/min/1.73 m2
  • Administer postdialysis in hemodialysis requiring patients
Linagliptin
  • No restrictions
Vildagliptin
  • Reduce dose to 50 mg daily when eGFR <50 mL/min/1.73 m2
Thiazolidinediones[65,69,70]
Rosiglitazone and Pioglitazone
  • No dose adjustment required
α-glucosidase inhibitors[65,70,74,77,78]
Acarbose and Miglitol
  • Not recommended if eGFR <25 mL/min/1.73 m2 or serum creatinine >2 mg/dL
Voglibose
  • Not well studied but is minimally absorbed and dose reduction unlikely needed
GLP-1 analogs[70,71,79,80,81,82,83,84,85,86]
Exenatide
  • Not recommended if eGFR <30 mL/min/1.73 m2
Liraglutide
  • Not recommended if eGFR <50 mL/min/1.73 m2
Albiglutide and Dulaglutide
  • Experience is limited. No dose adjustment required per FDA approval but the European Medicines Agency recommended avoiding their use in patients with GFR <30 mL/min/1.73 m2)
SGLT2 inhibitors[72,87,88,89,90]
Dapagliflozin
  • Not recommended if eGFR <60 mL/min/1.73 m2
Canagliflozin
  • Reduce dose to 100 mg once daily if eGFR 45–60 mL/min/1.73 m2
  • Not recommended if eGFR <45 mL/min/1.73 m2
Empagliflozin
  • Reduced dose to 10 mg once daily if eGFR 45–60 mL/min/1.73 m2
  • Not recommended if eGFR <45 mL/min/1.73 m2
Insulin[42,52,70]
Insulin
  • Use with caution. Dose reduction usually necessary if eGFR <30 mL/min/1.73 m2
GLP-1 = Glucagon-like peptide-1; DPP-4 = Dipeptidyl peptidase 4; SGLT2 = Sodium-glucose co-transporter 2.
  • Metformin. The only route of elimination of metformin is via the kidneys. Consequently it may accumulate in people with impaired renal function. Most guidelines recommend reviewing or reducing metformin dose when eGFR is <60 mL/min/1.73 m2 (example, Canadian Diabetes Association and Swiss Society for Endocrinology and Diabetology [65,69]) or <45 mL/min/1.73 m2 (example, British National Institute for Health and Clinical Excellence, Australian Diabetes Society, and Japanese Society of Nephrology [66,67,68]) and avoiding its use altogether when eGFR is <30 mL/min/1.73 m2. The US Food and Drug Administration has stricter prescribing information limiting metformin use to men and women with serum creatinine <1.5 mg/dL (133 umol/L) and <1.4 mg/dL (124 umol/L), respectively [71]. On the other hand, a consensus statement of the American Diabetes Association mentions that metformin appears safe unless eGFR becomes <30 mL/min/1.73 m2 based on a review by Lipska et al. [72,73].
  • Sulfonylureas. Hypoglycemia risk is increased as a consequence of accumulation of the sulfonylurea and/or its active metabolites and their long duration of action [74]. Glibenclamide (glyburide) and its two active metabolites (M1 and M2) are cleared by the kidneys. Its use is not recommended for people with eGFRs < 60 mL/min/1.73 m2 [65,69,70]. Glimepiride and gliclazide can be used with caution in people with mild-moderate renal insufficiency, and dose reduction is usually necessary especially when eGFR is <30 mL/min/1.73 m2; however, it is recommended to consider alternative agents in people with moderate-severe renal insufficiency specifically when eGFR is <15 mL/min/1.73 m2 [65,70]. The metabolism of glipizide occurs mainly in the liver and its primary metabolites are either inactive or with very weak hypoglycemic effect that are excreted in the urine; therefore, glipizide is the preferred sulfonylurea, but usually at a reduced-dose, in people with CKD [70,74].
  • Meglitinides. Repaglinide can accumulate in patients with advanced renal dysfunction (eGFR <30 mL/min/1.73 m2) without significant increase in hypoglycemia [75]. A metabolite of nateglinide, that has modest hypoglycemic effect, accumulates in patients with CKD [76]. Both drugs may be used in CKD patients even in those with end-stage renal disease but with caution and at a reduced dose with careful upward titration [65,70].
