Nephrology Hypertension

Diabetic Kidney Disease: Hyperglycemia Management

Does this patient have chronic kidney disease related to diabetes mellitus?

The patient has had diabetes mellitus (DM) (type 1 or type 2) for at least 5 years. S/he has needed changes in therapy to include increasing doses of insulin or additional therapies to keep the blood sugars in control. S/he may have retinopathy, neuropathy and cardiovascular disease. S/he has been evaluated for the presence of chronic kidney disease (CKD) and has been diagnosed with diabetic nephropathy. Medication therapy appropriate for the level of CKD needs to be addressed in order to attain appropriate target glucose control.

What tests to perform?

Microvascular complications such as kidney disease typically develop over 5-10 years, which reflects the accumulation of excessive glucose exposure. Screening and diagnosis for diabetic kidney diease are covered in the chapter on Diabetic Kidney Disease: General Management.

In brief, for patients with type 1 diabetes, screening should start 5 years after diagnosis (Table 1). In patients with type 2 diabetes, screening should begin at initial diagnosis since the exact onset of diabetes is often unknown. Up to one-third of patients with newly diagnosed type 2 diabetes already have evidence of kidney disease, which in part can also be attributed to hypertension and possibly additional risk factors.

Table I.

A hemoglobin A1c should be measured every 3 months if therapy is changed or if the A1c is not at goal; it can otherwise be followed every 6 months if at goal and glucose control is stable. There can be some inaccuracy of the A1c in patients with CKD. This is in part related to the presence of anemia, hemolysis, reduced lifespan of the red blood cell, and iron deficiency.

Patients should be encouraged to check their blood sugars frequently. The intensity of blood glucose monitoring is dependent on the severity of diabetes and intensity of treatment. For example, a patient taking insulin injection four times daily should check blood glucose levels about four times per day or more. Conversely, a patient with mild diabetes controlled with lifestyle management may only need to check blood sugars several times per week. Goal fasting and premeal blood sugars are <130 mg/dl and goal post-prandial glucoses checked 1 to 2 hours after the meal are <180 mg/dl.

How should patients with diabetes mellitus in chronic kidney disease be managed?

Hyperglycemia is a prime cause of vascular complications, including kidney disease. Glycemic control is essential to delay the progression of diabetes-related kidney disease. Multiple factors must be taken into consideration when determining the appropriate level of glycemic control.

The Diabetes Control and Complications Trial (DCCT) compared intensive insulin treatment with conventional treatment in subjects with type 1 diabetes, with A1c levels of 7.2% vs. 9.1%, respectively. After a mean of 9 years, intensive therapy reduced the occurrence of microalbuminuria, albuminuria and falls in glomerular filtration rate (GFR).

Many of these subjects were then followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) Study, where they were followed for several years after the end of the DCCT. This follow-up study showed risk reduction of diabetic nephropathy persists long-term, even after glycemic control equalized between the two groups, with a mean A1c of 8% for both groups for several years after the DCCT.

Studies in type 2 diabetes show similar results. The UK Prospective Diabetes Study (UKPDS) demonstrated a reduction in development of microalbuminuria by 24% in subjects in the intensive management group achieving an A1c of 7.0% vs. 7.9% in the conventional treatment group. These subjects also had significantly reduced rates of rises in creatinine.

Similar findings were shown in the Veteran Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial, where subjects had significantly lower rates of microalbuminuria and albuminuria. These results were also found in the Kumamoto study and ADVANCE trial.

The general goal A1c in patients with diabetes is about 7% or less to prevent or slow progression of kidney disease. This overall glycemic goal is strongly supported by substantial data from multiple trials showing a reduction in microalbuminuria with tighter glycemic control. The data clearly demonstrates decreased rates of development of microalbuminuria. The number of subjects who then develop albuminuria and declines in GFR are generally reduced as well, albeit some of this is related to fewer patients developing microalbuminuria.

Additionally, any improvement in glycemic control even to A1c levels above 7% results in improvement in nephropathy, as well as retinopathy and neuropathy, when compared to a higher A1c. This supports the concept that the best A1c attainable should be achieved when possible, even if cannot be 7%.

Achieving an A1c of 7% can be difficult. It requires vigilance on the part of the patient and physician and is accompanied by higher rates of hypoglycemia. Thus, the target A1c should be based on the individual. Higher target A1c levels should be considered in children and patients with a prior history of severe hypoglycemia or hypoglycemia unawareness, shortened life expectancy, presence of comorbidities such as seizures, or a long (>25 years) history of diabetes with development of only minimal complications.

