Africanjournalofdiabetesmedicine.com

Glycaemic control and glucose-lowering
therapy in diabetic patients with kidney disease
histological findings on renal biopsy.16 Microalbuminuria, Chronic kidney disease (CKD) is a common condition however, is less associated with typical pathological that affects approximately more than 50 million people lesions, but still indicates a risk of progression to CKD, worldwide.1 Diabetes mellitus, one of the chronic non- especially when a patient has co-morbidities such as communicable diseases is of increasing prevalence hypertension.17 In type 2 diabetes, microalbuminuria worldwide including in developing countries where is less associated with DKD,18,19 however patients with it was previously a disease of less importance.2 This retinopathy and microalbuminuria are strongly sugges- rapid increase in prevalence has been attributed to rapid tive of DKD, with a sensitivity over 90%.19 population growth, ageing, urbanisation, and increasing prevalence of obesity and sedentary lifestyles.2 The use Measurement of glycaemic control
of antiretroviral therapy for the treatment of human im- Glycated haemoglobin (HbA ) is used as a measure of munodeficiency virus (HIV) has been shown to increase glycaemic control for patients with diabetes. The recom- the risk of diabetes by causing insulin resistance and mended target value for patients with diabetes is <7.0%, metabolic syndrome.3 It is estimated that by the year 2030 including those with DKD.20 Studies have shown that the number of people with diabetes mellitus worldwide there is no significant difference between the correla- will be approximately double the number in 2000.2 Dia- tion of the level of HbA and the level of blood glucose betes has been implicated as one of the causes of renal between patients with CKD not requiring dialysis and diseases.4 It is estimated that in up to 45% of patients with those with diabetes without CKD.21 With such evidence renal failure, diabetes is the cause.5 Studies show that 15 therefore, the same target value of HbA of <7.0% can to 24% of patients with diabetes also have moderate to be used in this population.20 For patients with CKD on severe CKD,6–8 although a higher prevalence of 40% was dialysis, however, the correlation between HbA and found in one stud.9 Scientific evidence shows that patients the level of blood glucose is unclear. Some studies sug- with a combination of diabetes and CKD (especially as- gest that HbA provides an underestimate of glycaemic sociated with albuminuria) have higher mortality rates control,21,22 while others suggest that it provides an over- compared with those with diabetes alone.10–12 estimation.5,23 One of the studies suggests that continuous glucose monitoring is more effective for the evaluation Definition and diagnosis of CKD
of glycaemic control in patients on haemodialysis as Until recently, CKD resulting from diabetes has been compared to HbA .24 Alternatives as markers for gly- referred to as diabetic nephropathy. Currently CKD re- caemic control in this group of patients may be glycated sulting from diabetes is generally referred to as diabetic albumin (GA) or glycated fructosamine.22 However, one kidney disease (DKD) after review by the Diabetes and study showed glycated fructosamine was not reliable in Chronic Kidney Disease Working Group of the National uraemic patients.21 Kidney Foundation. Diabetic nephropathy is currently reserved for renal disease attributed to diabetes with Choice of medications in diabetic patients
histopathological injury from renal biopsy.13,14 Regardless with CKD
of the underlying pathology, CKD is defined as kidney In patients with type 2 diabetes, tight glycaemic control damage or impaired renal function for 3 months or more.14 has been shown to reduce the risk of microvascular Proteinuria has been shown to be an important marker of complications.9,25,26 The Diabetes Control And Complica- impaired renal function.15 In patients with type 1 diabetes tions Trial (DCCT) proved that in type 1 diabetes, tight who are found to have proteinuria, CKD is most likely glycaemic control reduces the risk for microvascular com- caused by diabetes because studies have shown that there plications.27 It is therefore important to attain glycaemic is a strong correlation between proteinuria and typical control to the target value as far as is possible, to avoid the complications associated with poor glycaemic control.