  • Dipeptidyl peptidase 4 (DPP-4) inhibitors. Sitagliptin, vildagliptin, and saxagliptin require reduction in dose once eGFRs are <50 mL/min/1.73 m2 because accumulation may in theory increase side effects. However, linagliptin does not require dose adjustment since its renal excretion is minimal. All these agents may be used in patients with severe renal impairment [65,69,70].
  • Thiazolidinediones. Pioglitazone and rosiglitazone require no dose adjustment in renal disease and are not associated with a risk of hypoglycemia when used as monotherapy [65,69,70].
  • Alpha glucosidase inhibitors. Acarbose and miglitol are not generally recommended for people with CKD due to potential accumulation and lack of safety information. Serum levels of acarbose and its metabolites are increased in CKD patients despite its minimal intestinal absorption [74,77]. Miglitol undergoes kidney excretion after substantial intestinal absorption (>50%) [74,77]. Data are lacking on the significance of accumulation of these drugs on hypoglycemia risk. Both medications are not recommended when the eGFR is <25 mL/min/1.73 m2 [65,70,74,77]. Voglibose is poorly absorbed after clinically relevant oral dose suggesting that no dose adjustment is required. However, studies in patients with renal insufficiency are not available [78].
  • Glucagon-like peptide-1 (GLP-1) analogs. Exenatide clearance by the kidney is reduced in CKD and its use has been associated with acute kidney injury or acceleration of CKD progression [79,80]. It is therefore not recommended if the eGFR is <30 mL/min/1.73 m2 [70]. Experience is limited with liraglutide that is mostly metabolized outside the kidney. It is now recommended to avoid using it when eGFR is <50 mL/min/1.73 m2 until more data are available on its safety and risk of hypoglycemia [70,81]. Albiglutide and dulaglutide are new once weekly GLP-1 analogs. Experience of their use in patients with CKD is limited. In clinical pharmacology studies, there has been modest increase in their plasma concentration when used in type 2 diabetic patients with CKD [82,83]. There were also more hypoglycemia (when used in combination with insulin or insulin secretagogues) and more gastrointestinal side effects in this patient population [82,83,84]. The FDA has approved both drugs for patients with CKD without dose adjustment but the European Medicines Agency recommended avoiding their use in patients with GFR <30 mL/min/1.73 m2 and in patients on dialysis [83,84,85,86]. More data are expected in the future to clarify their safety further in patients with CKD.
  • Sodium-glucose co-transporter 2 (SGLT2) inhibitors. Dapagliflozin, canagliflozin and empagliflozin do not increase the risk of hypoglycemia but are associated with increased risk of hypovolemic side effects in people with moderate to severe renal impairment, who are elderly (>70 years of age), and taking loop diuretics. Furthermore, because their efficacy decreases as renal function decreases, their use is restricted to patients with eGFR >45 (canagliflozin and empagliflozin) and >60 (dapagliflozin) mL/min/1.73 m2 [71,87,88,89,90].
  • Insulin. There are no restrictions on the use of insulin in patients with renal disease, and clinically significant reductions in renal insulin metabolism are uncommon in patients with eGFRs >20 mL/min/1.73 m2 [50]. Nevertheless, people with severe renal disease (eGFRs <30 mL/min/1.73 m2) may have reduced glycogen stores and a reduced supply of gluconeogenic substrates, resulting in diminished capacity of the liver and kidney to release glucose and reverse insulin-mediated hypoglycemia. For all of the above considerations, insulin requirements may decrease by 20% or more when GFRs decrease below 45 mL/min/1.73 m2 [51]. Insulin requirements are often lower the day after hemodialysis [52]. The reduction varies among patients and regimen therefore must be individualized. Furthermore, special consideration needs to be made in people undergoing peritoneal dialysis depending on composition of the dialysate and mode of dialysis (continuous versus intermittent) [52].

