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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
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16 African Journal of Diabetes Medicine Vol 22 No 1 May 2014

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15. Joint Advisory Committee on the Ethics of Investment 1 Role and Function of the Committee 1.2 SRI Reporting RequirementsIn July 2000 regulations came into force 1.1 Terms of Reference that obliges all pension funds to consider The Joint Advisory Committee on their policy, if any, on socially responsible the Ethics of Investment (JACEI) was

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MIDLANDS TRENT MEDICINES INFORMATION SERVICE QIPP Detail Aid Support Document Providing support for quality in prescribing Sildenafil- a generic opportunity KEY MESSAGES Sildenafil came off patent in June 2013 and the cost of generic tablets has fallen dramatically. Ensure that all prescriptions for sildenafil are written generically.