The ACCORD study showed higher rates of hypoglycemia and mortality in the intensive treatment group attaining an A1c of 6.4% compared to the conventional group achieving a target A1c of 7.5%; the increased mortality could not be attributed to hypoglycemia. In the ADVANCE trial, the intensive treatment group did not have higher rates of mortality. Neither ACCORD, ADVANCE, nor VADT demonstrated improved cardiovascular outcomes with lower A1c levels; therefore, the target A1c is ~7% rather than 6.5% or lower.

In patients at risk of hypoglycemia, a higher target A1c should be strongly considered. The risk of hypoglycemia is greater in patients with Stages 4-5 CKD and the consequences of hypoglycemia may be greater as well. The presence of advanced CKD in an elderly patient who may have coronary artery disease and osteoporosis makes the presence of hypoglycemia particularly risky.

Patients on chronic diaylsis no longer need to achieve good glycemic control to prevent deterioration of kidney function. However, good control may still have benefits in delaying the progression of retinopathy, neuropathy and potentially macrovascular disease such as cardiovascular complications. Survival is also superior with lowering of A1c for patients on dialysis, no matter what the final level attained.

Blood pressure control, lipid management and weight control are vitally important. Please refer to chapters on Diabetic Kidney Disease: General Management and Blood Pressure Management.

Medications for treatment of diabetes

There are multiple therapies available to attain glucose control in diabetes in CKD.

Insulin

All available insulin preparations can be used in CKD, however the insulin type, dose and administration must be tailored to each individual patient to achieve goal glycemic levels but limit hypoglycemia. There are multiple insulin preparations now available.

The rapid-acting insulin analogs aspart (Novolog), lispro (Humalog) and glulisine (Apidra) are absorbed the quickest and are ideal for quick correction of elevated blood sugars or for prandial insulin needs. These insulins have an onset of action at 5 to 15 minutes, peak action at 30-90 minutes and an average duration of about 5 hours. Some studies have shown the duration of action of glulisine to be slightly longer than the other two rapid-acting insulins. These insulins should be given at most 15 minutes prior to a meal.

Patients with Stage 4-5 CKD and those on dialysis often have some degree of delayed gastric emptying; giving rapid-acting insulin after the meal may be helpful for matching the insulin peak with the time of the postprandial blood glucose peak. In patients with nausea who may not know ahead of time how much they will be able to eat, postprandial rapid-acting insulin dosing may be worth trying, Similarly, patients on peritoneal dialysis obtain large amounts of calories from their dialysis fluid and often eat less than they might expect so that postprandial dosing may be helpful for them as well.

The only short-acting insulin available is regular crystalline insulin, which has an onset of action at 30 to 60 minutes, peak action at 2 to 3 hours and duration up to 5 to 8 hours. Regular insulin should ideally be given about 30 minutes prior to a meal.

The available intermediate-acting insulin is isophane, or NPH (neutral protamine Hagedorn). It has an onset of action at 2 to 4 hours, peak concentration at 4 to 10 hours and duration up to 10 to 18 hours. Its use can be limited by its highly variable absorption. In patients getting overnight peritoneal dialysis using a cycler, sometimes the time duration of NPH or premixed insulins (see below) may be useful to cover the glucose absorption that occurs from the dialysis fluid.

The long-acting insulin analogs glargine (Lantus) and detemir (Levemir) are now readily available. Glargine has an onset of action at 2 to 4 hours, with minimal peak and lasts approximately 20 to 24 hours. Detemir has an onset of action at 1 to 3 hours, with a small peak at 6 to 8 hours and approximate duration of action of 18 to 22 hours.

There are various premixed preparations of insulin available that include a fixed percentage of an intermediate-acting insulin and a rapid- or short-acting insulin. One such example is "70/30" which is 70% NPH and 30% regular insulin. Because they contain a combination of 2 different insulin types, they have two separate peaks in insulin. These preparations can offer convenience for the patient with twice daily dosing but offer less flexibility and restrictions in ability to titrate insulin doses. The insulin must be taken at fixed times and the patient must have regular meal times and size. As noted above, sometimes these premixed insulins are useful to cover the glucose absorption that occurs with overnight peritoneal dialysis.