8. Conclusions

Hypoglycemia is often the rate-limiting factor in achieving optimal glycemic control in patients with diabetes and is associated with substantial morbidity and mortality.
CKD with a GFR <60 mL/min/1.73 m2 is found in up to 40% of people with diabetes. It is an independent risk factor for hypoglycemia, augments the risk for hypoglycemia that is already present in people with diabetes, and increases the risk of cardiovascular disease and death.
In addition to impaired hormonal counterregulation, people with CKD may have other risk factors for hypoglycemia, such as altered drug metabolism, albuminuria, malnutrition, impaired renal glucose release and insulin clearance, and dialysis associated problems.
Presence of CKD presents a challenge when deciding on appropriate antidiabetic drugs to use in patients with diabetes. Some agents (glipizide, meglitinides, DPP-4 inhibitors, thiazolidinediones, albiglutide, dulaglutide, orlistat, colesevelam, and insulin) can be used in all categories of CKD, provided they are used with caution or at a reduced dose. Other agents (metformin, glibenclamide (glyburide), glimepiride, gliclazide, exenatide, liraglutide, alpha glucosidase inhibitors, and SGLT2 inhibitors) are not recommended particularly in people with moderate to severe CKD (eGFR <45–60 mL/min/1.73 m2) because their efficacy is reduced and/or the risks of hypoglycemia or other adverse events are increased.

Author Contributions

Both authors contributed equally to this work.

Abbreviations

ACR
albumin-to-creatinine ratio
CKD
chronic kidney disease
DKD
diabetic kidney disease
eGFR
estimated glomerular filtration rate
KDIGO
Kidney Disease Improving Global Outcomes
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus

Conflict of Interest

John E. Gerich is a consultant/member of the speaker bureau for Bristol-Myers Squibb, AstraZeneca, Merck, Janssen Pharmaceuticals, Eli Lilly, and Boehringer Ingelheim. Mazen Alsahli has no conflicts.

