This is presentation on 2023 ASC updated guidelines on complication-centric management of patient with type 2 diabetes. 2023 update stresses importance of individualized treatment of patient and idea of complication-centric and patient with chronic kidney disease, atherosclerotic heart disease, and heart failure. At this point, diabetic kidney disease or chronic kidney disease and diabetes is a leading cause of kidney failure worldwide. It is a major amplifier of morbidity and mortality in type 2 diabetes. We diagnose it as persistent structural and functional damage to kidney reflected in loss of glomerular filtration rate and albuminuria that persist for longer than 90 days. Epidemiological study indicate that 30% to 40% of patients with type 2 diabetes will develop in their lifetime diabetic kidney disease. Some studies actually indicate that close to 50% of patients will develop different degrees of kidney disease during their lifetime. Since type 2 diabetes is frequently diagnosed late, kidney disease may be present even at the time of diagnosis, prompting recommendations to start screening yearly for kidney disease in patients with type 2 diabetes using both GFR and albuminuria criteria. Chronic kidney disease is a major amplifier and risk for cardiovascular disease and is actually recognized as a cardiovascular risk equivalent. In a study of 25 to 34 years old patients with kidney failure, it was found that their annual mortality is increased between 500 and 1,000 fold compared to their peers with no kidney disease and is similar to those of 85 year old individuals in general population. 2017 study assessed effect of development of diabetic kidney disease on lifespan of patients with type 2 diabetes. They found that CKD without diabetes shortens lifespan by 6 years, diabetes without kidney disease shortens lifespan by 10 years, but a combination of diabetes and kidney disease shortens lifespan by 16 years. We need to remind ourselves that there are very few conditions that shortens lifespan similar to this and that mortality of advanced stages of diabetic kidney disease is similar to those of patients with stage 4 lung cancer. Because of recognition of increased risk of progression kidney disease and cardiovascular risk, Kidego workgroup developed now well-recognized heat map measuring both albuminuria and glomerular filtration rate. They stratified risk of patients from low to very high risk depending on the level of GFI decline and proteinuria. This map is very useful not just in diagnosing chronic kidney disease and diabetes, but also understanding of risk progression to kidney failure or dying from cardiovascular disease. And helps understand the updated complication-centric algorithm of 2023 AAC guidelines. To better understand adjustments and individualization of glycemic targets in patients with diabetes 2 and chronic kidney disease, it's important to remind ourselves that kidney actually plays an important role in maintaining glucose homostasis. The role of kidney is important in two main aspects. One in gluconeogenesis, as kidney provides about a quarter of circulating glucose in postprandial state. And also in reabsorption of glucose from primary filtrate in the kidney. This role of reabsorption of glucose in kidney is used as a main mechanism of action for certain glucose transporters to inhibitors. Another important aspect of patients with advanced kidney disease is understanding of insulin resistance, which develops in all patients and correlates well with the severities of disease. And it's very prominent in a patient with kidney failure on hemodialysis. And also of reduced gluconeogenesis in patients with advanced kidney disease because of loss of nephron mass. In addition, this patient has different pharmacodynamic alterations of glucose-lowering drugs. This approach was challenged by several studies, which were published between 2009-2014 in a patient with advanced diabetes with complication, both micro- and macrovascular complications. Three studies, ACCORD, ADVANCE, and VADT, showed that in patients with advanced kidney disease and cardiovascular disease, tight control of hyperglycemia actually carries no cardiovascular or all-cause mortality benefits and does increase risk of hyperglycemia. So in patients with already existing microvascular circulation, tight control of glucose does not translate in improved clinical outcomes. Actually, patients with a kidney disease have an increased risk for hyperglycemia, and this risk actually corresponds well with a degree of kidney damage. With this in mind, current guidelines shift from glucose-lowering to complication-centric targets in management of patients with heart failure, atherosclerotic heart disease, and chronic kidney disease. In this population, it is recommended to use