Oral medications and other preparations

Metformin (a biguanide) increases insulin sensitivity and decreases hepatic gluconeogenesis. Metformin does not cause hypoglycemia. Lactic acidosis is a rare and serious side effect of metformin use, which can occur when toxic levels of metformin accumulate. Metformin is cleared by the kidney, thus its use in CKD is restricted. An FDA-mandated black-box warning exists regarding the risk of lactic acidosis with metformin use. The FDA guidelines indicate that metformin should not be used in men with a serum creatinine of 1.5 mg/dl or greater or women with a serum creatinine of 1.4 mg/dl or greater.

It is also reasonable to consider a GFR-cutoff for metformin use as well, since serum creatinine can translate into different eGFRs depending on weight, race or age. A GFR restriction of <60 ml/min/1.73m2 may be prudent since clearance of metformin decreases as the GFR decreases. It should be noted that even with modest decreases in GFR, the risk of lactic acidosis is quite rare and the exact cut-off for metformin use to avoid lactic acidosis is controversial, especially considering how effective the drug is.

Second-generation sulfonylureas (glipizide, glyburide, glimepiride and glicazide) bind to a sulfonyurea receptor on pancreatic beta-cells and therefore increase insulin secretion. They can lead to hypoglycemia. Glipizide and glicazide may be used in CKD stage 3 or worse. It is best to avoid the use of glyburide, which has a long half-life and can cause hypoglycemia in patients with decreased GFR. Glimepiride can be used starting at the lowest dose (1 mg) and titrated with caution.

Meglitinides (nateglinide, repaglinide) work in a glucose-dependent mechanism and result in quick insulin release through an ATP-dependent potassium channel on beta-cells of the pancreas. Their ideal use is for control of post-prandial hyperglycemia; they can also lead to hypoglycemia. Nateglinide has decreased clearance in renal disease, thus it should likely not be used with a GFR <30 ml/min/1.73m2; caution should be used if the GFR is <60 ml/min/1.73m2, perhaps using the lowest dose only. Similar guidelines should be used with repaglinide as decreased clearance was seen in patients with severe renal dysfunction.

Thiazolidinediones (pioglitazone, rosiglitazone) increase insulin sensitivity by acting as peroxisome proliferator-activated receptor gamma agonists. They do not lead to hypoglycemia. They are metabolized by the liver and thus can be used in CKD. However, fluid retention is a major limiting side effect and they should not be used in advanced heart failure. This also makes their use in CKD, particularly patients on dialysis, limiting. They have been linked with increased fracture rates and bone loss, thus the appropriate use in patients with underlying bone disease (such as renal osteodystrophy) needs to be considered.

In September 2010, the FDA restricted use of rosiglitazone based on RECORD and additional studies linking the medication to increased cardiovascular events. Rosiglitazone should only be used in individuals who cannot control their blood glucose levels with other agents after appropriate documentation by the physician and a clear understanding of the risks by the patient.

Alpha-glucosidase inhibitors (acarbose, miglitol) inhibit absorption of carbohydrates and thus slow glucose elevation post-prandially. Miglitol should not be used in CKD, and acarbose should not be used with a GFR <26. These agents are not associated with hypoglycemia but side effects of bloating, flatulence and abdominal cramping can be limiting.

Dipeptidyl peptidase 4 (DPP 4) inhibitors decrease the breakdown of incretin hormones such as GLP-1 and include sitagliptin (Januvia) and saxagliptin (Onglyza), which are both oral medications. They do not cause hypoglycemia. Sitagliptin can be used at the full dose of 100 mg if the GFR is >50. If the GFR is 30-50, 50 mg daily is recommended and for a GFR <30, 25 mg daily is recommended. For saxagliptin, with a GFR >50, 5 mg daily can be used; for GFR 50 or less, the recommended dose is 2.5 mg daily.

Glucagon-like peptide-1 (GLP-1) receptor agonists such as exenatide (Byetta) and liraglutide (Victoza) are injectable medications that mimic gut hormones known as incretins. They are both approved for use in type 2 diabetes along with sulfonyureas and metformin although in many instances they are used with insulin as well. These agents decrease appetite by increasing satiety, which leads to weight loss in many patients.

Both agents have been associated with pancreatitis, and nausea is a common side effect that can limit its use. In addition, liraglutide has been associated with the development of thyroid C-cell tumors in animal studies and thus should not be given to patients with or at risk for medullary thyroid cancer. Exenatide is given twice daily whereas liraglutide is given once daily. Exenatide is not recommended for use with a GFR <30 and is linked with decreased kidney functionin some case reports. Liraglutide is not cleared by the kidney; no dose adjustment in CKD appears to be needed.