References

  1. Gerich, J.E. Glucose counterregulation and its impact on diabetes mellitus. Diabetes 1988, 37, 1608–1617. [Google Scholar] [CrossRef] [PubMed]
  2. Ben-Ami, H.; Nagachandran, P.; Mendelson, A.; Edoute, Y. Drug-induced hypoglycemic coma in 102 diabetic patients. Arch. Intern Med. 1999, 159, 281–284. [Google Scholar] [CrossRef] [PubMed]
  3. McCoy, R.G.; van Houten, H.K.; Ziegenfuss, J.Y.; Shah, N.D.; Wermers, R.A.; Smith, S.A. Increased Mortality of Patients With Diabetes Reporting Severe Hypoglycemia. Diabetes Care 2012, 35, 1897–1901. [Google Scholar] [CrossRef] [PubMed]
  4. Patrick, A.W.; Campbell, I.W. Fatal hypoglycaemia in insulin-treated diabetes mellitus: Clinical features and neuropathological changes. Diabet. Med. 1990, 7, 349–354. [Google Scholar] [CrossRef] [PubMed]
  5. Shorr, R.I.; Ray, W.A.; Daugherty, J.R.; Griffin, M.R. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch. Intern. Med. 1997, 157, 1681–1686. [Google Scholar] [CrossRef] [PubMed]
  6. Wredling, R.; Levander, S.; Adamson, U.; Lins, P.E. Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia 1990, 33, 152–157. [Google Scholar] [CrossRef] [PubMed]
  7. Moen, M.F.; Zhan, M.; Hsu, V.D.; Walker, L.D.; Einhorn, L.M.; Seliger, S.L.; Fink, J.C. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 2009, 4, 1121–1127. [Google Scholar] [CrossRef] [PubMed]
  8. Weir, M.A.; Gomes, T.; Mamdani, M.; Juurlink, D.N.; Hackam, D.G.; Mahon, J.L.; Jain, A.K.; Garg, A.X. Impaired renal function modifies the risk of severe hypoglycaemia among users of insulin but not glyburide: A population-based nested case-control study. Nephrol. Dial. Transpl. 2011, 26, 1888–1894. [Google Scholar] [CrossRef]
  9. Yun, J.S.; Ko, S.H.; Ko, S.H.; Song, K.H.; Ahn, Y.B.; Yoon, K.H.; Park, Y.M.; Ko, S.H. Presence of Macroalbuminuria Predicts Severe Hypoglycemia in Patients with Type 2 Diabetes: A 10-year follow-up study. Diabetes Care 2013, 36, 1283–1289. [Google Scholar] [CrossRef] [PubMed]
  10. Pyram, R.; Kansara, A.; Banerji, M.A.; Loney-Hutchinson, L. Chronic kidney disease and diabetes. Maturitas 2012, 71, 94–103. [Google Scholar] [CrossRef] [PubMed]
  11. Anavekar, N.S.; McMurray, J.J.; Velazquez, E.J.; Solomon, S.D.; Kober, L.; Rouleau, J.L.; White, H.D.; Nordlander, R.; Maggioni, A.; Dickstein, K.; et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N. Engl. J. Med. 2004, 351, 1285–1295. [Google Scholar] [CrossRef] [PubMed]
  12. Mahmoodi, B.K.; Matsushita, K.; Woodward, M.; Blankestijn, P.J.; Cirillo, M.; Ohkubo, T.; Rossing, P.; Sarnak, M.J.; Stengel, B.; Yamagishi, K.; et al. Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: A meta-analysis. Lancet 2012, 380, 1649–1661. [Google Scholar] [CrossRef] [PubMed]
  13. Levey, A.S.; Coresh, J. Chronic kidney disease. Lancet 2012, 379, 165–180. [Google Scholar] [CrossRef] [PubMed]
  14. Alsahli, M.; Gerich, J.E. Hypoglycemia, chronic kidney disease and diabetes. Mayo Clin. Proc. 2014, 89, 1564–1571. [Google Scholar] [CrossRef] [PubMed]
  15. Seaquist, E.R.; Anderson, J.; Childs, B.; Cryer, P.; Dagogo-Jack, S.; Fish, L.; Heller, S.R.; Rodriguez, H.; Rosenzweig, J.; Vigersky, R. Hypoglycemia and diabetes: A report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013, 36, 1384–1395. [Google Scholar] [CrossRef] [PubMed]
  16. KDIGO. Summary of recommendation statements. Kidney Int. 2013, 3, 1–150. [Google Scholar]
  17. Perkins, B.A.; Ficociello, L.H.; Roshan, B.; Warram, J.H.; Krolewski, A.S. In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int. 2010, 77, 57–64. [Google Scholar] [CrossRef] [PubMed]
  18. Caramori, M.L.; Fioretto, P.; Mauer, M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: An indicator of more advanced glomerular lesions. Diabetes 2003, 52, 1036–1040. [Google Scholar] [CrossRef] [PubMed]
  19. MacIsaac, R.J.; Panagiotopoulos, S.; McNeil, K.J.; Smith, T.J.; Tsalamandris, C.; Hao, H.; Matthews, P.G.; Thomas, M.C.; Power, D.A.; Jerums, G. Is nonalbuminuric renal insufficiency in type 2 diabetes related to an increase in intrarenal vascular disease? Diabetes Care 2006, 29, 1560–1566. [Google Scholar] [CrossRef] [PubMed]