sodium-glucose co-transporter inhibitors and a glucagon-like peptide 1-receptor agonist independent of individualized glycemic targets. This therapy is recommended based on a number of initially cardiovascular outcome trials, later kidney and heart failure outcomes trials, that established and confirmed astonishing improvement of heart and kidney outcomes as well as a risk of dying. The first signal of SGL-2 effect on the progression of kidney disease and improved outcomes of heart failure were found in cardiovascular outcome trials. These trials were dictated by FDA, and since 2008, all new antidiabetic therapies had to prove in a real-life setting non-inferiority to all therapies. And they had to prove that they do not increase risk of cardiovascular events. In these cardiovascular outcome trials, SGL-2s and GLP-1 actually outperformed traditional antihyperglycemic therapies. In SGL-2 inhibitor case, the benefits were primarily observed in progression of kidney disease and heart failure outcomes. And with the GLP-1 receptor agonist, benefits were established with atherosclerotic cardiovascular disease and new onset of progression of alpha-minoria. Following cardiovascular outcome trials, we saw dedicated kidney and heart failure trials with SGL-2 inhibitors and a dedicated kidney outcome trial with a semaglutide, which is still ongoing and is expected to report within the next 12 months. This slide outlines meta-analysis done on 27 SGL-2 inhibitor studies studying effects of SGL-2 inhibitors. These studies enrolled over 7,000 patients with GFR less than 60 and show significant benefits on cardiovascular death, myocardial infarction admissions for heart failure, GFR slope, and composite kidney failure. Another meta-analysis included patients enrolled in all kidney outcomes dedicated trials, namely CREDENCE with aconoglyphosin and SGL-2 inhibitors. Patients with diabetes and kidney disease scored, which studied aconoglyphosin in patients with kidney disease. BAPA-CKD studied apoglyphosin in patients with and without diabetes caused chronic kidney disease. EMPA-Kidney, which studied apoglyphosin in patients with kidney disease with and without diabetes and showed improved kidney outcomes in progression of kidney disease of any etiology. Similarly, meta-analysis of trials with SGL-2 inhibitors showed their effect on improved non-cardiovascular death, all-cause death, as well as heart failure in a patient with diabetes. To help understand observed heart, kidney, and mortality outcomes in SGL-2 inhibitor trials, it is helpful to remind ourselves of mechanism of action of these medications. As I mentioned earlier, one of the main functions of the kidney in maintaining glucose hemostasis is reabsorption of glucose in proximal tubule. This process is achieved via SGL-2. This is the active process, and with the glucose co-transporters reabsorbs sodium and chloride. In diabetes, there is a paradoxical increase of sodium-glucose co-transporter in proximal tubule, resulting in increased reabsorption of glucose and passively sodium and chloride in the plasma. As a result, there is a decrease in delivery of solutes to maculodensin, which results in changes of efferent incoming arteriole in glomerul and increased glomerular pressure, resulting with glomerular hypertension. Introduction of sodium-glucose co-transporters in kidney blocks reabsorption of glucose as well as sodium chloride, resulting in increased delivery of solutes to maculodensin and normalization of glucose. As a result, pressures or hypertension in glomerul is normalized, which helps preserve glomerul. Also, the blocking of reabsorption helps decrease the pressure on tubule. After reviewing mechanism of action of SGL-2 inhibitors, we shortly point out several biological actions that help us understand cardio-renal protection observed in clinical trials and a prompting changing of recommendations. For pharmacological interventions in patients with heart failure and kidney disease. Inhibition of SGL-2 co-transporters increases the solute delivery to distal tubule and helps restore glomerular feedback, which then helps with renal hemodynamics and glomerular hypertension. This blockage of co-transporters also blocks reabsorption of glucose and results in glucosuria which ultimately leads to calorie loss even after organism adjusts to continue calorie loss. Because of decreased reabsorption of glucose in proximal tubular workload is improved. As well as oxidative stress. Diuretic like effect of nitreoresis and diuresis helps with the blood pressure control and decreases circulating plasma volume. This effect reminds us on importance of checking and adjusting patient medications prior to initiation sodium glucose inhibition. Specifically we should pay attention to diuretic therapy and adjust the dose. Because