Diabetes at the limits

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1 Earn 3 CPD Points online Extending the limits of diabetes care Diabetes at the limits KEY MESSAGES There is a very close relationship between the extent of hypoglycaemia and the failure of glucose lowering to have macrovascular benefits Professor Mark Cooper The Baker Institute Australia Good glucose control reduces the risk of end-stage renal disease (ESRD) by 50% in type 2 diabetes patients. However, very few patients die from renal disease; the majority die from cardiovascular disease The benefits of tight glycaemic control on peripheral neuropathy are relatively disappointing. Amputations and peripheral vascular disease (PVD) are still a major hospital cost in diabetic care There are very poor data to show any benefit of tight glycaemic control on heart failure or stroke using currently available agents The lack of macrovascular benefit from intensive glucose control is likely to be due to the use of drugs with significant complications of hypoglycaemia and weight gain New agents such as SGLT-2 inhibitors offer an opportunity to address this issue as they do not cause weight gain or hypoglycaemia. Real world clinical evidence from Western countries shows that better care of type 2 diabetic patients is resulting in a reduction in cardiovascular disease and a modest reduction in kidney disease This article was made possible by an unrestricted educational grant from AstraZeneca, which had no control over content Real world clinical evidence from Western countries shows that better care of type 2 diabetic patients is resulting in a reduction in cardiovascular disease and a modest reduction in kidney disease, Professor Mark Cooper, from the Baker Institute, Australia, noted. However, clinical trial evidence with regard to macrovascular disease reduction from good glycaemic control is still disappointing in type 2 diabetes. The real-world improvement in preventative care of adults with diabetes (type 1 and type 2) is supported by a recent data review of the national health statistics in the United States. 1 The rates of all five complications declined with the largest relative declines being in acute myocardial infarction (MI) (reduced by 68%) and death from hyperglycaemic crisis (reduced by 28%). While the rate of complications may be decreasing, we are, of course, still flooding the cardiologists rooms and the dialysis service because of the large numbers of type 2 diabetes patients. With regard to type 1 diabetes, life expectancy now is only seven years lower than that of a non-diabetic person; and if a type 1 diabetic patient does not have kidney disease, they will live longer than their non-diabetic counterparts. This is much better than 20 years ago, when life expectancy of type 1 diabetics was in the 50-year range. The limits of glucose control The ADVANCE, ACCORD and VADT trials explored the limits to which glucose reduction incurs more harm than benefit; these studies have showed that the tipping point with traditional drugs (insulin, sulphonylureas and thiazolidinediones) is reached when HbA 1c drops to 6.5%, causing more macrovascular complications than at higher HbA 1c levels. This is likely to be due to the very close association between hypoglycaemia and an increased risk of cardiovascular events. 2 The evidence for microvascular benefit from glycaemic control in type 2 diabetes is most robust for diabetic nephropathy. Diabetic nephropathy results from March