  20. Mogensen, C.E.; Vestbo, E.; Poulsen, P.L.; Christiansen, C.; Damsgaard, E.M.; Eiskjaer, H.; Frøland, A.; Hansen, K.W.; Nielsen, S.; Pedersen, M.M. Microalbuminuria and potential confounders. A review and some observations on variability of urinary albumin excretion. Diabetes Care 1995, 18, 572–581. [Google Scholar] [CrossRef] [PubMed]
  21. Levey, A.S.; Stevens, L.A.; Schmid, C.H.; Zhang, Y.L.; Castro, A.F., III; Feldman, H.I.; Kusek, J.W.; Eggers, P.; van Lente, F.; et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 2009, 150, 604–612. [Google Scholar] [CrossRef] [PubMed]
  22. Earley, A.; Miskulin, D.; Lamb, E.J.; Levey, A.S.; Uhlig, K. Estimating equations for glomerular filtration rate in the era of creatinine standardization: A systematic review. Ann. Intern. Med. 2012, 156, 785–795. [Google Scholar] [CrossRef] [PubMed]
  23. Collins, A.J.; Foley, R.N.; Herzog, C.; Chavers, B.; Gilbertson, D.; Herzog, C.; Ishani, A.; Johansen, K.; Kasiske, B.; Kutner, N.; et al. US Renal Data System 2012 Annual Data Report. Am. J. Kidney Dis. 2013, 61 (Suppl. 1), e1–e476. [Google Scholar] [CrossRef]
  24. New, J.P.; Middleton, R.J.; Klebe, B.; Farmer, C.K.; de Lusignan, S.; Stevens, P.E.; O’Donoghue, D.J. Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared with those without diabetes in general practice. Diabet. Med. 2007, 24, 364–369. [Google Scholar] [CrossRef] [PubMed]
  25. US Renal Data System: USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Available online: http://www.usrds.org/adr.aspx (accessed on 22 December 2013).
  26. Gerich, J.E.; Mokan, M.; Veneman, T.; Korytkowski, M.; Mitrakou, A. Hypoglycemia unawareness. Endocr. Rev. 1991, 12, 356–371. [Google Scholar] [CrossRef] [PubMed]
  27. Guillod, L.; Comte-Perret, S.; Monbaron, D.; Gaillard, R.C.; Ruiz, J. Nocturnal hypoglycaemias in type 1 diabetic patients: What can we learn with continuous glucose monitoring? Diabetes Metab. 2007, 33, 360–365. [Google Scholar] [CrossRef] [PubMed]
  28. Wentholt, I.M.E.; Maran, A.; Masurel, N.; Heine, R.J.; Hoekstra, J.B.L.; DeVries, J.H. Nocturnal hypoglycaemia in Type 1 diabetic patients, assessed with continuous glucose monitoring: Frequency, duration and associations. Diabet. Med. 2007, 24, 527–532. [Google Scholar] [CrossRef] [PubMed]
  29. Akram, K.; Pedersen-Bjergaard, U.; Borch-Johnsen, K.; Thorsteinsson, B. Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: A literature survey. J. Diabetes Complicat. 2006, 20, 402–408. [Google Scholar] [CrossRef] [PubMed]
  30. Amiel, S.A.; Dixon, T.; Mann, R.; Jameson, K. Hypoglycaemia in Type 2 diabetes. Diabet. Med. 2008, 25, 245–254. [Google Scholar] [CrossRef] [PubMed]
  31. Gerich, J.E. Hypoglycaemia and counterregulation in type 2 diabetes. Lancet 2000, 356, 1946–1947. [Google Scholar] [CrossRef] [PubMed]
  32. Leese, G.P.; Wang, J.; Broomhall, J.; Kelly, P.; Marsden, A.; Morrison, W.; Frier, B.M.; Morris, A.D.; DARTS/MEMO Collaboration. Frequency of Severe Hypoglycemia Requiring Emergency Treatment in Type 1 and Type 2 Diabetes: A population-based study of health service resource use. Diabetes Care 2003, 26, 1176–1180. [Google Scholar] [CrossRef] [PubMed]
  33. Group UHS. Risk of hypoglycaemia in types 1 and 2 diabetes: Effects of treatment modalities and their duration. Diabetologia, 2007; 50, 1140–1147. [Google Scholar]
  34. Zammitt, N.N.; Frier, B.M. Hypoglycemia in type 2 diabetes: Pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care 2005, 28, 2948–2961. [Google Scholar] [CrossRef] [PubMed]
  35. Avram, M.M.; Wolf, R.E.; Gan, A.; Pahilan, A.N.; Paik, S.K.; Iancu, M. Uremic hypoglycemia. A preventable life-threatening complication. N. Y. State J. Med. 1984, 84, 593–596. [Google Scholar] [PubMed]
  36. Rutsky, E.A.; McDaniel, H.G.; Tharpe, D.L.; Alred, G.; Pek, S. Spontaneous hypoglycemia in chronic renal failure. Arch. Intern. Med. 1978, 138, 1364–1368. [Google Scholar] [CrossRef] [PubMed]