The amylin analog pramlintide (Symlin) is also an injectable medication that is used with meals as an adjunct to insulin therapy. Amylin is secreted along with insulin by pancreatic beta-cells and levels are below normal in patients with diabetes. It can be used in type 1 and type 2 diabetes. No dose adjustment appears necessary for CKD.

Glycemic control in Type 1 and Type 2 diabetes mellitus

Glycemic management differs between type 1 and type 2 diabetes. The overall goal to optimize glycemic control in order to reduce micro- and macrovascular complications and minimize hypoglycemia, however, is the same. An individual with type 1 diabetes needs, of course, insulin; there are multiple ways insulin can be administered. A wide range of therapies can be applied to those with type 2 diabetes depending on patient desire, response and co-morbidities.

Type 1 DM

The ideal insulin regimen in individuals with type 1 diabetes reproduces physiologic insulin secretion by the pancreas. This is best accomplished by the use of multiple daily injections (MDI), which combines a long-acting basal insulin and a rapid-acting insulin with meals.

Prior to the development of insulin analogs, conventional treatment for type 1 diabetes combined twice daily NPH and regular insulin, usually given before breakfast and before dinner. This required stable daily regimens with fixed meal times and meal sizes each day.

With the availability of insulin analogs, glargine has surpassed the use of NPH as a basal insulin. It can be given once daily in most individuals and results in more stable glucose control, with improved fasting glucose levels and overall less hypoglycemia compared to NPH. Detemir has also shown promise compared to NPH. It is given twice daily and also results in less hypoglycemia with superior glucose control compared to NPH. Once daily glargine is an optimal choice as a basal insulin, next followed by twice daily detemir.

The rapid-acting insulin analogs are superior to regular insulin when used for prandial insulin. Studies show less hypoglycemia with better post-prandial glucose levels. These insulins also allow for flexibility in mealtimes and meal sizes, as the insulin can be given immediately before a meal and tailored to the amount of carbohydrates being eaten. Any of the rapid-acting insulins are considered optimal choices for prandial insulin.

An even closer approximation of physiologic insulin secretion can be achieved by using an insulin pump that delivers insulin by continuous subcutaneous insulin infusion (CSII). Insulin is given both basally and as a bolus prior to meals through the pump. The pump can be programmed to deliver different basal rates at different times of the day, so this has an advantage over the injection of a long-acting insulin such as glargine or detemir. Insulin pumps can be used at all stages of CKD. However, adjustment of insulin dosing can be very complicated and insulin pump use should be supervised by diabetes clinicians and diabetes educators experienced in their use.

External devices that can measure glucose continuously are now available. Such Continuous Glucose Monitoring Systems (CGMS) involve the insertion of a small catheter into the subcutaneous fat, and glucose is measured every 5 minutes with real time instantaneous as well as computerized downloadable readouts possible. In this way, the patient can detect upward or downward trends in glucose levels in real time and the more detailed evaluation of patterns allows for adjustment of insulin dosing. The CGMS readouts can be linked to insulin pumps to facilitate insulin dosing. The use of CGMS and its coupling to insulin pumps should be supervised by diabetes clinicians and diabetes educators experienced in their use.

Type 2 DM

Multiple options and combinations of therapies are available for the treatment of type 2 diabetes.

Oral medications are an ideal starting point. Metformin is a first-line agent because it does not cause hypoglycemia, is associated with weight loss and is inexpensive. It can cause mild to moderate gastrointestinal upset and the dose should be increased slowly. It should not be used with GFR < 60 ml/min/1.73m2, however. The sulfonylureas are also a logical choice as they are inexpensive and are effective in reducing hyperglycemia.

In CKD, glipizide or glicazide are preferable. Use must be monitored closely as these agents can cause hypoglycemia. They may also contribute to premature beta-cell failure as they "squeeze" further insulin production from the pancreas. Pioglitazone can be considered next, though fluid retention and weight gain makes it a less optimal choices. Lastly, DPP 4 inhibitors can be safely used at the appropriate dose in CKD, though the reduction in A1c and hyperglycemia is modest with an average reduction in A1c between 0.5-1%.

GLP-1 receptor agonists can be added to oral agents such as sulfonylureas (but not DPP 4 inhibitors); in CKD, liraglutide is the preferred choice. These are injectable medications which may not be desirable to patients, but the potential for reduction in hyperglycemia along with weight loss can be appealing. They can also be used as single agents.