of glucosuria and calorie loss metabolism is switched on utilization of ketones which are very efficient cell fuel. This switch in cellular fuel from carbohydrates to ketones has two repercussions. One is improved cardiac function but also increased risk of euglycemic ketoacidosis. In the heart we see decreased left ventricular wall stress as well as decreased oxidative stress with increased oxygen delivery. It is very important to point out that cardio-renal protection is independent of anti-hyperglycemic effect of SGL2 inhibition. This statement is supported by several analysis of major SGL2 inhibitor trials. But also by preserved cardio-renal protective effect of in the patients with reduced GFR to less than 45 ml per minute who have blunted anti-hyperglycemic effect. This table outlines current indication and dose adjustments suggested dose adjustments for empaglifosin, trapaglifosin, and canaglifosin. It is very important to remind ourselves that anti-hyperglycemic effect of these therapies is reduced in a patient with advanced kidney failure because of their mechanism of action. In the patients with heart failure and kidney disease, they are primarily used as organ protective therapies independent of need for glucose lowering. It is very important to discuss adverse events observed with sodium-glucose contra-supporting inhibitors. The most serious adverse effect is glucosemic diabetic ketoacidosis. And actually, all adverse events associated with this class of medication is closely related to their mechanism of action. As I mentioned previously, they cause glucosuria resulting in increased ketone utilization. And in the patients with acute illness, they can cause glucosemic diabetic ketoacidosis. It is crucial to increase awareness because this patient don't necessarily have to have low pH. So it's crucial to increase awareness of this condition. This adverse effect should be discussed with the patient at the time of initiation of therapy. We also should keep in mind that the basal insulin needs to be titrated gradually. Patients should be warned that if they feel sick, they need to stop taking SGL2 inhibitor, especially if they develop nausea, vomiting, or diarrhea. They need to keep themselves hydrated. And if they're not able to do so, they need to go to emergency room period. One of the possible solutions is also giving patient prescriptions for urine acetone strips so they can test themselves for ketoacidosis if they don't feel well. Genital mycotic infections are closely related to glucosuria and warning patients on frequent change of underwear. And the hygiene is very important. Because of the glucosuria associated with osmotic diuresis, one of the considerations should be adjustment of diuretic at the time of initiation of these therapies. Amputation is observed only in trials of canaglifazine and develops in patients who already have microvascular changes and a history of limb amputation. So it's important to encourage self-examination and examine patients feed very closely during the visits. Hypoglycemia is infrequent adverse event, mostly in patients with a preserved glomerular filtration rate. It is important to discuss changes in glomerular filtration rate as a result of normalization of glomerular filtration pressures. Loss of GFR of 3 to 5 mLs following initiation of therapy is observed in all trials. However, that does not translate in the progression of kidney disease. Contrary-wise, if we look at the pink with the inpatient with ampaglifazine and a gray line, which is the glomerular filtration rate in the patient with the placebo, notice that after initial dip in glomerular filtration rate, this patient actually preserve kidney function and GFR decline over time is preserved. The same thing is noticed with canaglifazine after initial dip. This patient preserve their glomerular filtration rate compared with a patient on placebo. Because of potential decrease of GFR of 3 to 5 mLs after initiation of therapy, it's important to follow them, to follow the patient a few weeks after they are put on therapy to ensure return to baseline. Actually, even if they do not return to baseline, which is noticed in some of the patients, the long-term preservation effect of GFR is observed. So initial drip of 3 to 5 mLs following initiation of therapy is not observed. 