  37. Mühlhauser, I.; Toth, G.; Sawicki, P.T.; Berger, M. Severe hypoglycemia in type I diabetic patients with impaired kidney function. Diabetes Care 1991, 14, 344–346. [Google Scholar] [CrossRef] [PubMed]
  38. Gangji, A.S.; Cukierman, T.; Gerstein, H.C.; Goldsmith, C.H.; Clase, C.M. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: A comparison of glyburide with other secretagogues and with insulin. Diabetes Care 2007, 30, 389–394. [Google Scholar] [CrossRef] [PubMed]
  39. Holman, R.R.; Farmer, A.J.; Davies, M.J.; Levy, J.C.; Darbyshire, J.L.; Keenan, J.F.; Paul, S.K.; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N. Engl. J. Med. 2009, 361, 1736–1747. [Google Scholar] [CrossRef] [PubMed]
  40. Taylor, J.R.; Dietrich, E.; Powell, J.G. New and emerging pharmacologic therapies for type 2 diabetes, dyslipidemia, and obesity. Clin. Ther. 2013, 35. [Google Scholar] [CrossRef]
  41. Rorsman, P.; Ramracheya, R.; Rorsman, N.J.; Zhang, Q. ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: Similar functions but reciprocal effects on secretion. Diabetologia 2014, 57, 1749–1761. [Google Scholar] [CrossRef] [PubMed]
  42. Cryer, P.E. Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes. N. Engl. J. Med. 2013, 369, 362–372. [Google Scholar] [CrossRef] [PubMed]
  43. Reno, C.M.; Litvin, M.; Clark, A.L.; Fisher, S.J. Defective counterregulation and hypoglycemia unawareness in diabetes: Mechanisms and emerging treatments. Endocrinol. Metab. Clin. North Am. 2013, 42, 15–38. [Google Scholar] [CrossRef] [PubMed]
  44. Bolli, G.B.; Tsalikian, E.; Haymond, M.W.; Cryer, P.E.; Gerich, J.E. Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions. J. Clin. Investig. 1984, 73, 1532–1541. [Google Scholar] [CrossRef] [PubMed]
  45. Woerle, H.J.; Meyer, C.; Popa, E.M.; Cryer, P.E.; Gerich, J.E. Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: Further evidence for hepatorenal reciprocity. Diabetes 2003, 52, 1386–1392. [Google Scholar] [CrossRef] [PubMed]
  46. Gerich, J. Hypoglycemia. In DeGroot’s Endocrinology, 4th ed.; DeGroot, L, Ed.; WB Saunders: Philadelphia, PA, USA, 2001; pp. 921–940. [Google Scholar]
  47. Torffvit, O.; Lindqvist, A.; Agardh, C.D.; Pahlm, O. The association between diabetic nephropathy and autonomic nerve function in type 1 diabetic patients. Scand. J. Clin. Lab. Investig. 1997, 57, 183–192. [Google Scholar] [CrossRef]
  48. Cersosimo, E.; Garlick, P.; Ferretti, J. Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans. Diabetes 2000, 49, 1186–1193. [Google Scholar] [CrossRef] [PubMed]
  49. Garber, A.J.; Bier, D.M.; Cryer, P.E.; Pagliara, A.S. Hypoglycemia in compensated chronic renal insufficiency. Substrate limitation of gluconeogenesis. Diabetes 1974, 23, 982–986. [Google Scholar] [CrossRef] [PubMed]
  50. Mak, R.H.; DeFronzo, R.A. Glucose and insulin metabolism in uremia. Nephron 1992, 61, 377–382. [Google Scholar] [CrossRef] [PubMed]
  51. DeFronzo, R.A.; Tobin, J.D.; Rowe, J.W.; Andres, R. Glucose intolerance in uremia. Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin. J. Clin. Investig. 1978, 62, 425–435. [Google Scholar] [CrossRef] [PubMed]
  52. O’Toole, S.M.; Fan, S.L.; Yaqoob, M.M.; Chowdhury, T.A. Managing diabetes in dialysis patients. Postgrad. Med. J. 2012, 88, 160–166. [Google Scholar] [CrossRef] [PubMed]
  53. Mak, R.H. Effect of recombinant human erythropoietin on insulin, amino acid, and lipid metabolism in uremia. J. Pediatr. 1996, 129, 97–104. [Google Scholar] [CrossRef] [PubMed]
  54. Borissova, A.M.; Djambazova, A.; Todorov, K.; Dakovska, L.; Tankova, T.; Kirilov, G. Effect of erythropoietin on the metabolic state and peripheral insulin sensitivity in diabetic patients on haemodialysis. Nephrol. Dial. Transplant. 1993, 8, 93. [Google Scholar] [PubMed]
  55. Kautzky-Willer, A.; Pacini, G.; Barnas, U.; Ludvik, B.; Streli, C.; Graf, H.; Prager, R. Intravenous calcitriol normalizes insulin sensitivity in uremic patients. Kidney Int. 1995, 47, 200–206. [Google Scholar] [CrossRef] [PubMed]