In patients with uncontrolled A1c levels, high levels of insulin resistance or progressive beta-cell failure, insulin should be introduced. Typically, a basal insulin such as once daily glargine, once daily detemir, or once to twice daily NPH is initiated first. A starting dose of 10 to 15 units can be used, with further escalation based on blood sugars. The insulin dose can be increased by 1-2 units every 3 days to get to a target fasting blood sugar of 100-140 mg/dl.

Some patients may achieve goal glucose control with the combination of basal insulin and oral agents. Insulin may also be combined with GLP-1 receptor agonists, though this is not an FDA-approved indication for the latter. If goal glycemic control cannot be obtained with basal insulin alone, or there is concurrent hypo- and uncontrolled hyperglycemia, then a rapid-acting insulin analog should be started. This may be needed in a patient who has goal fasting blood sugars but daytime hyperglycemia.

Conversely, some patients may achieve goal fasting glucose levels with oral agents alone but continue to have daytime hyperglycemia. In this instance, prandial rapid-acting insulin can be used (or a trial of meglitinides) or perhaps once daily NPH in the morning.

What happens to patients with diabetes mellitus and chronic kidney disease?

Diabetes is one of the most common causes of kidney failure worldwide and it is the most common cause of kidney failure in the US. Kidney disease affects 20-40% of patients with diabetes. Kidney pathology is similar in type 1 and type 2 diabetes, as is the natural history, with the exception that hypertension and vascular disease occurs earlier in the course of kidney disease in type 2 diabetes.

Individuals with diabetes have higher rates of cardiovascular disease, and diabetes is considered a risk factor equivalent to coronary artery disease. Cardiovascular disease (CVD) is the leading cause of mortality in CKD stage 5. The presence of CKD in DM is therefore a potent combination putting the patient at great risk for CVD.

Individuals with diabetes carry higher rates of CVD if microalbuminuria is present, and the risk escalates as kidney disease worsens to albuminuria and decreasing GFR. Patients with stage 5 CKD and diabetes have a 40% increased annual mortality compared to those without DM. The risk is further exacerbated by the presence of hypertension (HTN) and dyslipidemia.

In addition to medications to control hyperglycemia and proteinuria, the use of blood pressure medications and lipid lowering agents should be aggressively pursued. Please see additional chapters on Diabetic Kidney Disease: General Management and Blood Pressure Management for further information.

How to utilize team care?

As appropriate, consider referral to an endocrinologist for diabetes management, especially if insulin pump or CGMS use is desired. The patient should also follow with an ophthalmologist or optometrist for an annual dilated exam to examine for retinopathy. The ophthalmologist or optometrist will determine whether more frequent visits are necessary.

Referral to a podiatrist should be considered in the presence of neuropathy or foot ulcers. The use of a cardiologist or vascular surgeon is as indicated by the presence of coronary artery disease or peripheral vascular disease. Referral to a weight-loss specialist can also be considered, particularly in the presence of morbid obesity.

The use of a certfied diabetes educator is helpful to help the patient understand the treatment and management of diabetes, glucose meter use, and insulin teaching. Lifestyle modification is vitally important. Weight loss helps reduce insulin resistance and, in general, a body mass index <25 kg/m2 is the goal. Nutrition in patients with diabetes and CKD needs particular attention as it is a complicated balance of carbohydrate, protein, potassium, phosphorus, sodium and fluid intake. A dietician can be helpful to counsel the patient in regards to appropriate dietary considerations. Physical or occupational therapy may be indicated, particularly in the presence of severe neuropathy.

Are there clinical practice guidelines to inform decision making?

  • Kidney Disease Outcomes Quality Initiative (KDOQI): Clinical Practice Guidelines and Clinical Practice recommendations for Diabetes and Chronic Kidney Disease.

  • American Diabetes Association: Standards of Medical Care in Diabetes

Other considerations

Additional diagnoses that are common in diabetes and CKD: retinopathy, neuropathy, HTN, hyperlipidemia, foot ulcers, cardiovascular disease including coronary artery disease, peripheral vascular disease, cerebrovascular disease.

What is the evidence?

Gerstein, HC, Miller, ME, Byington, RP, Goff, DC, Bigger, JT, Buse, JB, Cushman, WC, Genuth, S, Ismail-Beigi, F, Grimm, RH, Probstfield, JL, Simons-Morton, DG, Friedewald, WT. "Effects of intensive glucose lowering in type 2 diabetes". N Engl J Med. vol. 358. 2008. pp. 2545-2559.