Bonaventura Mpondo, Department of Internal Medicine, For patients with both diabetes and CKD however, College of Health Sciences, University of Dodoma, achieving glycaemic control is not a straightforward Tanzania. issue. Treatment options are limited in this group of patients because with the reduced glomerular filtration 12 African Journal of Diabetes Medicine Vol 22 No 1 May 2014 rate (GFR), there is accumulation of the drugs used up to 33% of the prescriptions for hypoglycaemic drugs or their metabolites, some of which are active.28 There in America were for sulphonylureas.39 Clearance of are important considerations that need to be made in sulphonylureas and their metabolites is dependent on choosing the correct medications to use in this patient renal function. Studies have shown a high prevalence group. Here we will review the commonly used hypo- of hypoglycaemic episodes in dialysis patients using glycaemic agents to aid the right choice of medications sulphonylureas.38 The risk of hypoglycaemia is reduced in this patient group.
when shorter-acting agents are used. First-generation sulphonylureas should be avoided in CKD stages 3 to 5. Of the second-generation sulphonylureas, glipizide Exogenous insulin is mainly eliminated by the kidneys. is recommended with no dose adjustment being neces- In patients with renal insufficiency, the degradation of sary because its metabolites are not active and there is exogenous insulin is impaired leading to prolongation of a lower potential for the development of hypoglycae- the half-life of insulin.29 Several studies have shown that mia.14,40 The major metabolites of glipizide are products in patients with renal insufficiency there is decreased renal of aromatic hydroxylation that have no hypoglycaemic clearance of insulin with one study showing that there activity. Glibenclamide undergoes hepatic metabolism is 30–40% decreased clearance of short-acting insulins.30 to two weakly active metabolites. In patients with renal Because of this, there are more episodes of hypoglycaemia insufficiency, these accumulate and increase the risk of in patients on insulin with renal insufficiency compared hypoglycaemia.38, 41-43 Another of the second-generation with those without renal insufficiency,31 especially when sulphonylureas glimepiride also undergoes hepatic the GFR falls to <60 ml/min.32 It has been shown that in metabolism into two metabolites which are excreted patients with renal insufficiency, there is a reduced insulin in urine and faeces. The major metabolite is renally ex- requirement because of the decreased clearance.33,34 In creted and has a weak hypoglycaemic effect and may one study, however, it was found that despite decreased accumulate in renal insufficiency, increasing the risk for clearance of regular insulin there was also a reduction hypoglycaemia.44–46 However, low doses have been shown in its effect.30 In a more recent study, it has been shown to be safe in CKD.44 With this evidence, glipizide is the that reducing the dose of insulin in diabetic patients with sulphonylurea of choice in CKD. It has been shown to renal insufficiency reduced the episodes of hypoglycae- have the least risk in causing hypoglycaemia compared mia while having the same effect on glycaemic control as with the other sulphonylureas.47 comparedwith those receiving standard doses.35 Another study showed that higher weight-based insulin doses Biguanides (metformin)
were associated with a higher risk of hypoglycaemia as These are insulin sensitisers. They have no effect on the compared with lower doses.36 The American College of level of insulin, they rather lower hepatic gluconeogen- Physicians recommends a 25% decrease in the dose of esis and increase insulin-mediated glucose uptake by insulin when the GFR is between 10 and 50 ml/min and a insulin -sensitive peripheral tissues. Metformin is the 50% decrease of the dose when the GFR is <10 ml/min.37 only available drug in this group. Metformin is one of the Therefore in patients with renal insufficiency, insulin dose most efficacious oral hypoglycaemic agents and is associ- should be calculated based on the level of GFR to avoid ated with favourable clinical outcomes.48 Metformin is episodes of hypoglycaemia. In all cases, an ‘estimated' recommended as the drug of choice in patients with type GFR (eGFR) can be used.