  56. Mak, R.H. Intravenous 1,25 dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney Int. 1992, 41, 1049–1054. [Google Scholar] [CrossRef] [PubMed]
  57. Nadkarni, M.; Berns, J.S.; Rudnick, M.R.; Cohen, R.M. Hypoglycemia with hyperinsulinemia in a chronic hemodialysis patient following parathyroidectomy. Nephron 1992, 60, 100–103. [Google Scholar] [CrossRef] [PubMed]
  58. Bonds, D.E.; Miller, M.E.; Bergenstal, R.M.; Buse, J.B.; Byington, R.P.; Cutler, J.A.; Dudl, R.J.; Ismail-Beigi, F.; Kimel, A.R.; Hoogwerf, B.; et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: Retrospective epidemiological analysis of the ACCORD study. BMJ 2010, 340. [Google Scholar] [CrossRef] [PubMed]
  59. Ceriello, A.; Novials, A.; Ortega, E.; la Sala, L.; Pujadas, G.; Testa, R.; Bonfigli, A.R.; Esposito, K.; Giugliano, D. Evidence That Hyperglycemia after Recovery from Hypoglycemia Worsens Endothelial Function and Increases Oxidative Stress and Inflammation in Healthy Control Subjects and Subjects with Type 1 Diabetes. Diabetes 2012, 61, 2993–2997. [Google Scholar] [CrossRef] [PubMed]
  60. Zoungas, S.; Patel, A.; Chalmers, J.; de Galan, B.E.; Li, Q.; Billot, L.; Woodward, M.; Ninomiya, T.; Neal, B.; MacMahon, S.; et al. Severe hypoglycemia and risks of vascular events and death. N. Engl. J. Med. 2010, 363, 1410–1418. [Google Scholar] [CrossRef] [PubMed]
  61. Frier, B.M.; Schernthaner, G.; Heller, S.R. Hypoglycemia and Cardiovascular Risks. Diabetes Care 2011, 34 (Suppl. S2), 132–137. [Google Scholar] [CrossRef] [PubMed]
  62. Desouza, C.V.; Bolli, G.B.; Fonseca, V.A. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care 2010, 33, 1389–1394. [Google Scholar] [CrossRef] [PubMed]
  63. Robinson, R.T.; Harris, N.D.; Ireland, R.H.; Macdonald, I.A.; Heller, S.R. Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes. Diabetologia 2004, 47, 312–315. [Google Scholar] [CrossRef] [PubMed]
  64. Wright, R.J.; Frier, B.M. Vascular disease and diabetes: Is hypoglycaemia an aggravating factor? Diabetes Metab. Res. Rev. 2008, 24, 353–363. [Google Scholar] [CrossRef] [PubMed]
  65. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can. J. Diabetes 2013, 37 (Suppl. S1), 1–212. [Google Scholar]
  66. National Institute for Health and Clinical Excellence the Management of Type 2 Diabetes: 2010 NICE Guidelines (Internet). London, UK. National Institute for Health and Clinical Excellence, 2010. Available online: http://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf (accessed on 30 October 2013).
  67. Japanese Society of Nephrology. Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney Disease 2012 (In Japanese); Japanese Society of Nephrology (Tokyo Igakusya): Tokyo, Japan, 2012. [Google Scholar]
  68. National Evidence Based Guidelines for Blood Glucose Control in Type 2 Diabetes. Available online: http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/di19-diabetes-blood-glucose-control.pdf (accessed on 9 November 2014).
  69. Zanchi, A.; Lehmann, R.; Philippe, J. Antidiabetic drugs and kidney disease—Recommendations of the Swiss Society for Endocrinology and Diabetology. Swiss. Med. Wkly. 2012, 142. [Google Scholar] [CrossRef] [Green Version]
  70. Rocco, M.V.; Berns, J.S. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am. J. Kidney Dis. 2012, 60, 850–886. [Google Scholar] [CrossRef] [PubMed]
  71. US Food and Drug Administration Website. Human Drug Information Section. Available online: http://www.fda.gov/Drugs/default.htm (accessed on 8 January 2015).
  72. American Diabetes Association. Standards of medical care in diabetes 2015. Diabetes Care 2015, 38 (Suppl. S1), 58–66. [Google Scholar]
  73. Lipska, K.J.; Bailey, C.J.; Inzucchi, S.E. Use of met-formin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011, 34, 1431–1437. [Google Scholar] [CrossRef] [PubMed]
  74. Scheen, A.J. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin. Drug Metab. Toxicol. 2013, 9, 529–550. [Google Scholar] [CrossRef] [PubMed]