2 It is clear that most people with type 2 diabetes will not die from renal complications; they will die from cardiovascular complications, so this is the real issue. the interaction between metabolic and haemodynamic factors. Glucose is the main driver of the metabolic effects, causing nephropathy through activation of glucose-dependent pathways that induce oxidative stress, polyol pathway flux, hexosamine flux and accumulation of advanced glycated end-products (AGEs). 3 Glycaemic control reduces the incidence of end-stage renal disease (ESRD), but intensive glucose control has not been shown to further reduce the number of patients with the condition. 4 We have had to use a surrogate marker of kidney disease, microalbuminuria, to evaluate the extent of nephropathy. The ACCORD, ADVANCE and UKPDS data have shown a clear-cut but modest reduction in this marker, Professor Cooper noted. It is important to note that reduction in microalbuminuria took 9-12 years to emerge in the UKPDS trials of newly diagnosed type 2 diabetics, a timespan not usually covered by contemporary clinical trials. Interestingly, macroalbuminuria benefits are more clear-cut. This may suggest that renal improvements arising from tight glucose control are easier to measure when there is already existing kidney disease. Lifestyle is important. The LOOK- AHEAD study of lifestyle modification, aiming at weight loss through reduced caloric consumption and increased physical activity, which was conducted over 10 years, showed a significant reduction in the extent of retinopathy relative to those without lifestyle motivation. 5 The large scale ADVANCE trial of some patients without kidney disease at baseline showed that 100 patients developed subsequent kidney disease. There was a 50% reduction in ESRD in the intensive glycaemic arm. In my view, if one puts all these data together, there are renal protection benefits from glucose-lowering. It is clear that most people with type 2 diabetes will not die from renal complications; they will die from cardiovascular complications, so this is the real issue, Professor Cooper said. Improved real-world control of glucose in both type 1 and type 2 diabetes has resulted in a dramatic decrease in hospital admissions for ketoacidosis and hyperglycaemic coma, both of which carry a terrible burden of morbidity and mortality. The real prize of cardiovascular benefits from glucose-lowering remains elusive, however, Professor Cooper noted. A recent meta-analysis of intensive glucose control studies showed a trend towards a 15% reduction in non-fatal MI, which is supported by the classic physiological understanding of glucose s role in promoting atherosclerosis and increasing inflammation. There was also a trend to a reduction in fatal MI with intensive therapy, but this did not reach significance. Glucose control has not been shown to reduce heart failure or stroke, whether non-fatal or fatal, in a type 2 diabetic population. 6 In my view the reason we are not seeing cardiovascular benefit is because the drugs we are using (insulin, sulphonylureas, PPAR gamma-agonists) are associated with two adverse effects, weight gain and hypoglycaemia, Professor Cooper stressed. The new agents, such as the DDP-4 inhibitors in the EXAMINE trial, which looked at cardiovascular safety, did not show an increase in adverse cardiovascular events in type 2 diabetes patients who had had a recent acute coronary syndrome. 7 The SAVOR trial of saxagliptin in type 2 diabetes patients with moderate/severe renal impairment also did not show an effect on the risk of ischaemic cardiovascular events, but heart failure hospitalisation was increased. 8 The DPP-4 inhibitors to date have therefore not shown cardiovascular benefit, said Professor Cooper. Why are we not reducing cardiovascular mortality? Is it the way that we do things? Is it the drugs we are using? Is it because the outlook for type 2 diabetes has improved so much, that any relatively minor deleterious effect (hypoglycaemia) can mask the desired outcome of cardiovascular event reduction? The SGLT-2 inhibitors may offer a new opportunity to address this issue; as may the GLP-1 agonists. We now know that hypoglycaemia results in harm, Professor Cooper observed. In the setting of intensive 2 march 2015

3 control, there is a doubling of the rate of hypoglycaemia, which is neutralising desired benefit. Patients with higher BMIs in these intensive control trials tended to have more hyperglycaemic events, showing their vulnerability to agents that cause further weight gain. It is evident also that patients in the intensive glucose trials had evidence of macrovascular disease and perhaps these are the last patients we should try to target with intensive glucose control. We need to apply intensive therapy earlier in the course of the disease, he concluded. Professor George L Bakris Director, Comprehensive Hypertension Centre University of Chicago Medicine Chicago, USA Extending the limits of diabetes care in patients with chronic kidney disease Professor George Bakris, University of Chicago Medicine, United States, evaluates the treatment of diabetes at the limits of kidney function - egfr below 60ml/ min/1.73m 2 (mild-moderate kidney function) and extending to those patients with an egfr <30 (stage 4 nephropathy). He pointed out that as GFR drops below 60ml/min, the risk of hypoglycaemia dramatically increases and that those using insulin or oral antidiabetic agents must take cognisance of this severe complication. Insulin dosages can be halved at this level of kidney function; this concept of halving the dose is supported by clinical research in both type 1 and type 2 diabetic patients. 9 Clinicians need to be very selective in their choice of oral antidiabetic agents in patients with limited kidney function (<60ml/min). Sulphonylureas (glimepiride and glibenclamide) are associated with severe hypoglycaemia in type 2 diabetes. 10,11 Of those patients experiencing hypoglycaemia, 60% had egfr lower than 60ml/ min/1.73m 2. Both these sulphonylureas are hepatically cleared, but two metabolically active metabolites are partially cleared by the kidney, Professor Bakris noted. Glipizide is recommended in most guidelines for use in patients with chronic kidney disease (CKD), but it still caused hypoglycaemia in 3% of patients in a oneyear prospective, randomised study; double that of sitagliptin. 12 Metformin use is limited by declining kidney function and should not be used in those with an egfr <30 ml/min/1.73m 2. Professor Bakris endorsed a practical approach to metformin usage and dosing in CKD (Table 1) developed by KDIGO, a global initiative to improve outcomes in kidney disease. Table 1. Metformin dosing: What to do? egfr (ml/min/1.73m 2 ) <60 30 <45 Metformin dosing No limitation of dosing Caution with dosing Monitor egfr every 3 6 months Maximum dose 1000mg/ day Monitor egfr every 3 4 months <30 Stop metformin Stop metformin in in-patients if: Unstable Hypotensive Volume depleted Hypoxic Septic Acute worsening of renal function Adapted from KDIGO march