2 diabetes.49 Metformin does not exhibit the high risk of hypoglycaemia associated with other drugs used to treat Oral hypoglycaemic agents general conditions
diabetes, it is excreted unchanged in urine. Guidelines Clearance of many of the oral hypoglycaemic drugs or discourage the use of metformin in patients with CKD their metabolic products (like that of insulin) is reduced because of its alleged potential to cause lactic acidosis.14 in diabetic patients with renal insufficiency. As a result However, some studies challenge this by showing that of such effects, patients will be exposed to higher levels metformin has less risk of causing lactic acidosis than- of respective drugs or their metabolites potentiating previously thought. Metformin has been shown to have side-effects. This has been found to be serious in patients no effect on intracellular lactate production.50–52 Even in with CKD stages 3 to 5 (eGFR <60 ml/min). patients with renal failure, the use of metformin was not associated with significant rise in lactate levels.53–54 Diabetic patients on metformin developed significant These drugs are insulin secretagogues and increase the lactic acidosis only when they had other co-morbidities level of endogenous insulin. Because of their effect in such as hypotension, hypoxaemia, acute kidney injury, increasing the level of endogenous insulin, these drugs or other acute pathophysiological insults.55–57 CKD has have the potential to cause significant hypoglycaemia, been shown to cause insulin resistance;58 being an insu- especially in patients with renal insufficiency.38 These lin sensitiser metformin may improve this as well. Re- are one of the commonest prescribed group of medica- searchers have shown that metformin is safe to be used tions in diabetic patients, with one study showing that in patients with CKD provided that dose adjustments Vol 22 No 1 May 2014 African Journal of Diabetes Medicine 13 diabetes. It has been developed following improved un- are made according to the level of renal function.54 A derstanding of the incretin effect in the pathophysiology review article on the use of metformin in patients with of type 2 diabetes. In this group, we have glucagon-like CKD has shown that its use is beneficial with respect to peptide 1 receptor analogues and selective dipeptidyl cardiovascular outcomes and metabolic parameters in peptidase 4 inhibitor is approved for use. patients with diabetes and CKD.59,60 The long-time belief Exenatide is the glucagon-like peptide 1 receptor ana- that metformin use in patients with CKD is highly as- logue. Pharmacologically, it has only modest glycaemic sociated with lactic acidosis may be exaggerated based efficacy, but also has the advantage of causing weight loss, on recent evidence by investigators. unlike most of the other glycaemic agents.68 Exenatide Though the evidence for lactic acidosis-risk and CKD is cleared primarily by the kidneys. Studies have shown may be weak, it is generally agreed that the drug should that renal clearance of exenatide is significantly reduced not be used, or the dose reduced, in significant CKD. in patients with CKD stages 4 to 5. Several case reports An old system was to discontinue the drug if the serum show that the use of exenatide is associated with acute creatinine rose above 150 mmol/l, but current guidelines kidney injury or progression of CKD.69,70 Its use is there- use the estimated GFR (eGFR). One simple system is to fore not recommended in patients with CKD stages 4 and use metformin freely if the eGFR is >45; use with caution 5.20 The other available incretin mimetic, liragrutide, is (and in lower doses) when the eGFR is 30–45, and not fully metabolized elsewhere in the body and the kidneys to use at all if the eGFR is <30.61 are not a major organ in its elimination.71 When used in single dosing, it has not been shown to cause any effect Thiazolidinediones (pioglitazone)
in patients with CKD stages 4 to 5;70 however, there is Thiazolidinediones enhance insulin action in insulin not enough data on long-term use, hence it is not recom- target tissues through binding to peroxisome proliferator- mended when eGFR is <60 ml/min.20 activated receptor gamma. Pharmacologically, these The dipeptidyl peptidase (DPP-4) inhibitors work drugs have glycaemic efficacy proven to be equivalent to by decreasing the breakdown of endogenous incretin sulphonylureas and biguanides with less hypoglycaemic hormones, as a result improving postprandial and fast- episodes. Thiazolidinediones are metabolised by the ing blood glucose levels. This group includes drugs like liver to products that have either very weak action as sitagliptin, saxagliptin, vildagliptin, and linagliptin. in rosiglitazone or moderate activity as in pioglitazone. They have been shown to be safe in the management of These drugs have been shown to be effective without hyperglycaemia in patients with CKD.72–74 However, with increasing the risk of hypoglycaemia in patients with the exception of linagliptin, the rest require a downward renal insufficiency.62–64 Some studies have suggested dose adjustment with declining renal function.20,73 that the use of thiazolidinediones in diabetic patients with renal insufficiency may have renoprotective effects. Alpha-glucosidase inhibitors
Thiazolidinediones have been shown to either prevent Other oral agents include alpha-glucosidase inhibitors or slow progression of DKD independent of glycaemic (acarbose and miglitol). These act by inhibiting intestinal control.65 Other studies have shown that the use of thia- breakdown of oligosaccharides delaying digestion of zolidinediones is associated with reduction in urinary ingested carbohydrates. Acarbose is metabolised nearly excretion of albumin, essential for slowing progression of exclusively in the gastrointestinal tract (GIT) with only DKD.66 The pharmacokinetics of thiazolidinediones has about 2% being systemically absorbed. Miglitol on the not been shown to change even when there is decreasing other hand is largely absorbed systemically and excreted renal function and therefore no dose adjustment is re- unchanged in urine. There is not enough data to support quired when they are used in treating diabetes in patients the use of these drugs in patients with CKD, and their with CKD.67 However, this group of drugs has a known use is not recommended in patients with CKD stages 4 side-effect of fluid retention which may be accentuated to 5.20,47 in patients with renal failure. Also, due to concerns over increased risk of cardiovascular disease, rosiglitazone Meglitinides
has been withdrawn. Pioglitazone is thus now the only Meglitinides are insulin secretagogues which act by glitazone available. As mentioned, because of its hepatic binding to adenosine triphosphate (ATP) dependent metabolism, it can be safely used in all grades of CKD. potassium channels in beta cells in the pancreas. They However, because of lack of information, the manufac- have a potentially lower risk of hypoglycaemia than turers do not recommend its use for patients on dialysis. standard sulphonylureas in patients with CKD, but still Additionally, there have been recent concerns over a pos- need to be used with care.