3 to 5 mLs following initiation of therapy is not considered a reason to discontinue therapy. The current understanding of this dip is normalization of hyperfiltration and glomerular hemodynamics following reversal of increased glucose reabsorption and decreased delivery of solids to maculodensin. Also, glucagon-like receptor agonists have multiple biological effects primarily on decreased mortality of gut, decreased gastric amputation, increased insulin secretion, and decreased glucagon secretion. They also help with hunger. Hunger. In the kidney, they increase diuresis and nitreuresis and decrease inflammatory markers as well as activation of in-situ inflammatory cells and recruitment of circulatory inflammatory cells. Net effect of biological effect is weight loss, decreased inflammatory markers, and increased nitreuresis, which helps with multiple structural changes observed in diabetic kidney disease. They also display effect on cardioprotection and increased cardio output in glucose utilization, explaining their protective cardiac effect in patients with ischemic cardiovascular disease. Same meta-analysis reviewed three-point mis-outcomes as well as a cardiovascular death and confirmed cardioprotective effect observed in individual trials. It's very important to point out that cardiovascular protection was irrespective of baseline kidney function, which is very important if we remind ourselves of increased and progressive cardiovascular risk we discussed earlier in Kidney-GoHeatMap. This table outline suggests the adjustment of those two kidney function and current indication. It's important to remind ourselves that these medications are used as a not just as a antihyperglycemic agent but for their organ protections as a first-line therapy in people with atherosclerotic cardiovascular disease and stroke. In patients with a kidney disease, they are interchangeable with the SGL-2 inhibitors or can be added if glycemic targets are not achieved with the SGL-2 inhibitor. In contrast to SGL-2 inhibitors, they preserve their antihyperglycemic properties even in a patient with advanced kidney disease and kidney failure and can be used in dialysis patients. Again, used in patients with chronic kidney disease, TIA, or atherosclerotic cardiovascular disease, is based on their organ protective properties. Adverse events and mitigation strategies for GLP-1 receptor agonist are similar to sodium glucose contrasporter inhibitors are driven associated with their biological effect, primarily slowing down gastrointestinal motility and emptying stomach emptying. Gastrointestinal motility and stomach emptying. These patients can experience nausea, vomiting, and diarrhea, so it's suggested to start a patient on the lowest recommended dose and then titrate it slowly. GLP-1 receptor agonist preserves their antihyperglycemic effect even in patients on dialysis, and they decrease hemoglobin A1c to about 1%. Therefore, they can be used not just for cardio-renal protective therapy, but also as antihyperglycemic agent. A review of available evidence on the effect of SGL-2s and GLP-1 receptor agonist on cardio-renal outcomes, as well as improved cardiovascular and all-cause mortality, explains adjustments of recommendations for complication from antihyperglycemic or glycemic-centric approach to complication-centric algorithms for patients with chronic kidney disease, heart failure, and atherosclerotic heart disease like stroke, TIA, and atherosclerotic kidney disease. So, on top of lifestyle interventions and adjusted glycemic targets, that all patients with chronic kidney disease are supposed to be started on SGL-2 inhibitor or GLP-1 receptor agonist if intolerant of SGL-2. Similarly, patients with heart failure are to be started on SGL-2 receptor inhibitors, independent of diabetic status. Just one more reminder that these classes of agents are used in the patients with atherosclerotic heart disease, heart failure, and chronic kidney disease for their organ protective effects, not for their antihyperglycemic effects. The advantage of a GLP-1 receptor agonist in patients with advanced kidney disease is that they preserve their glucose-lowering effects, even in the patient with advanced kidney disease and kidney failure. And shortly to outline that a patient with a CKD should be started on SGL-2, independent or if intolerant on GLP-1. And if a glycemic target is not achieved within three months, in those on GLP-2, we can add GLP-1. And on those on GLP-1, we can add SGL-2. In patients with a stroke, patients with a stroke or TI-8 should be started on GLP-1 receptor agonist on pioglitazone. And those with heart failure, all of them should be on SGL-2 receptor agonist. We should, on those who are started on SGL-2, if there is a need for reaching glycemic target or improved albuminuria effect, the GLP-1 receptor agonist can be started and vice versa. Preferably in kidney disease and heart failure, the first-line therapy is SGL-2 inhibitor. In patients with atherosclerotic cardiovascular disease and stroke or TI-8, recommended first-line therapy is GLP-1 receptor agonist. Thank you.

type 2 diabetes

individualized treatment

chronic kidney disease

heart failure

SGL-2 inhibitors

GLP-1 receptor agonists

cardio-renal protective effects

glycemic control