(The ACCORD study evaluated the impact of intensive glucose control in type 2 diabetes on cardiovascular events. Patients treated with intensive therapy vs. standard therapy (A1c of 6.4% vs. 7.5%) had higher mortality (HR 1.22, P=0.04) but similar numbers of cardiovascular events (HR 0.9, P=0.16). The higher mortality was not thought to be related solely to hypoglycemia.)

Patel, A, MacMahon, S, Chalmers, J, Neal, B, Billot, L, Woodward, M, Marre, M, Cooper, M, Glasziou, P, Grobbee, D, Hamet, P, Harrap, S, Heller, S, Liu, L, Mancia, G, Mogensen, CE, Pan, C, Poulter, N, Rodgers, A, Williams, B, Bompoint, S, de Galan, BE, Joshi, R, Travert, F. " Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes". N Engl J Med. vol. 358. 2008. pp. 2560-2572.

(In the ADVANCE study, intensive glucose control (A1c 6.5% vs. 7.3%) led to fewer combined macro- and microvascular events (18.1% vs 20.0%, P=0.01), which was largely due to the decrease in development of nephropathy (4.1% vs. 5.2%, P=0.006). There was no impact on macrovascular events, death from cardiovascular causes or death in general.)

"American Diabetes Association: Standards of Medical Care in Diabetes - 2012". Diabetes Care. vol. 35. 2012. pp. S11-S63.

(This is a comprehensive guide to current medical care for type 1 and type 2 diabetes, providing a review of literature as well as expert opinion.)

"The Diabetes Control and Complications Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus". N Engl J Med. vol. 329. 1993. pp. 977-986.

(The DCCT is a landmark trial demonstrating the benefit of intensive glucose control in slowing the onset and progression of microvascular complications in type 1 diabetes. Patients who received intensive therapy had significantly lower rates of retinopathy, nephropathy and neuropathy.)

"The Diabetes Control and Complications Research Group: Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial". Kidney Int. vol. 47. 1995. pp. 1703-1720.

(This article focuses specifically on nephropathy in the DCCT demonstrating benefit of intensive glycemic control on the development of microalbuminuria and albuminuria.)

"The Epidemiology of Diabetes Interventions and Complications Study: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study". JAMA. vol. 290. 2003. pp. 2159-2167.

(In the EDIC the original DCCT cohort was followed for an additional 8 years but glycemic control was similar among the participants during this follow-up period. The EDIC demonstrated there was lasting long-term benefit to intensive glucose control as members of the intensive treatment group had a lower incidence of new albuminuria and hypertension during follow-up.)

"Kidney Disease Outcomes Quality Initiative: KDOQI Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease". Am J Kidney Dis. vol. 49. 2007. pp. S12-154.

(These are evidence-based guidelines from the National Kidney Foundation for chronic kidney disease and its related complications.)

Nathan, DM, Buse, JB, Davidson, MB, Ferrannini, E, Holman, RR, Sherwin, R, Zinman, B. "Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes". Diabetes Care. vol. 32. 2008. pp. 193-203.

(This is an algorithm targeted towards the management of type 2 diabetes. It discusses best inital choices for therapy and adjustment of current regimens, taking into account available evidence, expert opinion, and clinical experience.)

Salpeter, SR, Greyber, E, Pasternak, GA, Salpeter, EE. "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: a systematic review and meta-analysis". Arch Intern Med. vol. 163. 2003. pp. 2594-2602.

(Use of metformin is thought to be associated with an increased risk of lactic acidosis. This meta-analysis of studies published from 1959 to 2002 showed no cases of lactic acidosis in metformin users.)

Shichiri, M, Kishikawa, H, Ohkubo, Y, Wake, N. "Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients". Diabetes Care. vol. 23. 2000. pp. B21-29.

(In the Kumamoto Study, Japanese patients with type 2 diabetes were followed prospectively for 8 years. The study demonstrated that those receiving conventional insulin therapy had higher rates of worsening nephropathy, retinopathy and neuropathy compared to intensive insulin treatment.)

"UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)". Lancet. vol. 352. 1998. pp. 837-853.

(In the UKPDS patients with type 2 diabetes were treated with sulfonylurea agents or insulin to achieve intensive glycemic control. Intensive control was shown to reduce microvascular disease but not macrovascular disease. There was no signficant difference in death from any cause or death related to diabetes.)
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