sible association with bladder cancer, and pioglitazone In this group, repaglinide undergoes hepatic metabo- should not be used in those with a previous diagnosis lism resulting in inactive bi-products with a small risk of of bladder neoplasms, or with unexplained haematuria. hypoglycaemia in patients with CKD.75,76 Another drug in the group nateglinide is mainly metabolised in the Incretin-based insulin secretagogues
liver to weakly active metabolites, of which about 80% This is the new group of drugs for the treatment of type 2 are excreted in urine and 20% in faeces; about 15% of 14 African Journal of Diabetes Medicine Vol 22 No 1 May 2014 the drug is excreted unchanged in urine. With impaired diabetic adult out-patients in Tanzania. BMC Nephrology 2013; renal function, there is accumulation of the drug and 14: 183–8.
9. Detournay B, Simon D, Guillausseau PJ, et al. Chronic kidney its active metabolites which may increase the risk of disease in type 2 diabetes patients in France: prevalence, influence hypoglycaemia.77,78 Nateglinide therefore should be used of glycaemic control and implications for the pharmacological cautiously in patients with CKD. Studies have shown management of diabetes. Diabetes Metab 2012; 38: 102–12.
10. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and that repaglinide accumulation only occurs in severe renal the risk for cardiovascular disease, renal replacement, and death dysfunction, but this is not associated with increased in the United States Medicare population, 1998 to 1999. J Am Soc risk of hypoglycaemia.75,76 Based on this evidence, it is Nephrol 2005; 16: 489-95.
11. Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovas- recommended that both of these drugs be started at lower cular disease mortality associated with microalbuminuria and doses (0.5 mg for repaglinide and 60 mg for nateglinide, gross proteinuria in persons with older-onset diabetes mellitus. each with meals) in CKD.
Arch Intern Med 2000; 160: 1093-100.
12. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A Conclusions
systematic overview of the literature. Arch Intern Med 1997 ;157: Management of patients with diabetes and CKD is a 13. Vassalotti JA, Stevens LA, Levey AS. Testing for chronic kidney challenging task because multiple factors in each condi- disease: a position statement from the National Kidney Founda- tion may affect the other. Diabetes is a leading cause of tion. Am J Kidney Dis 2007; 50: 169–80.
14. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation CKD and a major source of morbidity and mortality in practice guidelines for chronic kidney disease: evaluation, clas- patients with established CKD. Loss of kidney function sification, and stratification. Ann Intern Med 2003; 139: 137–47.
conspires to change glycaemic regulation in ways that 15. Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the can both worsen and improve blood glucose control. National Kidney Foundation (NKF) and the National Institute Despite the unique nature of diabetes in patients with of Diabetes and Digestive and Kidney diseases (NIDDK). Am J CKD, there currently are no specific guidelines to direct Kidney Dis 2003; 42: 617–22.
16. Caramori ML, Kim Y, Huang C, et al. Cellular basis of diabetic glycaemic therapy in these patients. In summary, the nephropathy: 1. Study design and renal structural-functional majority of drugs available to treat hyperglycaemia, and relationships in patients with long-standing type 1 diabetes. especially first-generation sulfonylureas and alpha glu- Diabetes 2002; 51: 506–13.
17. Basi S, Lewis JB. Microalbuminuria as a target to improve cosidase inhibitors, are affected by kidney function and cardiovascular and renal outcomes. Am J Kidney Dis 2006; 47: therefore should be either avoided or used in reduced 18. Dalla Vestra M, Saller A, Bortoloso E, Mauer M, Fioretto P. Struc- doses for patients with CKD. The use of metformin is tural involvement in type 1 and type 2 diabetic nephropathy. controversial because recent evidence shows it may not Diabetes Metab 2000; 26 (Suppl 4): 8–14.
be as toxic as initially thought, but should be avoided 19. Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults when CDK is significant. Thiazolidinediones do not with type 2 diabetes mellitus. JAMA 2003; 289: 3273–7.
require dose adjustments for kidney disease and may 20. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 have an independent beneficial impact on the progres- Update. Am J Kidney Dis 2012; 60: 850–86.