  75. Schumacher, S.; Abbasi, I.; Weise, D.; Hatorp, V.; Sattler, K.; Sieber, J.; Hasslacher, C. Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur. J. Clin. Pharmacol. 2001, 57, 147–152. [Google Scholar] [CrossRef] [PubMed]
  76. Inoue, T.; Shibahara, N.; Miyagawa, K.; Itahana, R.; Izumi, M.; Nakanishi, T.; Takamitsu, Y. Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. Clin. Nephrol. 2003, 60, 90–95. [Google Scholar] [CrossRef] [PubMed]
  77. Snyder, R.W.; Berns, J.S. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin. Dial. 2004, 17, 365–370. [Google Scholar] [CrossRef] [PubMed]
  78. Voglibose Dispersible Tablets. Summary of Product Characteristics. Available online: http://www.biocon.com/docs/prescribing_information/diabetology/volicose_pi.pdf (accessed on 7 March 2015).
  79. Johansen, O.E.; Whitfield, R. Exenatide may aggravate moderate diabetic renal impairment: A case report. Br. J. Clin. Pharmacol. 2008, 66, 568–569. [Google Scholar] [CrossRef] [PubMed]
  80. Weise, W.J.; Sivanandy, M.S.; Block, C.A.; Comi, R.J. Exenatide associated ischemic renal failure. Diabetes Care 2009, 32. [Google Scholar] [CrossRef]
  81. Jacobsen, L.V.; Hindsberger, C.; Robson, R.; Zdravkovic, M. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br. J. Clin. Pharmacol. 2009, 68, 898–905. [Google Scholar] [CrossRef] [PubMed]
  82. Young, M.A.; Wald, J.A.; Matthews, J.E.; Yang, F.; Reinhardt, R.R. Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide. Postgrad. Med. 2014, 126, 35–46. [Google Scholar] [CrossRef] [PubMed]
  83. Trulicity (Dulaglutide) Summary of Product Characteristics. Available online: http://pi.lilly.com/us/trulicity-uspi.pdf (accessed on 7 March 2015).
  84. European Commission Website. Trulicity (dulaglutide) Product Information. Available online: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002825/human_med_001821.jsp&mid=WC0b01ac058001d124 (accessed on 7 March 2015).
  85. European Commission Website. Eperzan (Albiglutide) Product Information. Available online: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002735/human_med_001735.jsp&mid=WC0b01ac058001d124 (accessed on 7 March 2015).
  86. Tanzeum (Albiglutide) Summary of Product Characteristics. Available online: https://www.gsksource.com//gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF (accessed on 7 March 2015).
  87. European Commission Website. Forxiga (Dapagliflozin) Product Information. Available online: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002322/WC500136026.pdf (accessed on 9 November 2014).
  88. Paisley, A.N.; Yadav, R.; Younis, N.; Rao-Balakrishna, P.; Soran, H. Dapagliflozin: A review on efficacy, clinical effectiveness and safety. Expert Opin. Investig. Drugs 2013, 22, 131–140. [Google Scholar] [CrossRef] [PubMed]
  89. Komala, M.G.; Panchapakesan, U.; Pollock, C.; Mather, A. Sodium glucose cotransporter 2 and the diabetic kidney. Curr. Opin. Nephrol. Hypertens. 2013, 22, 113–119. [Google Scholar] [CrossRef] [PubMed]
  90. European Commission Website. Empagliflozin (Jardiance) Product Information. Available online: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf (accessed on 9 November 2014).

Share and Cite

MDPI and ACS Style

Alsahli, M.; Gerich, J.E. Hypoglycemia in Patients with Diabetes and Renal Disease. J. Clin. Med. 2015, 4, 948-964. https://doi.org/10.3390/jcm4050948

AMA Style

Alsahli M, Gerich JE. Hypoglycemia in Patients with Diabetes and Renal Disease. Journal of Clinical Medicine. 2015; 4(5):948-964. https://doi.org/10.3390/jcm4050948

Chicago/Turabian Style

Alsahli, Mazen, and John E. Gerich. 2015. "Hypoglycemia in Patients with Diabetes and Renal Disease" Journal of Clinical Medicine 4, no. 5: 948-964. https://doi.org/10.3390/jcm4050948

APA Style

Alsahli, M., & Gerich, J. E. (2015). Hypoglycemia in Patients with Diabetes and Renal Disease. Journal of Clinical Medicine, 4(5), 948-964. https://doi.org/10.3390/jcm4050948

Article Metrics

Back to TopTop