4 Turning to the newer agents, Professor Bakris noted that the incretin mimetics, the GLP-1 agonists and DPP-4 inhibitors can be used in CKD but doses need to be adjusted (Table 2). Table 2. Summary of oral agents in CKD Sulphonylureas Meglitinides (Repaglinide preferred) Disaccharidase inhibitors (Acarbose, miglitol) Thiazolidinediones (Pioglitazone) Biguanides (Metformin) SGLT-2 inhibitors (Canagliflozin and empagliflozin) DPP-4 inhibitors (Linagliptin, sitagliptin,saxagliptin) Glipizide only; KDIGO guideline approved No dose adjustment Cannot use with creatinine > 2mg/dl (~egfr < 30) Fluid retention and oedema. Worse if nephrotic Bone disease. Additive to renal osteodystrophy? Bladder cancer? Use down to egfr 30ml/min egfr use with caution egfr maximum dose 1000mg/d Discontinue for inpatients if risk factors for lactic acidosis To egfr <45ml/min Linagliptin (no dose adjustment) Others: Reduce dose by 50% to egfr 25ml/min; thereafter -25% full dose (Flynn C, Bakris GL. Noninsulin glucose-lowering agents for the treatment of patients on dialysis. Nat Rev Nephrol 2013; 9(3): ) Two of the new SGLT-2 inhibitors have been registered for use in CKD (canagliflozin and empagliflozin). The rationale for the use of renal sodium glucose co-transporter 2 inhibitors is based on inhibiting the high capacity glucose transporter (SGLT-2) which is located in the proximal tubule of the kidney. 12 The SGLT-2 co-transporter is responsible for 90% of glucose resorption from the kidney. We have known for many years that hereditary mutations of this co-transporter result in renal glycosuria in humans without any complications such as early kidney disease or increased urinary tract infections. This supported the concept of the development of these agents, Professor Bakris pointed out. The new selective SGLT-2 inhibitors can be regarded as osmotic diuretics but they also result in loss of calories, leading to weight loss of 2-3 kg and a small but significant drop in systolic blood pressure. In type 2 diabetes there is an increase in SGLT-2 co-transporter and an increase in the threshold for spill-over into the urine. This is an attempt at compensation for higher plasma glucose levels but fails because the kidney also exhibits increased gluconeogenesis under these conditions. A very important feature of the SGLT-2 inhibitors is that they do not cause hypoglycaemia, because they shift the threshold back to normal and beyond. The total urinary glucose losses are proportional to the ambient plasma glucose level with greater losses occurring at higher glucose levels - less excretion when glucose levels are lower; there is thus a built-in mechanism to prevent hypoglycaemia. The SGLT-2 inhibitors are approved for use in CKD down to 45 ml/min/1.73m 2. While they have some effects on lowering glucose down to egfrs between 30 and 35 (Stage 3b CKD), they are not approved for use at this level. This is an important new class of agents in diabetes management, Professor Bakris concluded. 4 march 2015

5 References 1. Gregg EW, Li Y, Wang J, et al. Changes in diabetesrelated complications in the United States N Engl J Med 2014; 370(16): Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic severe hypoglycaemia and mortality in type 2 diabetes. Retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340: b Forbes JM, Fukami K, Cooper ME. Diabetic nephopathy: where hemodyamincs meets metabolism. Exp Clin Endocrinol Diabetes 2007; 115(2): Coca SG, Ismail-Beigi F, Hag N, et al. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and metaanalysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012; 172(10): LOOK AHEAD Research Group. Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: A secondary analysis of the LOOK AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2014; 2(10): Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011; 343: d6898. Doi: /bmj.d White WB, Cannon CP, Heller SR, et al. The EXAMINE investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369(14): Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus and moderate or severe renal impairment: The SAVOR-TIMI53 trial. Diabetes Care 2015; 38(4): Biesenbach G, Rami A, Schmekal B, Eichbaier-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabetic Med 2003; 20(8): Holstein A, Ferrante SA, Davies MJ, et al. Lower risk of hypoglycaemia with sitagliptin compared to glipizide when either is added to metformin in therapy. Curr Med Res Opin 2012; 28(8): Holstein A, Ploschke A, Hammer C, Egberts EH. Characteristics and time course of severe glimepirideversus glibenclamide-induced hypoglycaemia. Eur J Clin Pharmacol 2003; 59(2): Chao EC, Henry RR. SGLT-2 inhibition a novel strategy for diabetes treatment. Ant Rev Drug Discov 2010; 9(7): Linked article Earn CPD points online Visit Click on Accredited CPD/CEU programmes. Log in or register and start earning CPD points today. Certificates will be ed to you. Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com march