21. Morgan L, Marenah CB, Jeffcoate WJ, Morgan AG. Glycated sion of DKD, though only pioglitazone is now available, proteins as indices of glycaemic control in diabetic patients with and other side-effects restrict its use. Overall, insulin chronic renal failure. Diabet Med 1996; 13: 514–9.
remains the safest glucose-lowering treatment, when 22. Vos FE, Schollum JB, Coulter CV, et al. Assessment of markers of glycaemic control in diabetic patients with chronic kidney CDK in diabetes is associated with markedly low eGFR.
disease using continuous glucose monitoring. Nephrology 2012; 17: 182–8.
23. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term gly- 1. Dirks JH, de Zeeuw D, Agarwal SK, et al. Prevention of chronic caemic control measurements in diabetic patients receiving kidney and vascular disease: toward global health equity-the hemodialysis. Am J Kidney Dis 2002; 39: 297–307.
Bellagio 2004 Declaration. Kidney Int Suppl 2005; 98: S1–6.
24. Riveline JP, Teynie J, Belmouaz S, et al. Glycaemic control in type 2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence 2 diabetic patients on chronic haemodialysis: use of a continu- of diabetes: estimates for the year 2000 and projections for 2030. ous glucose monitoring system. Nephrol Dial Transplant 2009; Diabetes Care 2004; 27: 1047–53.
24: 2866–71.
3. Young F, Critchley JA, Johnstone LK, Unwin NC. A review of 25. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia co-morbidity between infectious and chronic disease in sub- with macrovascular and microvascular complications of type Saharan Africa: TB and diabetes mellitus, HIV and metabolic 2 diabetes (UKPDS 35): prospective observational study. BMJ syndrome, and the impact of globalization. Global Health 2009; 2000; 321: 405–12.
5: 9. doi: 10.1186/1744–8603-5-9.
26. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose 4. Brown WV. Microvascular complications of diabetes mellitus: control and vascular outcomes in patients with type 2 diabetes. renal protection accompanies cardiovascular protection. Am J N Engl J Med 2008; 358: 2560–72.
Cardiol 2008; 102: 10L–13L.
27. Diabetes Control and Complications Trial (DCCT): results of 5. Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and feasibility study. The DCCT Research Group. Diabetes Care 1987; prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin Ther 2009; 31: 2608–17.
28. Yale JF. Oral antihyperglycaemic agents and renal disease: new 6. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence agents, new concepts. J Am Soc Nephrol 2005; 16 (Suppl 1): S7–10.
of chronic kidney disease and decreased kidney function in 29. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of the adult US population: Third National Health and Nutrition insulin. Diabetologia 1984; 27: 351–7.
Examination Survey. Am J Kidney Dis 2003; 41: 1–12.
30. Rave K, Heise T, Pfutzner A, Heinemann L, Sawicki PT. Impact 7. Middleton RJ, Foley RN, Hegarty J, et al. The unrecognized of diabetic nephropathy on pharmacodynamic and pharmaco- prevalence of chronic kidney disease in diabetes. Nephrol Dial kinetic properties of insulin in type 1 diabetic patients. Diabetes Transplant 2006; 21: 88–92.
Care 2001; 24: 886–90.
8. Janmohamed MN. Prevalence of chronic kidney disease in 31. Muhlhauser I, Toth G, Sawicki PT, Berger M. Severe hypoglycae- Vol 22 No 1 May 2014 African Journal of Diabetes Medicine 15 mia in type I diabetic patients with impaired kidney function. Dial Transplant 2009; 24: 2287–8.
Diabetes Care 1991; 14: 344–6.
55. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching 32. Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycaemia for a link with metformin in reports of ‘metformin-associated and its significance in chronic kidney disease. Clin J Am Soc lactic acidosis'. Diabetes Obes Metab 2001; 3: 195–201.
Nephrol 2009; 4: 1121-7.
56. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal 33. Mak RH. Impact of end-stage renal disease and dialysis on and nonfatal lactic acidosis with metformin use in type 2 diabetes glycaemic control. Semin Dial 2000; 13: 4–8.
mellitus. Cochrane Database Syst Rev 2010; 4: CD002967.
34. Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. De- 57. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal creased insulin requirement in relation to GFR in nephropathic and nonfatal lactic acidosis with metformin use in type 2 diabetes Type 1 and insulin-treated Type 2 diabetic patients. Diabet Med mellitus. Cochrane Database Syst Rev 2010; 1: CD002967.
2003; 20: 642–5.
58. Liao MT, Sung CC, Hung KC, et al. Insulin resistance in patients 35. Baldwin D, Zander J, Munoz C, et al. A randomized trial of two with chronic kidney disease. J Biomed Biotechnol 2012; 10: 691369.
weight-based doses of insulin glargine and glulisine in hospital- 59. Pilmore HL. Review: metformin: potential benefits and use in ized subjects with type 2 diabetes and renal insufficiency. Diabetes chronic kidney disease. Nephrology 2010; 15: 412–8.
Care 2012; 35: 1970–4.
60. Klachko D, Whaley-Connell A. Use of metformin in patients 36. Rubin DJ, Rybin D, Doros G, McDonnell ME. Weight-based, with kidney and cardiovascular diseases. Cardiorenal Med; 1: insulin dose-related hypoglycaemia in hospitalized patients with diabetes. Diabetes Care 2011; 34: 1723–8.
61. Sharif A. Metformin for patients with diabetes and comcomitant 37. Charpentier G, Riveline JP, Varroud-Vial M. Management of renal restrictions – is there an evidence base? Quart J Med 2013; drugs affecting blood glucose in diabetic patients with renal 106: 291–4.
failure. Diabetes Metab 2000; 26 (Suppl 4): 73–85.
62. Chapelsky MC, Thompson-Culkin K, Miller AK, et al. 38. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea- Pharmacokinetics of rosiglitazone in patients with varying induced hypoglycaemia in diabetic patients with end-stage degrees of renal insufficiency. J Clin Pharmacol 2003; 43: 252–9.
renal disease. Am J Kidney Dis 2000; 35: 500–5.
63. Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Phar- 39. Wysowski DK, Armstrong G, Governale L. Rapid increase in the macokinetics of rosiglitazone in patients with end-stage renal use of oral antidiabetic drugs in the United States, 1990–2001. disease. J Int Med Res 2002; 30: 391–9.
Diabetes Care 2003; 26: 1852–5.
64. Mohideen P, Bornemann M, Sugihara J, et al. The metabolic 40. Balant L, Zahnd G, Gorgia A, Schwarz R, Fabre J. Pharmaco- effects of troglitazone in patients with diabetes and end-stage kinetics of glipizide in man: influence of renal insufficiency. renal disease. Endocrine 2005; 28: 181–6.
Diabetologia 1973; 9: 331–8.
65. Sarafidis PA, Bakris GL. Protection of the kidney by thiazolidin- 41. Brier ME, Bays H, Sloan R, et al. Pharmacokinetics of oral gly- ediones: an assessment from bench to bedside. Kidney Int 2006; buride in subjects with non-insulin-dependent diabetes mellitus 70: 1223–33.
and renal failure. Am J Kidney Dis 1997; 29: 907–11.
66. Nakamura T, Ushiyama C, Suzuki S, et al. Effect of troglitazone 42. Jonsson A, Rydberg T, Sterner G, Melander A. Pharmacokinetics on urinary albumin excretion and serum type IV collagen con- of glibenclamide and its metabolites in diabetic patients with centrations in Type 2 diabetic patients with microalbuminuria impaired renal function. Eur J Clin Pharmacol 1998; 53: 429–35.
or macroalbuminuria. Diabet Med 2001; 18: 308–13.
43. Rydberg T, Jonsson A, Roder M, Melander A. Hypoglycaemic 67. Budde K, Neumayer HH, Fritsche L, et al. The pharmacokinet- activity of glyburide (glibenclamide) metabolites in humans. ics of pioglitazone in patients with impaired renal function. Br Diabetes Care 1994; 17: 1026–30.
J Clin Pharmacol 2003; 55: 368–74.
44. Rosenkranz B, Profozic V, Metelko Z, et al. Pharmacokinetics 68. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy and safety of glimepiride at clinically effective doses in diabetic in type 2 diabetes: systematic review and meta-analysis. JAMA patients with renal impairment. Diabetologia 1996; 39: 1617–24.
2007; 298: 194–206.
45. Asplund K, Wiholm BE, Lundman B. Severe hypoglycaemia 69. Weise WJ, Sivanandy MS, Block CA, Comi RJ. Exenatide- during treatment with glipizide. Diabet Med 1991; 8: 726–31.
associated ischemic renal failure. Diabetes Care 2009; 32: e22-3.
46. Holstein A, Plaschke A, Hammer C, Egberts EH. Characteristics 70. Johansen OE, Whitfield R. Exenatide may aggravate moderate and time course of severe glimepiride- versus glibenclamide- diabetic renal impairment: a case report. Br J Clin Pharmacol 2008; induced hypoglycaemia. Eur J Clin Pharmacol 2003; 59: 91–7.
66: 568–9.
47. Snyder RW, Berns JS. Use of insulin and oral hypoglycaemic 71. Jacobsen LV, Hindsberger C, Robson R, Zdravkovic M. Effect of medications in patients with diabetes mellitus and advanced renal impairment on the pharmacokinetics of the GLP-1 analogue kidney disease. Semin Dial 2004; 17: 365–70.
liraglutide. Br J Clin Pharmacol 2009; 68: 898–905.
48. UK Prospective Diabetes Study (UKPDS) Group. Effect of in- 72. Chan JC, Scott R, Arjona Ferreira JC, et al. Safety and efficacy tensive blood-glucose control with metformin on complications of sitagliptin in patients with type 2 diabetes and chronic renal in overweight patients with type 2 diabetes (UKPDS 34). Lancet insufficiency. Diabetes Obes Metab 2008; 10: 545–55.
1998; 352: 854–65.
73. Mikhail N. Use of dipeptidyl peptidase-4 inhibitors for the 49. Nathan DM, Buse JB, Davidson MB, et al. Management of hy- treatment of patients with type 2 diabetes mellitus and chronic perglycaemia in type 2 diabetes: A consensus algorithm for the kidney disease. Postgrad Med 2012; 124: 138–44.
initiation and adjustment of therapy: a consensus statement from 74. Nowicki M, Rychlik I, Haller H, et al. Long-term treatment with the American Diabetes Association and the European Association the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with for the Study of Diabetes. Diabetes Care 2006; 29: 1963–72.
type 2 diabetes mellitus and renal impairment: a randomised 50. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Meta- controlled 52-week efficacy and safety study. Int J Clin Pract bolic effects of metformin in non-insulin-dependent diabetes 2011; 65: 1230–9.
mellitus. N Engl J Med 1995; 333: 550–4.
75. Hasslacher C. Safety and efficacy of repaglinide in type 2 diabetic 51. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin patients with and without impaired renal function. Diabetes Care on glucose and lactate metabolism in noninsulin-dependent 2003; 26: 886–91.
diabetes mellitus. J Clin Endocrinol Metab 1996; 81: 4059–67.
76. Schumacher S, Abbasi I, Weise D, Hatorp V, Sattler K, Sieber J, 52. Velussi M, Cernigoi AM, Viezzoli L, Caffau C. [Median-term (4 et al. Single- and multiple-dose pharmacokinetics of repaglinide months) treatment with glibenclamide + metformin substituting in patients with type 2 diabetes and renal impairment. Eur J Clin for glibenclamide + phenformin lowers the lacticemia levels in Pharmacol 2001; 57: 147–52.
type-2 diabetics (NIDDM)]. Clin Ter 1992; 141: 483–92.
77. Inoue T, Shibahara N, Miyagawa K, et al. Pharmacokinetics of 53. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal nateglinide and its metabolites in subjects with type 2 diabetes and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus and renal failure. Clin Nephrol 2003; 60: 90–5.
mellitus: systematic review and meta-analysis. Arch Intern Med 78. Nagai T, Imamura M, Iizuka K, Mori M. Hypoglycaemia due 2003; 163: 2594–602.
to nateglinide administration in diabetic patient with chronic 54. Mani MK. Metformin in renal failure-weigh the evidence. Nephrol renal failure. Diabetes Res Clin Pract 2003; 59: 191–4.
16 African Journal of Diabetes Medicine Vol 22 No 1 May 2014

Source: http://www.africanjournalofdiabetesmedicine.com/articles/may_2014/AJDM%20pp12-16%20(Mpondo).pdf